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Pandurangan S, Easwaramoorthi S, Ayyadurai N. Engineering proteins with catechol chemistry for biotechnological applications. Crit Rev Biotechnol 2025; 45:606-624. [PMID: 39198031 DOI: 10.1080/07388551.2024.2387165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 04/01/2023] [Accepted: 06/27/2023] [Indexed: 09/01/2024]
Abstract
Developing proteins with increased chemical space by expanding the amino acids alphabet has been an emerging technique to compete for the obstacle encountered by their need in various applications. 3,4-Dihydroxyphenylalanine (L-DOPA) catecholic unnatural amino acid is abundantly present in mussels foot proteins through post-translational modification of tyrosine to give a strong adhesion toward wet rocks. L-DOPA forms: bidentate coordination, H-bonding, metal-ligand complexes, long-ranged electrostatic, and van der Waals interactions via a pair of donor hydroxyl groups. Incorporating catechol in proteins through genetic code expansion paved the way for developing: protein-based bio-sensor, implant coating, bio-conjugation, adhesive bio-materials, biocatalyst, metal interaction and nano-biotechnological applications. The increased chemical spaces boost the protein properties by offering a new chemically active interaction ability to the protein. Here, we review the technique employed to develop a genetically expanded organism with catechol to provide novel properties and functionalities; and we highlight the importance of L-DOPA incorporated proteins in biomedical and industrial fields.
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Affiliation(s)
- Suryalakshmi Pandurangan
- Department of Biochemistry and Biotechnology, Council of Scientific and Industrial Research - Central Leather Research Institute, Chennai, India
- Academy of Scientific and Innovative Research, Ghaziabad, India
| | - Shanmugam Easwaramoorthi
- Academy of Scientific and Innovative Research, Ghaziabad, India
- Department of Inorganic and Physical Chemistry, Council of Scientific and Industrial Research - Central Leather Research Institute, Chennai, India
| | - Niraikulam Ayyadurai
- Department of Biochemistry and Biotechnology, Council of Scientific and Industrial Research - Central Leather Research Institute, Chennai, India
- Academy of Scientific and Innovative Research, Ghaziabad, India
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2
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Zhang Z, Liu P, Zhang B, Shen J, Wu J, Huang S, Chu X. De novo Biosynthesis of Caffeic Acid and Chlorogenic Acid in Escherichia coli via Enzyme Engineering and Pathway Engineering. ACS Synth Biol 2025. [PMID: 40232288 DOI: 10.1021/acssynbio.4c00850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/16/2025]
Abstract
Caffeic acid (CA) and chlorogenic acid (CGA) have diverse health benefits, including hemostatic, antioxidant, and antiinflammatory, highlighting their potential for medical applications. However, the absence of high-performance production strains increases production costs, limiting their wider application. In this study, we engineered Escherichia coli for the de novo production of CA and CGA. To improve production, a highly efficient mutant tyrosine ammonia-lyase from Rhodotorula taiwanensis (RtTALT415M/Y458F) was identified using genome mining and protein engineering. By engineering the tyrosine biosynthetic pathway through the deletion of pheA and tyrR, along with the overexpression of aroGfbr and tyrAfbr, we developed an engineered E. coli strain, CA11, which produced 6.36 g/L of CA with a yield of 0.06 g/g glucose and a productivity of 0.18 g/L/h. This represents the highest titer reported for microbial synthesis of CA using glucose as the sole carbon source in E. coli. Based on strain CA11, we further developed strain CGA13, with optimized replicons, promoters, and ribosome-binding sites, which produced 1.53 g/L of CGA in fed-batch fermentation, highlighting its potential for industrial-scale production.
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Affiliation(s)
- Zhenyu Zhang
- Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, P. R. China
- Key Laboratory of Pharmaceutical Engineering of Zhejiang Province, Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, Zhejiang University of Technology, Hangzhou 310014, P. R. China
- ZhejiangYangtze River Delta Bio-Pharmaceutical Industry Technology Research Park, Deqing 313200, P. R. China
| | - Pengfu Liu
- Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, P. R. China
- Key Laboratory of Pharmaceutical Engineering of Zhejiang Province, Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, Zhejiang University of Technology, Hangzhou 310014, P. R. China
- ZhejiangYangtze River Delta Bio-Pharmaceutical Industry Technology Research Park, Deqing 313200, P. R. China
| | - Bin Zhang
- College of Bioscience and Bioengineering, Jiangxi Agricultural University, Nanchang 330045, China
| | - Jian Shen
- Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, P. R. China
- Key Laboratory of Pharmaceutical Engineering of Zhejiang Province, Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, Zhejiang University of Technology, Hangzhou 310014, P. R. China
- ZhejiangYangtze River Delta Bio-Pharmaceutical Industry Technology Research Park, Deqing 313200, P. R. China
| | - Jiequn Wu
- Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, P. R. China
- Key Laboratory of Pharmaceutical Engineering of Zhejiang Province, Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, Zhejiang University of Technology, Hangzhou 310014, P. R. China
- ZhejiangYangtze River Delta Bio-Pharmaceutical Industry Technology Research Park, Deqing 313200, P. R. China
| | - Shusheng Huang
- Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, P. R. China
- Key Laboratory of Pharmaceutical Engineering of Zhejiang Province, Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, Zhejiang University of Technology, Hangzhou 310014, P. R. China
- ZhejiangYangtze River Delta Bio-Pharmaceutical Industry Technology Research Park, Deqing 313200, P. R. China
| | - Xiaohe Chu
- Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, P. R. China
- Key Laboratory of Pharmaceutical Engineering of Zhejiang Province, Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, Zhejiang University of Technology, Hangzhou 310014, P. R. China
- ZhejiangYangtze River Delta Bio-Pharmaceutical Industry Technology Research Park, Deqing 313200, P. R. China
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Jeong C, Han SH, Lim CG, Kim SC, Jeong KJ. Metabolic engineering of Escherichia coli for enhanced production of p-coumaric acid via L-phenylalanine biosynthesis pathway. Bioprocess Biosyst Eng 2025; 48:565-576. [PMID: 39825898 DOI: 10.1007/s00449-025-03128-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Accepted: 01/05/2025] [Indexed: 01/20/2025]
Abstract
p-Coumaric acid (p-CA), an invaluable phytochemical, has novel bioactivities, including antiproliferative, anxiolytic, and neuroprotective effects, and is the main precursor of various flavonoids, such as caffeic acid, naringenin, and resveratrol. Herein, we report the engineering of Escherichia coli for de novo production of p-CA via the PAL-C4H pathway. As the base strain, we used the E. coli H-02 strain, which was previously engineered for sufficient supplementation of L-phenylalanine, the main precursor of p-CA. For the bioconversion of L-Phe to p-CA, we constructed and optimized an expression system for phenylalanine ammonia lyase (SmPAL), codon-optimized cinnamate 4-hydroxylase (AtC4H), and its redox partner, cytochrome P450 reductase (AtCPR1). We confirmed that the engineered cell showed higher production of p-CA at 30 °C and the addition of 0.5 mM 5-aminolevulinic acid could increase the production titer further. Subsequently, the main pathways of acetic acid (poxB and pta-ackA) were eliminated to reduce its accumulation and restore cell growth. Next, to increase the available pool of cofactor (NADPH), the co-expression system of the zwf gene in the pentose phosphate pathway (PPP) was integrated into genome and the expression level was optimized with synthetic promoters. Finally, by optimizing fed-batch culture in a 5 L-scale bioreactor, the engineered strain achieved 1.5 g/L p-CA with a productivity of 31.8 mg/L/h.
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Affiliation(s)
- Chorok Jeong
- Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Korea
| | - Seung Hee Han
- Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Korea
| | - Chang Gyu Lim
- Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Korea
| | - Sun Chang Kim
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Korea
- KI for BioCentury, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Korea
| | - Ki Jun Jeong
- Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Korea.
- KI for BioCentury, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Korea.
- Graduate School of Engineering Biology, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Korea.
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Ji A, Zou D, Ma A, Wei X. Rational design of DAHP synthase and prephenate dehydrogenase for metabolic engineering of Bacillus amyloliquefaciens to produce L-tyrosine. Int J Biol Macromol 2025; 307:142076. [PMID: 40090641 DOI: 10.1016/j.ijbiomac.2025.142076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 03/02/2025] [Accepted: 03/11/2025] [Indexed: 03/18/2025]
Abstract
The rational design of enzymes represents a critical strategy for achieving efficient and sustainable biocatalysis. In this study, enzyme evolution guided by rational design was utilized to engineer two key enzymes, DAHP synthase (AroA) and prephenate dehydrogenase (TyrA), within the biosynthetic pathway of L-tyrosine. The beneficial mutants AroAR27A/K38A and TyrAI309A/E330V were identified, leading to a 102 % and 105 % increase in L-tyrosine yield, respectively. Molecular dynamics simulations further explained the possible mechanism underlying their improved catalytic efficiency. Co-expression of these two mutant genes resulted in a significant increase in L-tyrosine yield. Additionally, modifications in the branching metabolic pathways, which altered both material and energy flux, further enhanced L-tyrosine production. Ultimately, the L-tyrosine yield (0.14 g/g) from xylose was much higher than that from glucose, and the final L-tyrosine titer (9.39 g/L) and productivity (0.26 g/(L·h)) were achieved through fermentation optimization in shake flasks. This represents the highest reported yield in shake flasks. The strategies described here will contribute to the development of microbial strains for the efficient production of L-tyrosine from sustainable biomass resources.
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Affiliation(s)
- Anying Ji
- National Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China
| | - Dian Zou
- National Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China
| | - Aimin Ma
- National Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China
| | - Xuetuan Wei
- National Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China.
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Gan Q, Jiang T, Li C, Gong X, Zhang J, Desai BK, Yan Y. De novo biosynthesis of 4,6-dihydroxycoumarin in Escherichia coli. GREEN CHEMISTRY : AN INTERNATIONAL JOURNAL AND GREEN CHEMISTRY RESOURCE : GC 2025; 27:3064-3076. [PMID: 40013057 PMCID: PMC11848710 DOI: 10.1039/d4gc05694a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Accepted: 02/12/2025] [Indexed: 02/28/2025]
Abstract
Coumarins and their derivatives possess crucial biochemical and pharmaceutical properties. However, the exploration of the coumarin biosynthesis pathways remains limited, restricting their microbial biosynthesis, especially for hydroxycoumarins. In this work, we designed and verified novel artificial pathways to produce a valuable compound 4,6-dihydroxycoumarin (4,6-DHC) in Escherichia coli. Based on the retrosynthesis analysis, multiple routes were designed and verified by extending the shikimate pathway, screening the potential enzymes, and characterizing the enzymes involved. Rare codon optimization and protein engineering strategies were applied to optimize the rate-limiting steps. De novo biosynthesis of 4,6-DHC was achieved using the cheap carbon source glycerol, and the titer can reach 18.3 ± 0.7 mg L-1. Ultimately, inducible regulation of critical pathway genes with a tetracycline-inducible controller yielded a significant boost in 4,6-DHC production, achieving a titer of 56.7 ± 2.1 mg L-1. This research successfully created a microbial platform for 4,6-dihydroxycoumarin production and demonstrated a generalizable strategy for synthesizing valuable compounds.
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Affiliation(s)
- Qi Gan
- School of Chemical, Materials and Biomedical Engineering, College of Engineering, University of Georgia Athens GA 30602 USA
| | - Tian Jiang
- School of Chemical, Materials and Biomedical Engineering, College of Engineering, University of Georgia Athens GA 30602 USA
| | - Chenyi Li
- School of Chemical, Materials and Biomedical Engineering, College of Engineering, University of Georgia Athens GA 30602 USA
| | - Xinyu Gong
- School of Chemical, Materials and Biomedical Engineering, College of Engineering, University of Georgia Athens GA 30602 USA
| | - Jianli Zhang
- School of Chemical, Materials and Biomedical Engineering, College of Engineering, University of Georgia Athens GA 30602 USA
| | - Bhaven K Desai
- School of Chemical, Materials and Biomedical Engineering, College of Engineering, University of Georgia Athens GA 30602 USA
| | - Yajun Yan
- School of Chemical, Materials and Biomedical Engineering, College of Engineering, University of Georgia Athens GA 30602 USA
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Zhao W, Liu J, Chen Y. Advances in the biosynthesis of naturally occurring benzylisoquinoline alkaloids. FRONTIERS IN PLANT SCIENCE 2025; 16:1548471. [PMID: 39949415 PMCID: PMC11821938 DOI: 10.3389/fpls.2025.1548471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Accepted: 01/14/2025] [Indexed: 02/16/2025]
Abstract
Benzylisoquinoline alkaloids (BIAs) are a prominent class of plant metabolites with significant pharmaceutical and industrial significance that have garnered substantial attention from researchers worldwide. BIAs exhibit several pharmacological activities and have been used extensively. Examples include analgesics such as morphine, tetrahydropalmatine, antimicrobials such as berberine, and antineoplastic agents including cepharanthine. Most BIAs are derived and isolated from medicinal plants; however, these plants are predominantly wild resources that are scarce. Their high environmental impact, slow growth rate, scarcity of resources, and expensive direct extraction costs pose a significant challenge. Certain BIAs are present in trace amounts in medicinal plants; moreover, they have complex chemical structures and unstable properties. Designing chemical synthesis routes and processes is challenging. Thus, a major obstacle in developing and utilizing these natural products in the pharmaceutical industry lies in their low abundance in nature. Consequently, the limited supply of these molecules fails to meet high research and market demands. In recent years, biosynthesis approaches have emerged as a novel and efficient method to obtain BIAs. In this review, recent progress in the field of enzymes related to the elucidation of biosynthetic pathways and the biosynthesis of BIAs are discussed, and future perspectives for designing viable strategies for their targeted manipulation are presented.
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Affiliation(s)
- Wanli Zhao
- Jiangsu Key Laboratory for the Research and Utilization of Plant Resources, Jiangsu Province Engineering Research Center of Eco-cultivation and High-value Utilization of Chinese Medicinal Materials, Institute of Botany, Jiangsu Province and Chinese Academy of Sciences (Nanjing Botanical Garden Mem. Sun Yat-Sen), Nanjing, China
| | - Jihua Liu
- Jiangsu Key Laboratory of Traditional Chinese Medicine. (TCM) Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Yu Chen
- Jiangsu Key Laboratory for the Research and Utilization of Plant Resources, Jiangsu Province Engineering Research Center of Eco-cultivation and High-value Utilization of Chinese Medicinal Materials, Institute of Botany, Jiangsu Province and Chinese Academy of Sciences (Nanjing Botanical Garden Mem. Sun Yat-Sen), Nanjing, China
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Watanabe S, Kato H, Yoshinaga K, Kohara A, Ukawa Y, Matsuyama A, Furuya T. Comparative analysis of substrate- and regio-selectivity of HpaB monooxygenases and their application to hydroxydaidzein synthesis. J Biotechnol 2025; 397:61-66. [PMID: 39577670 DOI: 10.1016/j.jbiotec.2024.11.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 11/17/2024] [Accepted: 11/18/2024] [Indexed: 11/24/2024]
Abstract
4-Hydroxyphenylacetate 3-hydroxylase (HpaB) has high potential for use in polyphenol synthesis via ortho-hydroxylation. Although the HpaB enzymes from Pseudomonas aeruginosa (PaHpaB) and Escherichia coli (EcHpaB) have been well studied, few studies have compared their activity and substrate selectivity. Thus, which HpaB is optimal for use in the biotechnological production of polyphenols is unclear. In this study, we performed a comparative analysis of the substrate- and regio-selectivity of PaHpaB, EcHpaB, and the recently discovered enzyme from Rhodococcus opacus (RoHpaB). The activity of these enzymes was first compared toward representative aromatic substrates. PaHpaB and EcHpaB exhibited very similar catalytic activity toward p-coumaric acid and tyrosol with one benzene ring, whereas PaHpaB exhibited greater activity than EcHpaB toward resveratrol and naringenin with two benzene rings. These results suggest that PaHpaB is superior to EcHpaB in converting bulky compounds. Furthermore, PaHpaB also exhibited catalytic activity toward a flavonoid, daidzein (7,4'-dihydroxyisoflavone), whereas EcHpaB did not. RoHpaB also exhibited strong activity toward daidzein in addition to other aromatic substrates. Interestingly, PaHpaB hydroxylated the 6-position of daidzein, whereas RoHpaB hydroxylated the 3'-position. PaHpaB and RoHpaB enabled the facile synthesis of not only 6-hydroxydaidzein and 3'-hydroxydaidzein but also 6,3'-dihydroxydaidzein via the cascade reaction. This study is the first to demonstrate synthesis of hydroxydaidzeins using HpaB enzymes.
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Affiliation(s)
- Sachiko Watanabe
- Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan
| | - Hideki Kato
- Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan
| | - Kento Yoshinaga
- Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan
| | - Akiko Kohara
- Daicel Corporation, 2-18-1 Konan, Minato-ku, Tokyo 108-8230, Japan
| | - Yuichi Ukawa
- Daicel Corporation, 2-18-1 Konan, Minato-ku, Tokyo 108-8230, Japan
| | | | - Toshiki Furuya
- Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
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Wang X, Shang D, Chen J, Cheng S, Chen D, Zhang Z, Liu C, Yu J, Cao H, Li L, Li L. Serum metabolomics reveals the effectiveness of human placental mesenchymal stem cell therapy for Crohn's disease. Talanta 2024; 277:126442. [PMID: 38897006 DOI: 10.1016/j.talanta.2024.126442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 06/10/2024] [Accepted: 06/15/2024] [Indexed: 06/21/2024]
Abstract
Mesenchymal stem cell (MSC) therapy offers a promising cure for Crohn's disease (CD), however, its therapeutic effects vary significantly due to individual differences. Therefore, identifying easily detectable biomarkers is essential to assess the efficacy of MSC therapy. In this study, SAMP1/Yit mice were used as a model of CD, which develop spontaneous chronic ileitis, closely resembling the characteristics present in CD patients. Serum metabolic alterations during treatment were analyzed, through the application of differential 12C-/13C-dansylation labeling liquid chromatography-mass spectrometry. Based on the significant differences and time-varying trends of serum amine/phenol-containing metabolites abundance between the control group, the model group, and the treatment group, four serum biomarkers were ultimately screened for evaluating the efficacy of MSC treatment for CD, namely 4-hydroxyphenylpyruvate, 4-hydroxyphenylacetaldehyde, caffeate, and N-acetyltryptamine, whose abundances both increased in the serum of CD model mice and decreased after MSC treatment. These metabolic alterations were associated with tyrosine metabolism, which was validated by the dysregulation of related enzymes. The discovery of biomarkers may help to improve the targeting and effectiveness of treatment and provide innovative prospects for the clinical application of MSC for CD.
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Affiliation(s)
- Xiao Wang
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan City 250117, China
| | - Dandan Shang
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan City 250117, China
| | - Junyao Chen
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City 310003, China
| | - Sheng Cheng
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City 310003, China
| | - Deying Chen
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City 310003, China
| | - Zhehua Zhang
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City 310003, China
| | - Chaoxu Liu
- Department of Colorectal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City 310003, China
| | - Jiong Yu
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan City 250117, China; State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City 310003, China; Zhejiang Key Laboratory for Diagnosis and Treatment of Physic-chemical and Aging-related Injuries, 79 Qingchun Rd, Hangzhou City 310003, China.
| | - Hongcui Cao
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan City 250117, China; State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City 310003, China; Zhejiang Key Laboratory for Diagnosis and Treatment of Physic-chemical and Aging-related Injuries, 79 Qingchun Rd, Hangzhou City 310003, China.
| | - Liang Li
- Department of Chemistry, University of Alberta, Edmonton, Alberta, T6G 2G2, Canada
| | - Lanjuan Li
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan City 250117, China; State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City 310003, China
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Li J, Lu X, Zou X, Ye BC. Recent Advances in Microbial Metabolic Engineering for Production of Natural Phenolic Acids. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:4538-4551. [PMID: 38377566 DOI: 10.1021/acs.jafc.3c07658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/22/2024]
Abstract
Phenolic acids are important natural bioactive compounds with varied physiological functions. They are extensively used in food, pharmaceutical, cosmetic, and other chemical industries and have attractive market prospects. Compared to plant extraction and chemical synthesis, microbial fermentation for phenolic acid production from renewable carbon sources has significant advantages. This review focuses on the structural information, physiological functions, current applications, and biosynthesis pathways of phenolic acids, especially advances in the development of metabolically engineered microbes for the production of phenolic acids. This review provides useful insights concerning phenolic acid production through metabolic engineering of microbial cell factories.
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Affiliation(s)
- Jin Li
- College of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China
| | - Xiumin Lu
- College of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China
| | - Xiang Zou
- College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China
| | - Bang-Ce Ye
- Laboratory of Biosystems and Microanalysis, Institute of Engineering Biology and Health, State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, China
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Wang Y, Tan H, Wang Y, Qin JL, Zhao X, Di Y, Xie L, Wang Y, Zhao X, Li Z, Ma G, Jiang L, Liu B, Huang D. High-Level Biosynthesis of Chlorogenic Acid from Mixed Carbon Sources of Xylose and Glucose through a Rationally Refactored Pathway Network. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:3633-3643. [PMID: 38330270 DOI: 10.1021/acs.jafc.3c08587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/10/2024]
Abstract
Chlorogenic acid (CGA) has incredible potential for various pharmaceutical, nutraceutical, and agricultural applications. However, the traditional extraction approach from plants is time-consuming, further limiting its production. Herein, we design and construct the de novo biosynthesis pathway of CGA using modular coculture engineering in Escherichia coli, which is composed of MG09 and BD07 strains. To accomplish this, the phenylalanine-deficient MG09 strain was engineered to utilize xylose preferentially and to overproduce precursor caffeic acid, while the tyrosine-deficient BD07 strain was constructed to consume glucose exclusively to enhance another precursor quinic acid availability for the biosynthesis of CGA. Further pathway modularization and balancing in the context of syntrophic cocultures resulted in additional production improvement. The coculture strategy avoids metabolic flux competition in the biosynthesis of two CGA precursors, caffeic acid and quinic acid, and allows for production improvement by balancing module proportions. Finally, the optimized coculture based on the aforementioned efforts produced 131.31 ± 7.89 mg/L CGA. Overall, the modular coculture engineering strategy in this study provides a reference for constructing microbial cell factories that can efficiently biomanufacture complex natural products.
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Affiliation(s)
- Yuhui Wang
- Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, Nankai University, Tianjin 300071, China
- National Glycoengineering Research Center, Shandong University, Qingdao, Shandong 266237, China
| | - Haining Tan
- National Glycoengineering Research Center, Shandong University, Qingdao, Shandong 266237, China
| | - Yanling Wang
- Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, Nankai University, Tianjin 300071, China
- National Glycoengineering Research Center, Shandong University, Qingdao, Shandong 266237, China
| | - Jing Liang Qin
- Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, Nankai University, Tianjin 300071, China
| | - Xinyu Zhao
- Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, Nankai University, Tianjin 300071, China
| | - Yuhan Di
- National Glycoengineering Research Center, Shandong University, Qingdao, Shandong 266237, China
| | - Lijie Xie
- Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, Nankai University, Tianjin 300071, China
| | - Yujie Wang
- Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, Nankai University, Tianjin 300071, China
| | - Xiaojing Zhao
- Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, Nankai University, Tianjin 300071, China
| | - Ziyu Li
- Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, Nankai University, Tianjin 300071, China
| | - Guozhen Ma
- Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, Nankai University, Tianjin 300071, China
| | - Lingyan Jiang
- Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, Nankai University, Tianjin 300071, China
| | - Bin Liu
- Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, Nankai University, Tianjin 300071, China
- TEDA Institute of Biological Sciences and Biotechnology, Tianjin Key Laboratory of Microbial Functional Genomics, Nankai University, Tianjin 300457, China
| | - Di Huang
- Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, Nankai University, Tianjin 300071, China
- TEDA Institute of Biological Sciences and Biotechnology, Tianjin Key Laboratory of Microbial Functional Genomics, Nankai University, Tianjin 300457, China
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11
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Zhu Z, Chen R, Zhang L. Simple phenylpropanoids: recent advances in biological activities, biosynthetic pathways, and microbial production. Nat Prod Rep 2024; 41:6-24. [PMID: 37807808 DOI: 10.1039/d3np00012e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/10/2023]
Abstract
Covering: 2000 to 2023Simple phenylpropanoids are a large group of natural products with primary C6-C3 skeletons. They are not only important biomolecules for plant growth but also crucial chemicals for high-value industries, including fragrances, nutraceuticals, biomaterials, and pharmaceuticals. However, with the growing global demand for simple phenylpropanoids, direct plant extraction or chemical synthesis often struggles to meet current needs in terms of yield, titre, cost, and environmental impact. Benefiting from the rapid development of metabolic engineering and synthetic biology, microbial production of natural products from inexpensive and renewable sources provides a feasible solution for sustainable supply. This review outlines the biological activities of simple phenylpropanoids, compares their biosynthetic pathways in different species (plants, bacteria, and fungi), and summarises key research on the microbial production of simple phenylpropanoids over the last decade, with a focus on engineering strategies that seem to hold most potential for further development. Moreover, constructive solutions to the current challenges and future perspectives for industrial production of phenylpropanoids are presented.
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Affiliation(s)
- Zhanpin Zhu
- Department of Pharmaceutical Botany, School of Pharmacy, Naval Medical University, Shanghai 200433, China.
| | - Ruibing Chen
- Department of Pharmaceutical Botany, School of Pharmacy, Naval Medical University, Shanghai 200433, China.
| | - Lei Zhang
- Department of Pharmaceutical Botany, School of Pharmacy, Naval Medical University, Shanghai 200433, China.
- Institute of Interdisciplinary Integrative Medicine Research, Medical School of Nantong University, Nantong 226001, China
- Innovative Drug R&D Centre, College of Life Sciences, Huaibei Normal University, Huaibei 235000, China
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12
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Sun P, Xu S, Tian Y, Chen P, Wu D, Zheng P. 4-Hydroxyphenylacetate 3-Hydroxylase (4HPA3H): A Vigorous Monooxygenase for Versatile O-Hydroxylation Applications in the Biosynthesis of Phenolic Derivatives. Int J Mol Sci 2024; 25:1222. [PMID: 38279222 PMCID: PMC10816480 DOI: 10.3390/ijms25021222] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 01/16/2024] [Accepted: 01/17/2024] [Indexed: 01/28/2024] Open
Abstract
4-Hydroxyphenylacetate 3-hydroxylase (4HPA3H) is a long-known class of two-component flavin-dependent monooxygenases from bacteria, including an oxygenase component (EC 1.14.14.9) and a reductase component (EC 1.5.1.36), with the latter being accountable for delivering the cofactor (reduced flavin) essential for o-hydroxylation. 4HPA3H has a broad substrate spectrum involved in key biological processes, including cellular catabolism, detoxification, and the biosynthesis of bioactive molecules. Additionally, it specifically hydroxylates the o-position of the C4 position of the benzene ring in phenolic compounds, generating high-value polyhydroxyphenols. As a non-P450 o-hydroxylase, 4HPA3H offers a viable alternative for the de novo synthesis of valuable natural products. The enzyme holds the potential to replace plant-derived P450s in the o-hydroxylation of plant polyphenols, addressing the current significant challenge in engineering specific microbial strains with P450s. This review summarizes the source distribution, structural properties, and mechanism of 4HPA3Hs and their application in the biosynthesis of natural products in recent years. The potential industrial applications and prospects of 4HPA3H biocatalysts are also presented.
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Affiliation(s)
| | | | | | | | | | - Pu Zheng
- The Key Laboratory of Industrial Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi 214122, China; (P.S.); (Y.T.); (P.C.); (D.W.)
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13
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Yu H, Chen R, Zhou Z, Liu R, Wen J. Efficacy and safety of caffeic acid tablets in the treatment of thrombocytopenia: A systematic review and meta-analysis. Medicine (Baltimore) 2023; 102:e35353. [PMID: 37800784 PMCID: PMC10553084 DOI: 10.1097/md.0000000000035353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Accepted: 09/01/2023] [Indexed: 10/07/2023] Open
Abstract
BACKGROUND Caffeic acid tablets (CFA) are a proprietary Chinese medicine in treating thrombocytopenia. The efficacy and safety of CFA compared with other platelet-raising drugs for the treatment of thrombocytopenia have been widely reported in the literature, but there is no systematic evaluation. Therefore, we designed this meta-analysis to further establish the efficacy and safety of CFA in treating thrombocytopenia. METHODS A computerized search was conducted in the Chinese biomedical database (CBM), Chinese National Knowledge Infrastructure (CNKI), Wanfang database, Chinese Scientific Journal Database (VIP), PubMed, and Web of Science databases using the keywords "caffeic acid tablets" and "thrombocytopenia." All randomized controlled trials were selected for the timeframe of build to 02/2023 and then screened and analyzed using RevMan 5.4 and stata17.0 software. RESULTS A total of 35 publications with an overall 2533 patients were included in the study. The results of the meta-analysis showed that CFA were effective in the treatment of thrombocytopenia with a statistically significant difference [relative risk ratio (RR) = 1.24, 95% CI (1.17, 1.31), P < .00001] and in increasing platelet counts [standardized mean difference (SMD) = 1.50, 95% CI (1.09, 1.91), P < .00001], white blood cell count [SMD = 1.08, 95% CI (0.77, 1.39), P < .00001], and neutrophil count [SMD = 0.73, 95% CI (0.19, 1.28), P = .009], and CFA reduced myelosuppression [RR = 0.19, 95% CI (0.1, 0.37), P < .00001] and adverse effects [RR = 0.75, 95% CI (0.58, 0.96), P = .02]. CONCLUSION CFA can effectively improve the clinical outcome of patients with thrombocytopenia with a good safety profile and are worth promoting. However, due to the low quality and small sample size of the included literature, a larger sample size and more standardized, high-quality studies are needed to validate these results.
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Affiliation(s)
- Hongxiu Yu
- School of Pharmacy, Dali University, Dali, Yunnan, China
- Department of Pharmacy, The Third People’s Hospital of Yunnan Province, Kunming, Yunnan, China
| | - Ruixiang Chen
- Department of Pharmacy, The Third People’s Hospital of Yunnan Province, Kunming, Yunnan, China
| | - Zhengwen Zhou
- School of Pharmacy, Dali University, Dali, Yunnan, China
- Department of Pharmacy, The Third People’s Hospital of Yunnan Province, Kunming, Yunnan, China
| | - Rongchun Liu
- Department of Pharmacy, The Third People’s Hospital of Yunnan Province, Kunming, Yunnan, China
| | - Jin Wen
- Department of Pharmacy, The Third People’s Hospital of Yunnan Province, Kunming, Yunnan, China
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14
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Yang K, Zhang Q, Zhao W, Hu S, Lv C, Huang J, Mei J, Mei L. Advances in 4-Hydroxyphenylacetate-3-hydroxylase Monooxygenase. Molecules 2023; 28:6699. [PMID: 37764475 PMCID: PMC10537072 DOI: 10.3390/molecules28186699] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 09/16/2023] [Accepted: 09/18/2023] [Indexed: 09/29/2023] Open
Abstract
Catechols have important applications in the pharmaceutical, food, cosmetic, and functional material industries. 4-hydroxyphenylacetate-3-hydroxylase (4HPA3H), a two-component enzyme system comprising HpaB (monooxygenase) and HpaC (FAD oxidoreductase), demonstrates significant potential for catechol production because it can be easily expressed, is highly active, and exhibits ortho-hydroxylation activity toward a broad spectrum of phenol substrates. HpaB determines the ortho-hydroxylation efficiency and substrate spectrum of the enzyme; therefore, studying its structure-activity relationship, improving its properties, and developing a robust HpaB-conducting system are of significance and value; indeed, considerable efforts have been made in these areas in recent decades. Here, we review the classification, molecular structure, catalytic mechanism, primary efforts in protein engineering, and industrial applications of HpaB in catechol synthesis. Current trends in the further investigation of HpaB are also discussed.
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Affiliation(s)
- Kai Yang
- Department of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027, China
- School of Biological and Chemical Engineering, Ningbo Tech University, Ningbo 315100, China
| | - Qianchao Zhang
- School of Biological and Chemical Engineering, Ningbo Tech University, Ningbo 315100, China
| | - Weirui Zhao
- School of Biological and Chemical Engineering, Ningbo Tech University, Ningbo 315100, China
| | - Sheng Hu
- School of Biological and Chemical Engineering, Ningbo Tech University, Ningbo 315100, China
| | - Changjiang Lv
- Department of Chemical and Biological Engineering, Zhejiang University of Science and Technology, Hangzhou 310023, China
| | - Jun Huang
- Department of Chemical and Biological Engineering, Zhejiang University of Science and Technology, Hangzhou 310023, China
| | - Jiaqi Mei
- Hangzhou Huadong Medicine Group Co., Ltd., Hangzhou 310011, China
| | - Lehe Mei
- Department of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027, China
- School of Biological and Chemical Engineering, Ningbo Tech University, Ningbo 315100, China
- Jinhua Advanced Research Institute, Jinhua 321019, China
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15
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Marchut-Mikołajczyk O, Chlebicz M, Kawecka M, Michalak A, Prucnal F, Nielipinski M, Filipek J, Jankowska M, Perek Z, Drożdżyński P, Rutkowska N, Otlewska A. Endophytic bacteria isolated from Urtica dioica L.- preliminary screening for enzyme and polyphenols production. Microb Cell Fact 2023; 22:169. [PMID: 37649058 PMCID: PMC10466763 DOI: 10.1186/s12934-023-02167-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Accepted: 08/05/2023] [Indexed: 09/01/2023] Open
Abstract
Endophytes, especially those isolated from herbal plants, may act as a reservoir of a variety of secondary metabolites exhibiting biological activity. Some endophytes express the ability to produce the same bioactive compounds as their plant hosts, making them a more sustainable industrial supply of these substances. Urtica dioica L. (common stinging nettle) is a synanthropic plant that is widely used in herbal medicine due to the diversity of bioactive chemicals it contains, e.g., polyphenols, which demonstrate anti-inflammatory, antioxidant, and anti-cancerous capabilities. This study aimed at isolating endophytic bacteria from stinging nettles for their bioactive compounds. The endophytic isolates were identified by both biochemical and molecular methods (16S rRNA) and investigated for enzymes, biosurfactants, and polyphenols production. Each of the isolated bacterial strains was capable of producing biosurfactants and polyphenols. However, three of the isolated endophytes, identified as two strains of Bacillus cereus and one strain of Bacillus mycoides, possessed the greatest capacity to produce biosurfactants and polyphenols. The derivatized extracts from culture liquid showed the 1.633 mol l-1 (9.691 mg l-1) concentration of polyphenol compounds. Therefore, the present study signifies that endophytic B. cereus and B. mycoides isolated from Urtica dioica L. could be a potential source of biosurfactants and polyphenols. However, further study is required to understand the mechanism of the process and achieve efficient polyphenol production by endophytic bacteria.
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Affiliation(s)
- Olga Marchut-Mikołajczyk
- Institute of Molecular and Industrial Biotechnology, Faculty of Biotechnology and Food Sciences, Lodz University of Technology, Stefanowskiego 2/22, 90-537, Lodz, Poland.
| | - Magdalena Chlebicz
- Biotechnology Students Association Ferment, Faculty of Biotechnology and Food Sciences, Lodz University of Technology, Wolczanska 171/173, 90-530, Lodz, Poland
| | - Monika Kawecka
- Biotechnology Students Association Ferment, Faculty of Biotechnology and Food Sciences, Lodz University of Technology, Wolczanska 171/173, 90-530, Lodz, Poland
| | - Agnieszka Michalak
- Biotechnology Students Association Ferment, Faculty of Biotechnology and Food Sciences, Lodz University of Technology, Wolczanska 171/173, 90-530, Lodz, Poland
| | - Filip Prucnal
- Biotechnology Students Association Ferment, Faculty of Biotechnology and Food Sciences, Lodz University of Technology, Wolczanska 171/173, 90-530, Lodz, Poland
| | - Maciej Nielipinski
- Institute of Molecular and Industrial Biotechnology, Faculty of Biotechnology and Food Sciences, Lodz University of Technology, Stefanowskiego 2/22, 90-537, Lodz, Poland
| | - Jakub Filipek
- Biotechnology Students Association Ferment, Faculty of Biotechnology and Food Sciences, Lodz University of Technology, Wolczanska 171/173, 90-530, Lodz, Poland
| | - Michalina Jankowska
- Biotechnology Students Association Ferment, Faculty of Biotechnology and Food Sciences, Lodz University of Technology, Wolczanska 171/173, 90-530, Lodz, Poland
| | - Zofia Perek
- Biotechnology Students Association Ferment, Faculty of Biotechnology and Food Sciences, Lodz University of Technology, Wolczanska 171/173, 90-530, Lodz, Poland
| | - Piotr Drożdżyński
- Institute of Molecular and Industrial Biotechnology, Faculty of Biotechnology and Food Sciences, Lodz University of Technology, Stefanowskiego 2/22, 90-537, Lodz, Poland
| | - Natalia Rutkowska
- Institute of Molecular and Industrial Biotechnology, Faculty of Biotechnology and Food Sciences, Lodz University of Technology, Stefanowskiego 2/22, 90-537, Lodz, Poland
| | - Anna Otlewska
- Institute of Fermentation Technology And Microbiology, Faculty of Biotechnology and Food Sciences, Lodz University of Technology, Wolczanska 171/173, 90-530, Lodz, Poland
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16
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Ji A, Bao P, Ma A, Wei X. An Efficient Prephenate Dehydrogenase Gene for the Biosynthesis of L-tyrosine: Gene Mining, Sequence Analysis, and Expression Optimization. Foods 2023; 12:3084. [PMID: 37628083 PMCID: PMC10453860 DOI: 10.3390/foods12163084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 08/14/2023] [Accepted: 08/15/2023] [Indexed: 08/27/2023] Open
Abstract
L-tyrosine is a key precursor for synthesis of various functional substances, but the microbial production of L-tyrosine faces huge challenges. The development of new microbial chassis cell and gene resource is especially important for the biosynthesis of L-tyrosine. In this study, the optimal host strain Bacillus amyloliquefaciens HZ-12 was firstly selected by detecting the production capacity of L-tyrosine. Subsequently, the recombinant expression of 15 prephenate dehydrogenase genes led to the discovery of the best gene, Bao-tyrA from B. amyloliquefaciens HZ-12. After the overexpression of Bao-tyrA, the L-tyrosine yield of the recombinant strain HZ/P43-Bao-tyrA reach 411 mg/L, increased by 42% compared with the control strain (HZ/pHY300PLK). Moreover, the nucleic acid sequence and deduced amino acid sequence of the gene Bao-tyrA were analyzed, and their conservative sites and catalytic mechanisms were proposed. Finally, the expression of Bao-tyrA was regulated through a promoter and 5'-UTR sequence to obtain the optimal expression elements. Thereby, the maximum L-tyrosine yield of 475 mg/L was obtained from HZ/P43-UTR3-Bao-tyrA. B. amyloliquefaciens was applied for the first time to produce L-tyrosine, and the optimal prephenate dehydrogenase gene Bao-tyrA and corresponding expression elements were obtained. This study provides new microbial host and gene resource for the construction of efficient L-tyrosine chassis cells, and also lays a solid foundation for the production of various functional tyrosine derivatives.
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Affiliation(s)
- Anying Ji
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China; (A.J.); (P.B.); (A.M.)
- Shenzhen Institute of Nutrition and Health, Huazhong Agricultural University, Wuhan 430070, China
- Shenzhen Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Genome Analysis Laboratory of the Ministry of Agriculture, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen 518000, China
| | - Pengfei Bao
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China; (A.J.); (P.B.); (A.M.)
- Shenzhen Institute of Nutrition and Health, Huazhong Agricultural University, Wuhan 430070, China
- Shenzhen Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Genome Analysis Laboratory of the Ministry of Agriculture, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen 518000, China
| | - Aimin Ma
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China; (A.J.); (P.B.); (A.M.)
- Shenzhen Institute of Nutrition and Health, Huazhong Agricultural University, Wuhan 430070, China
- Shenzhen Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Genome Analysis Laboratory of the Ministry of Agriculture, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen 518000, China
| | - Xuetuan Wei
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China; (A.J.); (P.B.); (A.M.)
- Shenzhen Institute of Nutrition and Health, Huazhong Agricultural University, Wuhan 430070, China
- Shenzhen Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Genome Analysis Laboratory of the Ministry of Agriculture, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen 518000, China
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17
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Tan Z, Li J, Hou J, Gonzalez R. Designing artificial pathways for improving chemical production. Biotechnol Adv 2023; 64:108119. [PMID: 36764336 DOI: 10.1016/j.biotechadv.2023.108119] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 02/01/2023] [Accepted: 02/06/2023] [Indexed: 02/11/2023]
Abstract
Metabolic engineering exploits manipulation of catalytic and regulatory elements to improve a specific function of the host cell, often the synthesis of interesting chemicals. Although naturally occurring pathways are significant resources for metabolic engineering, these pathways are frequently inefficient and suffer from a series of inherent drawbacks. Designing artificial pathways in a rational manner provides a promising alternative for chemicals production. However, the entry barrier of designing artificial pathway is relatively high, which requires researchers a comprehensive and deep understanding of physical, chemical and biological principles. On the other hand, the designed artificial pathways frequently suffer from low efficiencies, which impair their further applications in host cells. Here, we illustrate the concept and basic workflow of retrobiosynthesis in designing artificial pathways, as well as the most currently used methods including the knowledge- and computer-based approaches. Then, we discuss how to obtain desired enzymes for novel biochemistries, and how to trim the initially designed artificial pathways for further improving their functionalities. Finally, we summarize the current applications of artificial pathways from feedstocks utilization to various products synthesis, as well as our future perspectives on designing artificial pathways.
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Affiliation(s)
- Zaigao Tan
- State Key Laboratory of Microbial Metabolism, Shanghai Jiao Tong University, Shanghai, China; School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China; Department of Bioengineering, Shanghai Jiao Tong University, Shanghai, China.
| | - Jian Li
- State Key Laboratory of Microbial Metabolism, Shanghai Jiao Tong University, Shanghai, China; School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China; Department of Bioengineering, Shanghai Jiao Tong University, Shanghai, China
| | - Jin Hou
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao, China
| | - Ramon Gonzalez
- Department of Chemical, Biological, and Materials Engineering, University of South Florida, Tampa, FL, USA.
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18
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Sakae K, Nonaka D, Kishida M, Hirata Y, Fujiwara R, Kondo A, Noda S, Tanaka T. Caffeic acid production from glucose using metabolically engineered Escherichia coli. Enzyme Microb Technol 2023; 164:110193. [PMID: 36621069 DOI: 10.1016/j.enzmictec.2023.110193] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 01/03/2023] [Accepted: 01/04/2023] [Indexed: 01/07/2023]
Abstract
Caffeic acid (3,4-dihydroxycinnamic acid) is a precursor for high-valued compounds with anticancer, antiviral activities, and anti-inflammatory making it an important substance in the food additive, cosmetics, and pharmaceutical industries. Here, we developed an engineered Escherichia coli strain capable of directly producing high levels of caffeic acid from glucose. Tyrosine ammonia-lyase from Rhodotorula glutinis (RgTAL) and p-coumaric acid 3-hydroxylase from Saccharothrix espanaensis (SeC3H) were expressed. Next, feedback-resistant chorismate mutase/prephenate dehydrogenase, was introduced to promote l-tyrosine synthesis. This engineered strain CA3 produced 1.58 g/L of caffeic acid from glucose without tyrosine supplemented to the medium. Furthermore, to reduce p-coumaric acid accumulation, 4-hydroxyphenylacetate 3-hydroxylase from Pseudomonas aeruginosa (PaHpaBC) was introduced. Finally, an engineered strain CA8 directly produced 6.17 g/L of caffeic acid from glucose using a jar fermenter. The E. coli developed in this study would be helpful as a chassis strain to produce value-added caffeic acid-derivatives.
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Affiliation(s)
- Kosuke Sakae
- Department of Chemical Science and Engineering, Graduate School of Engineering, Kobe University, 1-1 Rokkodai, Nada, Kobe 657-8501, Japan
| | - Daisuke Nonaka
- Department of Chemical Science and Engineering, Graduate School of Engineering, Kobe University, 1-1 Rokkodai, Nada, Kobe 657-8501, Japan
| | - Mayumi Kishida
- Department of Chemical Science and Engineering, Graduate School of Engineering, Kobe University, 1-1 Rokkodai, Nada, Kobe 657-8501, Japan
| | - Yuuki Hirata
- Department of Chemical Science and Engineering, Graduate School of Engineering, Kobe University, 1-1 Rokkodai, Nada, Kobe 657-8501, Japan
| | - Ryosuke Fujiwara
- Department of Chemical Science and Engineering, Graduate School of Engineering, Kobe University, 1-1 Rokkodai, Nada, Kobe 657-8501, Japan
| | - Akihiko Kondo
- Center for Sustainable Resource Science, RIKEN, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan; Graduate School of Science, Technology and Innovation, Kobe University, 1-1 Rokkodai, Nada, Kobe 657-8501, Japan
| | - Shuhei Noda
- Center for Sustainable Resource Science, RIKEN, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan
| | - Tsutomu Tanaka
- Department of Chemical Science and Engineering, Graduate School of Engineering, Kobe University, 1-1 Rokkodai, Nada, Kobe 657-8501, Japan.
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19
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Ganguly R, Singh SV, Jaiswal K, Kumar R, Pandey AK. Modulatory effect of caffeic acid in alleviating diabetes and associated complications. World J Diabetes 2023; 14:62-75. [PMID: 36926656 PMCID: PMC10011896 DOI: 10.4239/wjd.v14.i2.62] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Revised: 11/04/2022] [Accepted: 12/14/2022] [Indexed: 02/14/2023] Open
Abstract
Diabetes mellitus (DM) is one of the most common metabolic disorders characterized by elevated blood glucose levels. Prolonged uncontrolled hyperglycemia often leads to multi-organ damage including diabetic neuropathy, nephropathy, retinopathy, cardiovascular disorders, and diabetic foot ulcers. Excess production of free radicals causing oxidative stress in tissues is often considered to be the primary cause of onset and progression of DM and associated complications. Natural polyphenols can be used to induce or inhibit the expression of antioxidant enzymes such as glutathione peroxidase, heme oxygenase-1, superoxide dismutase, and catalase that are essential in maintaining redox balance, and ameliorate oxidative stress. Caffeic acid (CA) is a polyphenolderived from hydroxycinnamic acid and possesses numerous physiological properties includ-ing antioxidant, anti-inflammatory, anti-atherosclerotic, immune-stimulatory, cardioprotective, antiproliferative, and hepatoprotective activities. CA acts as a regulatory compound affecting numerous biochemical pathways and multiple targets. These include various transcription factors such as nuclear factor-B, tumor necrosis factor-α, interleukin-6, cyclooxygenase-2, and nuclear factor erythroid 2-related factor 2. Therefore, this review summarizes the pharmacological properties, molecular mechanisms, and pharmacokinetic profile of CA in mitigating the adverse effects of DM and associated complications. The bioavailability, drug delivery, and clinical trials of CA have also been discussed.
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Affiliation(s)
- Risha Ganguly
- Department of Biochemistry, University of Allahabad, Allahabad (Prayagraj) 211002, India
| | - Shiv Vardan Singh
- Department of Biochemistry, University of Allahabad, Allahabad (Prayagraj) 211002, India
| | - Kritika Jaiswal
- Department of Biochemistry, University of Allahabad, Allahabad (Prayagraj) 211002, India
| | - Ramesh Kumar
- Department of Biochemistry, University of Allahabad, Allahabad (Prayagraj) 211002, India
| | - Abhay K Pandey
- Department of Biochemistry, University of Allahabad, Allahabad (Prayagraj) 211002, India
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20
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Ercole F, Kim CJ, Dao NV, Tse WKL, Whittaker MR, Caruso F, Quinn JF. Synthesis of Thermoresponsive, Catechol-Rich Poly(ethylene glycol) Brush Polymers for Attenuating Cellular Oxidative Stress. Biomacromolecules 2023; 24:387-399. [PMID: 36469858 DOI: 10.1021/acs.biomac.2c01211] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Herein, we report a platform to integrate customizable quantities of catechol units into polymers by reacting caffeic acid carbonic anhydride with polymers having pendant amine groups. Brush poly(ethylene glycol)-caffeamide (PEG-CAF) copolymers based on oligo(ethylene glycol)methyl ether methacrylate (OEGMA500) were obtained with a catechol content of approximately 30, 40, and 50 mol % (vs OEGMA content). Owing to the hydrophobicity of the introduced CAF groups, the catechol copolymers exhibited cloud points in the range of 23-46 °C and were used to fabricate thermoresponsive FeIII metal-phenolic network capsules. Polymers with the highest CAF content (50 mol %) proved most effective for attenuating reactive oxygen species levels in vitro, in co-cultured fibroblasts, and breast cancer cells, even in the presence of an exogenous oxidant source. The reported approach to synthesize customizable catechol materials could be generalized to other amine-functional polymers, with potential biomedical applications such as adhesives or stimuli-responsive drug delivery systems.
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Affiliation(s)
- Francesca Ercole
- Drug Delivery, Disposition and Dynamics Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia
| | - Chan-Jin Kim
- Department of Chemical Engineering, The University of Melbourne, Parkville, Victoria 3010, Australia
| | - Nam V Dao
- Drug Delivery, Disposition and Dynamics Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.,Department of Physical Chemistry and Physics, Hanoi University of Pharmacy, Hanoi 10000, Vietnam
| | - Warren K L Tse
- Department of Chemical Engineering, Faculty of Engineering, Monash University, Clayton, Victoria 3800, Australia
| | - Michael R Whittaker
- Drug Delivery, Disposition and Dynamics Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia
| | - Frank Caruso
- Department of Chemical Engineering, The University of Melbourne, Parkville, Victoria 3010, Australia
| | - John F Quinn
- Drug Delivery, Disposition and Dynamics Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.,Department of Chemical Engineering, Faculty of Engineering, Monash University, Clayton, Victoria 3800, Australia
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21
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Pan H, Li H, Wu S, Lai C, Guo D. De novo biosynthesis of N-acetyltyramine in engineered Escherichia coli. Enzyme Microb Technol 2023; 162:110149. [DOI: 10.1016/j.enzmictec.2022.110149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 09/29/2022] [Accepted: 10/20/2022] [Indexed: 11/13/2022]
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22
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Wang L, Li N, Yu S, Zhou J. Enhancing caffeic acid production in Escherichia coli by engineering the biosynthesis pathway and transporter. BIORESOURCE TECHNOLOGY 2023; 368:128320. [PMID: 36379296 DOI: 10.1016/j.biortech.2022.128320] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 10/31/2022] [Accepted: 11/01/2022] [Indexed: 06/16/2023]
Abstract
Caffeic acid is a phenylpropanoid which is widely used in medical industry. Microbial fermentation provides a green strategy for producing caffeic acid. To improve the capacity for caffeic acid production in Escherichia coli, the competing pathways for l-tyrosine synthesis were knocked out. The biosynthesis pathway of the cofactor FAD and the expression of previously reported polyphenol transporters were enhanced to promote the production of caffeic acid. Transcriptomics analysis was conducted to mine potential transporters that could further enhance the titer of caffeic acid in engineered E. coli. Transcriptomics data of E. coli under caffeic acid and ferulic acid stress showed that 19 transporters were upregulated. Among them, overexpression of ycjP, which was previously identified as a sugar ABC transporter permease, improved the caffeic acid titer to 775.7 mg/L. The caffeic acid titer was further improved to 7922.0 mg/L in a 5-L fermenter, the highest titer achieved by microorganisms.
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Affiliation(s)
- Lian Wang
- Engineering Research Center of Ministry of Education on Food Synthetic Biotechnology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China; Science Center for Future Foods, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China
| | - Ning Li
- Engineering Research Center of Ministry of Education on Food Synthetic Biotechnology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China; Science Center for Future Foods, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China
| | - Shiqin Yu
- Engineering Research Center of Ministry of Education on Food Synthetic Biotechnology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China; Science Center for Future Foods, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China
| | - Jingwen Zhou
- Engineering Research Center of Ministry of Education on Food Synthetic Biotechnology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China; Science Center for Future Foods, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China; Key Laboratory of Industrial Biotechnology, Ministry of Education and School of Biotechnology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China; Jiangsu Province Engineering Research Center of Food Synthetic Biotechnology, Jiangnan University, Wuxi 214122, China.
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23
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De novo biosynthesis of vanillin in engineered Saccharomyces cerevisiae. Chem Eng Sci 2022. [DOI: 10.1016/j.ces.2022.118049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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24
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Development of Semisynthetic Apoptosis-Inducing Agents Based on Natural Phenolic Acids Scaffold: Design, Synthesis and In-Vitro Biological Evaluation. Molecules 2022; 27:molecules27196724. [PMID: 36235260 PMCID: PMC9571594 DOI: 10.3390/molecules27196724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 10/02/2022] [Accepted: 10/04/2022] [Indexed: 11/06/2022] Open
Abstract
A crucial target in drug research is magnifying efficacy and decreasing toxicity. Therefore, using natural active constituents as precursors will enhance both safety and biological activities. Despite having many pharmacological activities, caffeic and ferulic acids showed limited clinical usage due to their poor bioavailability and fast elimination. Therefore, semisynthetic compounds from these two acids were prepared and screened as anticancer agents. In this study, CA and FA showed very potent anticancer activity against Caco-2 cells. Consequently, eighteen derivatives were tested against the same cell line. Four potent candidates were selected for determination of the selectivity index, where compound 10 revealed a high safety margin. Compound 10 represented a new scaffold and showed significant cytotoxic activity against Caco-2. Cell-cycle analysis and evaluation of apoptosis showed that derivatives 10, 7, 11, 15 and 14 showed the highest proportion of cells in a late apoptotic stage.
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25
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Zhou Z, Zhang X, Wu J, Li X, Li W, Sun X, Wang J, Yan Y, Shen X, Yuan Q. Targeting cofactors regeneration in methylation and hydroxylation for high level production of Ferulic acid. Metab Eng 2022; 73:247-255. [PMID: 35987433 DOI: 10.1016/j.ymben.2022.08.007] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Revised: 07/05/2022] [Accepted: 08/12/2022] [Indexed: 10/15/2022]
Abstract
Ferulic acid (FA) is a natural methylated phenolic acid which represents various bioactivities. Bioproduction of FA suffers from insufficient methyl donor supplement and inefficient hydroxylation. To overcome these hurdles, we first activate the S-adenosylmethionine (SAM) cycle in E. coli by using endogenous genes to supply sufficient methyl donor. Then, a small protein Fre is introduced into the pathway to efficiently regenerate FADH2 for the hydroxylation. Remarkably, regeneration of these two cofactors dramatically promotes FA synthesis. Together with decreasing the byproducts formation and boosting precursor supply, the titer of FA reaches 5.09 g/L under fed-batch conditions, indicating a 20-fold improvement compared with the original producing E. coli strain. This work not only establishes a promising microbial platform for industrial level production of FA and its derivatives, but also highlights a convenient and effective strategy to enhance the biosynthesis of chemicals requiring methylation and FADH2-dependent hydroxylation.
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Affiliation(s)
- Zhao Zhou
- State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing, 100029, China
| | - Xiangyan Zhang
- State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing, 100029, China
| | - Jun Wu
- State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing, 100029, China
| | - Xianglai Li
- State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing, 100029, China
| | - Wenna Li
- State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing, 100029, China
| | - Xinxiao Sun
- State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing, 100029, China
| | - Jia Wang
- State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing, 100029, China
| | - Yajun Yan
- School of Chemical, Materials and Biomedical Engineering, College of Engineering, University of Georgia, Athens, GA, 30602, USA
| | - Xiaolin Shen
- State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing, 100029, China.
| | - Qipeng Yuan
- State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing, 100029, China.
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26
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A targeted metabolomics method for extra- and intracellular metabolite quantification covering the complete monolignol and lignan synthesis pathway. Metab Eng Commun 2022; 15:e00205. [PMID: 36119807 PMCID: PMC9474286 DOI: 10.1016/j.mec.2022.e00205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/16/2022] [Accepted: 08/22/2022] [Indexed: 11/25/2022] Open
Abstract
Microbial synthesis of monolignols and lignans from simple substrates is a promising alternative to plant extraction. Bottlenecks and byproduct formation during heterologous production require targeted metabolomics tools for pathway optimization. In contrast to available fractional methods, we established a comprehensive targeted metabolomics method. It enables the quantification of 17 extra- and intracellular metabolites of the monolignol and lignan pathway, ranging from amino acids to pluviatolide. Several cell disruption methods were compared. Hot water extraction was best suited regarding monolignol and lignan stability as well as extraction efficacy. The method was applied to compare enzymes for alleviating bottlenecks during heterologous monolignol and lignan production in E. coli. Variants of tyrosine ammonia-lyase had a considerable influence on titers of subsequent metabolites. The choice of multicopper oxidase greatly affected the accumulation of lignans. Metabolite titers were monitored during batch fermentation of either monolignol or lignan-producing recombinant E. coli strains, demonstrating the dynamic accumulation of metabolites. The new method enables efficient time-resolved targeted metabolomics of monolignol- and lignan-producing E. coli. It facilitates bottleneck identification and byproduct quantification, making it a valuable tool for further pathway engineering studies. This method will benefit the bioprocess development of biotransformation or fermentation approaches for microbial lignan production.
Monolignols and lignans were heterologously produced in Escherichia coli A targeted metabolomics method was developed covering 17 out of 20 metabolites. Hot water extraction is well suited for intracellular monolignol & lignan analysis. Metabolite accumulation identifies bottlenecks and dynamic activity. Assessment of pathway activity enables efficient cell factory engineering.
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27
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Bio-inspired Synthesis of Metal and Metal Oxide Nanoparticles: The Key Role of Phytochemicals. J CLUST SCI 2022. [DOI: 10.1007/s10876-022-02276-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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28
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Wu X, Liu J, Liu D, Yuwen M, Koffas MAG, Zha J. Biosynthesis of eriodictyol from tyrosine by Corynebacterium glutamicum. Microb Cell Fact 2022; 21:86. [PMID: 35568867 PMCID: PMC9107716 DOI: 10.1186/s12934-022-01815-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 03/27/2022] [Indexed: 02/07/2023] Open
Abstract
Background Eriodictyol is a bioactive flavonoid compound that shows potential applications in medicine development and food processing. Microbial synthesis of eriodictyol has been attracting increasing attention due to several benefits. In this study, we employed a GRAS strain Corynebacterium glutamicum as the host to produce eriodictyol directly from tyrosine. Results We firstly optimized the biosynthetic module of naringenin, the upstream intermediate for eriodictyol production, through screening of different gene orthologues. Next, to improve the level of the precursor malonyl-CoA necessary for naringenin production, we introduced matB and matC from Rhizobium trifolii into C. glutamicum to convert extracellular malonate to intracellular malonyl-CoA. This combinatorial engineering resulted in around 35-fold increase in naringenin production from tyrosine compared to the initial recombinant C. glutamicum. Subsequently, the hpaBC genes from E. coli encoding 4-hydroxyphenylacetate 3-hydroxylase were expressed in C. glutamicum to synthesize eriodictyol from naringenin. Further optimization of the biotransformation process parameters led to the production of 14.10 mg/L eriodictyol. Conclusions The biosynthesis of the ortho-hydroxylated flavonoid eriodictyol in C. glutamicum was achieved for the first time via functional expression of E. coli hpaBC, providing a baseline strain for biosynthesis of other complex flavonoids. Our study demonstrates the potential application of C. glutamicum as a host microbe for the biosynthesis of value-added natural compounds from tyrosine.
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Affiliation(s)
- Xia Wu
- School of Food and Biological Engineering, Shaanxi University of Science and Technology, Xi'an, 710021, Shaanxi, China
| | - Jingyi Liu
- School of Food and Biological Engineering, Shaanxi University of Science and Technology, Xi'an, 710021, Shaanxi, China
| | - Dan Liu
- School of Food and Biological Engineering, Shaanxi University of Science and Technology, Xi'an, 710021, Shaanxi, China
| | - Miaomiao Yuwen
- School of Food and Biological Engineering, Shaanxi University of Science and Technology, Xi'an, 710021, Shaanxi, China
| | - Mattheos A G Koffas
- Department of Chemical and Biological Engineering, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY, 12180, USA.
| | - Jian Zha
- School of Food and Biological Engineering, Shaanxi University of Science and Technology, Xi'an, 710021, Shaanxi, China.
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29
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Engineering cofactor supply and recycling to drive phenolic acid biosynthesis in yeast. Nat Chem Biol 2022; 18:520-529. [PMID: 35484257 DOI: 10.1038/s41589-022-01014-6] [Citation(s) in RCA: 93] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Accepted: 03/15/2022] [Indexed: 01/14/2023]
Abstract
Advances in synthetic biology enable microbial hosts to synthesize valuable natural products in an efficient, cost-competitive and safe manner. However, current engineering endeavors focus mainly on enzyme engineering and pathway optimization, leaving the role of cofactors in microbial production of natural products and cofactor engineering largely ignored. Here we systematically engineered the supply and recycling of three cofactors (FADH2, S-adenosyl-L-methion and NADPH) in the yeast Saccharomyces cerevisiae, for high-level production of the phenolic acids caffeic acid and ferulic acid, the precursors of many pharmaceutical molecules. Tailored engineering strategies were developed for rewiring biosynthesis, compartmentalization and recycling of the cofactors, which enabled the highest production of caffeic acid (5.5 ± 0.2 g l-1) and ferulic acid (3.8 ± 0.3 g l-1) in microbial cell factories. These results demonstrate that cofactors play an essential role in driving natural product biosynthesis and the engineering strategies described here can be easily adopted for regulating the metabolism of other cofactors.
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30
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Alam M, Ashraf GM, Sheikh K, Khan A, Ali S, Ansari MM, Adnan M, Pasupuleti VR, Hassan MI. Potential Therapeutic Implications of Caffeic Acid in Cancer Signaling: Past, Present, and Future. Front Pharmacol 2022; 13:845871. [PMID: 35355732 PMCID: PMC8959753 DOI: 10.3389/fphar.2022.845871] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Accepted: 01/26/2022] [Indexed: 12/20/2022] Open
Abstract
Caffeic acid (CA) has been present in many herbs, vegetables, and fruits. CA is a bioactive compound and exhibits various health advantages that are linked with its anti-oxidant functions and implicated in the therapy and prevention of disease progression of inflammatory diseases and cancer. The anti-tumor action of CA is attributed to its pro-oxidant and anti-oxidant properties. CA’s mechanism of action involves preventing reactive oxygen species formation, diminishing the angiogenesis of cancer cells, enhancing the tumor cells’ DNA oxidation, and repressing MMP-2 and MMP-9. CA and its derivatives have been reported to exhibit anti-carcinogenic properties against many cancer types. CA has indicated low intestinal absorption, low oral bioavailability in rats, and pitiable permeability across Caco-2 cells. In the present review, we have illustrated CA’s therapeutic potential, pharmacokinetics, and characteristics. The pharmacological effects of CA, the emphasis on in vitro and in vivo studies, and the existing challenges and prospects of CA for cancer treatment and prevention are discussed in this review.
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Affiliation(s)
- Manzar Alam
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
| | - Ghulam Md Ashraf
- Pre-Clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.,Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Kayenat Sheikh
- Department of Computer Science, Jamia Millia Islamia, New Delhi, India
| | - Anish Khan
- Chemistry Department, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia.,Center of Excellence for Advanced Materials Research, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Sabeeha Ali
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
| | - Md Meraj Ansari
- Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, SAS Nagar Mohali, India
| | - Mohd Adnan
- Department of Biology, College of Science, University of Hail, Hail, Saudi Arabia
| | - Visweswara Rao Pasupuleti
- Department of Biomedical Sciences and Therapeutics, Faculty of Medicine and Health Sciences, Universiti Malaysia Sabah, Kota Kinabalu, Malaysia.,Department of Biochemistry, Faculty of Medicine and Health Sciences, Abdurrab University, Pekanbaru, Indonesia.,Centre for International Collaboration and Research, Reva University, Bangalore, India
| | - Md Imtaiyaz Hassan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
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31
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Qi H, Yu L, Li Y, Cai M, He J, Liu J, Hao L, Xu H, Qiao M. Developing Multi-Copy Chromosomal Integration Strategies for Heterologous Biosynthesis of Caffeic Acid in Saccharomyces cerevisiae. Front Microbiol 2022; 13:851706. [PMID: 35300487 PMCID: PMC8923693 DOI: 10.3389/fmicb.2022.851706] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 02/09/2022] [Indexed: 11/13/2022] Open
Abstract
Caffeic acid, a plant-sourced phenolic compound, has a variety of biological activities, such as antioxidant and antimicrobial properties. The caffeic acid biosynthetic pathway was initially constructed in S. cerevisiae, using codon-optimized TAL (coTAL, encoding tyrosine ammonia lyase) from Rhodobacter capsulatus, coC3H (encoding p-coumaric acid 3-hydroxylase) and coCPR1 (encoding cytochrome P450 reductase 1) from Arabidopsis thaliana in 2 μ multi-copy plasmids to produce caffeic acid from glucose. Then, integrated expression of coTAL via delta integration with the POT1 gene (encoding triose phosphate isomerase) as selection marker and episomal expression of coC3H, coCPR1 using the episomal plasmid pLC-c3 were combined, and caffeic acid production was proved to be improved. Next, the delta and rDNA multi-copy integration methods were applied to integrate the genes coC3H and coCPR1 into the chromosome of high p-coumaric acid yielding strain QT3-20. The strain D9 constructed via delta integration outperformed the other strains, leading to 50-fold increased caffeic acid production in optimized rich media compared with the initial construct. The intercomparison between three alternative multi-copy strategies for de novo synthesis of caffeic acid in S. cerevisiae suggested that delta-integration was effective in improving caffeic acid productivity, providing a promising strategy for the production of valuable bio-based chemicals in recombinant S. cerevisiae.
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Affiliation(s)
- Hang Qi
- The Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, College of Life Sciences, Nankai University, Tianjin, China
| | - Long Yu
- The Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, College of Life Sciences, Nankai University, Tianjin, China
| | - Yuanzi Li
- The Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, College of Life Sciences, Nankai University, Tianjin, China.,School of Light Industry, Beijing Technology and Business University, Beijing, China
| | - Miao Cai
- The Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, College of Life Sciences, Nankai University, Tianjin, China
| | - Jiaze He
- The Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, College of Life Sciences, Nankai University, Tianjin, China
| | - Jiayu Liu
- The Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, College of Life Sciences, Nankai University, Tianjin, China
| | - Luyao Hao
- The Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, College of Life Sciences, Nankai University, Tianjin, China
| | - Haijin Xu
- The Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, College of Life Sciences, Nankai University, Tianjin, China
| | - Mingqiang Qiao
- The Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, College of Life Sciences, Nankai University, Tianjin, China
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32
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Alam M, Ashraf GM, Sheikh K, Khan A, Ali S, Ansari MM, Adnan M, Pasupuleti VR, Hassan MI. Potential Therapeutic Implications of Caffeic Acid in Cancer Signaling: Past, Present, and Future. Front Pharmacol 2022. [DOI: 10.3389/fphar.2022.845871
expr 835330423 + 878857932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2023] Open
Abstract
Caffeic acid (CA) has been present in many herbs, vegetables, and fruits. CA is a bioactive compound and exhibits various health advantages that are linked with its anti-oxidant functions and implicated in the therapy and prevention of disease progression of inflammatory diseases and cancer. The anti-tumor action of CA is attributed to its pro-oxidant and anti-oxidant properties. CA’s mechanism of action involves preventing reactive oxygen species formation, diminishing the angiogenesis of cancer cells, enhancing the tumor cells’ DNA oxidation, and repressing MMP-2 and MMP-9. CA and its derivatives have been reported to exhibit anti-carcinogenic properties against many cancer types. CA has indicated low intestinal absorption, low oral bioavailability in rats, and pitiable permeability across Caco-2 cells. In the present review, we have illustrated CA’s therapeutic potential, pharmacokinetics, and characteristics. The pharmacological effects of CA, the emphasis onin vitro and in vivostudies, and the existing challenges and prospects of CA for cancer treatment and prevention are discussed in this review.
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33
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Park SY, Yang D, Ha SH, Lee SY. Production of phenylpropanoids and flavonolignans from glycerol by metabolically engineered Escherichia coli. Biotechnol Bioeng 2022; 119:946-962. [PMID: 34928495 DOI: 10.1002/bit.28008] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 11/27/2021] [Accepted: 12/06/2021] [Indexed: 01/07/2023]
Abstract
Phenylpropanoids are a group of plant natural products with medicinal importance derived from aromatic amino acids. Here, we report the production of two representative phenylpropanoids-coniferyl alcohol (CA) and dihydroquercetin (DHQ)-from glycerol by engineered Escherichia coli. First, an E. coli strain capable of producing 187.7 mg/L of CA from glycerol was constructed by the introduction of hpaBC from E. coli and OMT1, 4CL4, and CCR1 from Arabidopsis thaliana to the p-coumaric acid producer. Next, an E. coli strain capable of producing 239.4 mg/L of DHQ from glycerol was constructed by the introduction of F3H, TT7, and CPR from A. thaliana to the naringenin producer, followed by engineering the signal peptide of a cytochrome P450 TT7. Furthermore, to demonstrate the production of flavonolignans, a group of heterodimeric phenylpropanoids, from glycerol, ascorbate peroxidase 1 from Silybum marianum was employed and engineered to produce 0.04 μg/L of silybin and 1.29 μg/L of isosilybin from glycerol by stepwise culture. Finally, a single strain harboring all the 16 necessary genes was constructed, resulting in 0.12 μg/L of isosilybin production directly from glycerol. The strategies described here will be useful for the production of pharmaceutically important yet complex natural products.
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Affiliation(s)
- Seon Young Park
- Department of Chemical and Biomolecular Engineering (BK21 Four Program), Metabolic and Biomolecular Engineering National Research Laboratory, Systems Metabolic Engineering and Systems Healthcare (SMESH) Cross-Generation Collaborative Laboratory, Institute for the BioCentury, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
- BioProcess Engineering Research Center, KAIST, Daejeon, Republic of Korea
| | - Dongsoo Yang
- Department of Chemical and Biomolecular Engineering (BK21 Four Program), Metabolic and Biomolecular Engineering National Research Laboratory, Systems Metabolic Engineering and Systems Healthcare (SMESH) Cross-Generation Collaborative Laboratory, Institute for the BioCentury, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
- BioProcess Engineering Research Center, KAIST, Daejeon, Republic of Korea
| | - Shin Hee Ha
- Department of Chemical and Biomolecular Engineering (BK21 Four Program), Metabolic and Biomolecular Engineering National Research Laboratory, Systems Metabolic Engineering and Systems Healthcare (SMESH) Cross-Generation Collaborative Laboratory, Institute for the BioCentury, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
| | - Sang Yup Lee
- Department of Chemical and Biomolecular Engineering (BK21 Four Program), Metabolic and Biomolecular Engineering National Research Laboratory, Systems Metabolic Engineering and Systems Healthcare (SMESH) Cross-Generation Collaborative Laboratory, Institute for the BioCentury, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
- BioProcess Engineering Research Center, KAIST, Daejeon, Republic of Korea
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34
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Zeraati M, Rahdar A, Medina DI, Sargazi G. Synthesis of Al-Based Metal-Organic Framework in Water With Caffeic Acid Ligand and NaOH as Linker Sources With Highly Efficient Anticancer Treatment. Front Chem 2021; 9:784461. [PMID: 34917591 PMCID: PMC8669676 DOI: 10.3389/fchem.2021.784461] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 11/10/2021] [Indexed: 11/20/2022] Open
Abstract
In this study, novel nanostructures of aluminum base metal-organic framework (Al-MOF) samples were synthesized using a sustainable, non-toxic, and cost-effective green synthesis route. Satureja hortensis extract was used as an effective source of linker for the development of the Al-MOF structures. The Fourier-transformed infrared (FTIR) spectrum confirmed the presence of characterization bonds related to the Al-MOF nanostructures synthesized by the green synthesis route. The scanning electron microscopy (SEM) and transmission electron microscopy (TEM) analyses revealed that the sample synthesized by Na2-CA was composed of multilayers, although it was agglomerated, but it had dispersed and occurred in spherical particles, indicating active organic matter. N2 adsorption/desorption isotherms demonstrated the significant porosity of the Al-MOF samples that facilitate the high potential of these nanostructures in medical applications. The anticancer treatment of Al-MOF samples was performed with different concentrations using the MTT standard method with untreated cancer cells for 24 and 48 h periods. The results exhibited the significant anticancer properties of Al-MOF samples developed in this study when compared with other MOF samples. Thus, the development of a novel Al-MOF and its application as a natural linker can influence the anticancer treatment of the samples. According to the results, the products developed in this study can be used in more applications such as biosensors, catalysts, and novel adsorbents.
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Affiliation(s)
- Malihe Zeraati
- Department of Materials Engineering, Shahid Bahonar University of Kerman, Kerman, Iran
| | - Abbas Rahdar
- Department of Physics, Faculty of Science, University of Zabol, Zabol, Iran
| | - Dora I Medina
- Tecnologico de Monterrey, School of Engineering and Sciences, Atizapan de Zaragoza, Estado de Mexico, Mexico
| | - Ghasem Sargazi
- Noncommunicable Diseases Research Center, Bam University of Medical Sciences, Bam, Iran
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35
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Lv H, Zhang Y, Shao J, Liu H, Wang Y. Ferulic acid production by metabolically engineered Escherichia coli. BIORESOUR BIOPROCESS 2021; 8:70. [PMID: 38650224 PMCID: PMC10992898 DOI: 10.1186/s40643-021-00423-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Accepted: 07/28/2021] [Indexed: 11/10/2022] Open
Abstract
Ferulic acid (p-hydroxy-3-methoxycinnamic acid, FA) is a natural active substance present in plant cell walls, with antioxidant, anticancer, antithrombotic and other properties; it is widely used in medicine, food, and cosmetics. Production of FA by eco-friendly bioprocess is of great potential. In this study, FA was biosynthesized by metabolically engineered Escherichia coli. As the first step, the genes tal (encoding tyrosine ammonia-lyase, RsTAL) from Rhodobacter sphaeroides, sam5 (encoding p-coumarate 3-hydroxylase, SeSAM5) from Saccharothrix espanaensis and comt (encoding Caffeic acid O-methytransferase, TaCM) from Triticum aestivum were cloned in an operon on the pET plasmid backbone, E. coli strain containing this construction was proved to produce FA from L-tyrosine successfully, and confirmed the function of TaCM as caffeic acid O-methytransferase. Fermentation result revealed JM109(DE3) as a more suitable host cell for FA production than BL21(DE3). After that the genes expression strength of FA pathway were optimized by tuning of promoter strength (T7 promoter or T5 promoter) and copy number (pBR322 or p15A), and the combination p15a-T5 works best. To further improve FA production, E. coli native pntAB, encoding pyridine nucleotide transhydrogenase, was selected from five NADPH regeneration genes to supplement redox cofactor NADPH for converting p-coumaric acid into caffeic acid in FA biosynthesis process. Sequentially, to further convert caffeic acid into FA, a non-native methionine kinase (MetK from Streptomyces spectabilis) was also overexpressed. Based on the flask fermentation data which show that the engineered E. coli strain produced 212 mg/L of FA with 11.8 mg/L caffeic acid residue, it could be concluded that it is the highest yield of FA achieved by E. coli K-12 strains reported to the best of our knowledge.
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Affiliation(s)
- Huajun Lv
- CAS Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Shanghai Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai, 200032, China
| | - Ying Zhang
- CAS Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Shanghai Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai, 200032, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Jie Shao
- CAS Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Shanghai Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai, 200032, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Haili Liu
- CAS Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Shanghai Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai, 200032, China
| | - Yong Wang
- CAS Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Shanghai Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai, 200032, China.
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Metabolic engineering of Saccharomyces cerevisiae for enhanced production of caffeic acid. Appl Microbiol Biotechnol 2021; 105:5809-5819. [PMID: 34283270 DOI: 10.1007/s00253-021-11445-1] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 06/09/2021] [Accepted: 07/03/2021] [Indexed: 01/15/2023]
Abstract
As a natural phenolic acid product of plant source, caffeic acid displays diverse biological activities and acts as an important precursor for the synthesis of other valuable compounds. Limitations in chemical synthesis or plant extraction of caffeic acid trigger interest in its microbial biosynthesis. Recently, Saccharomyces cerevisiae has been reported for the biosynthesis of caffeic acid via episomal plasmid-mediated expression of pathway genes. However, the production was far from satisfactory and even relied on the addition of precursor. In this study, we first established a controllable and stable caffeic acid pathway by employing a modified GAL regulatory system to control the genome-integrated pathway genes in S. cerevisiae and realized biosynthesis of 222.7 mg/L caffeic acid. Combinatorial engineering strategies including eliminating the tyrosine-induced feedback inhibition, deleting genes involved in competing pathways, and overexpressing rate-limiting enzymes led to about 2.6-fold improvement in the caffeic acid production, reaching up to 569.0 mg/L in shake-flask cultures. To our knowledge, this is the highest ever reported titer of caffeic acid synthesized by engineered yeast. This work showed the prospect for microbial biosynthesis of caffeic acid and laid the foundation for constructing biosynthetic pathways of its derived metabolites. KEY POINTS: Genomic integration of ORgTAL, OHpaB, and HpaC for caffeic acid production in yeast. Feedback inhibition elimination and Aro10 deletion improved caffeic acid production. The highest ever reported titer (569.0 mg/L) of caffeic acid synthesized by yeast.
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Mirzaei S, Gholami MH, Zabolian A, Saleki H, Farahani MV, Hamzehlou S, Far FB, Sharifzadeh SO, Samarghandian S, Khan H, Aref AR, Ashrafizadeh M, Zarrabi A, Sethi G. Caffeic acid and its derivatives as potential modulators of oncogenic molecular pathways: New hope in the fight against cancer. Pharmacol Res 2021; 171:105759. [PMID: 34245864 DOI: 10.1016/j.phrs.2021.105759] [Citation(s) in RCA: 97] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 06/18/2021] [Accepted: 07/05/2021] [Indexed: 02/06/2023]
Abstract
As a phenolic acid compound, caffeic acid (CA) can be isolated from different sources such as tea, wine and coffee. Caffeic acid phenethyl ester (CAPE) is naturally occurring derivative of CA isolated from propolis. This medicinal plant is well-known due to its significant therapeutic impact including its effectiveness as hepatoprotective, neuroprotective and anti-diabetic agent. Among them, anti-tumor activity of CA has attracted much attention, and this potential has been confirmed both in vitro and in vivo. CA can induce apoptosis in cancer cells via enhancing ROS levels and impairing mitochondrial function. Molecular pathways such as PI3K/Akt and AMPK with role in cancer progression, are affected by CA and its derivatives in cancer therapy. CA is advantageous in reducing aggressive behavior of tumors via suppressing metastasis by inhibiting epithelial-to-mesenchymal transition mechanism. Noteworthy, CA and CAPE can promote response of cancer cells to chemotherapy, and sensitize them to chemotherapy-mediated cell death. In order to improve capacity of CA and CAPE in cancer suppression, it has been co-administered with other anti-tumor compounds such as gallic acid and p-coumaric acid. Due to its poor bioavailability, nanocarriers have been developed for enhancing its ability in cancer suppression. These issues have been discussed in the present review with a focus on molecular pathways to pave the way for rapid translation of CA for clinical use.
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Affiliation(s)
- Sepideh Mirzaei
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | | | - Amirhossein Zabolian
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Hossein Saleki
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | | | | | - Fatemeh Bakhtiari Far
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Seyed Omid Sharifzadeh
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Saeed Samarghandian
- Department of Basic Medical Sciences, Neyshabur University of Medical Sciences, Neyshabur, Iran
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University, Mardan 23200, Pakistan
| | - Amir Reza Aref
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Vice President at Translational Sciences, Xsphera Biosciences Inc. 6 Tide Street, Boston, MA, 02210, USA
| | - Milad Ashrafizadeh
- Faculty of Engineering and Natural Sciences, Sabanci University, Orta Mahalle, Üniversite Caddesi No. 27, Orhanlı, Tuzla, 34956 Istanbul, Turkey; Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, 34956, Istanbul, Turkey.
| | - Ali Zarrabi
- Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, 34956, Istanbul, Turkey.
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Cancer Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
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Khan F, Bamunuarachchi NI, Tabassum N, Kim YM. Caffeic Acid and Its Derivatives: Antimicrobial Drugs toward Microbial Pathogens. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2021; 69:2979-3004. [PMID: 33656341 DOI: 10.1021/acs.jafc.0c07579] [Citation(s) in RCA: 121] [Impact Index Per Article: 30.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/11/2023]
Abstract
Caffeic acid is a plant-derived compound that is classified as hydroxycinnamic acid which contains both phenolic and acrylic functional groups. Caffeic acid has been greatly employed as an alternative strategy to combat microbial pathogenesis and chronic infection induced by microbes such as bacteria, fungi, and viruses. Similarly, several derivatives of caffeic acid such as sugar esters, organic esters, glycosides, and amides have been chemically synthesized or naturally isolated as potential antimicrobial agents. To overcome the issue of water insolubility and poor stability, caffeic acid and its derivative have been utilized either in conjugation with other bioactive molecules or in nanoformulation. Besides, caffeic acid and its derivatives have also been applied in combination with antibiotics or photoirradiation to achieve a synergistic mode of action. The present review describes the antimicrobial roles of caffeic acid and its derivatives exploited either in free form or in combination or in nanoformulation to kill a diverse range of microbial pathogens along with their mode of action. The chemistry employed for the synthesis of the caffeic acid derivatives has been discussed in detail as well.
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Affiliation(s)
- Fazlurrahman Khan
- Institute of Food Science, Pukyong National University, Busan 48513, South Korea
| | - Nilushi Indika Bamunuarachchi
- Department of Food Science and Technology, Pukyong National University, Busan 48513, South Korea
- Department of Fisheries and Marine Sciences, Ocean University of Sri Lanka, Tangalle 82200, Sri Lanka
| | - Nazia Tabassum
- Industrial Convergence Bionix Engineering, Pukyong National University, Busan 48513, South Korea
| | - Young-Mog Kim
- Institute of Food Science, Pukyong National University, Busan 48513, South Korea
- Department of Food Science and Technology, Pukyong National University, Busan 48513, South Korea
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Li S, Liang C, Liu G, Jin JM, Tao Y, Tang SY. De Novo Biosynthesis of Chlorogenic Acid Using an Artificial Microbial Community. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2021; 69:2816-2825. [PMID: 33629856 DOI: 10.1021/acs.jafc.0c07588] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Engineering an artificial microbial community for natural product production is a promising strategy. As mono- and dual-culture systems only gave non-detectable or minimal chlorogenic acid (CGA) biosynthesis, here, a polyculture of three recombinant Escherichia coli strains, acting as biosynthetic modules of caffeic acid (CA), quinic acid (QA), and CGA, was designed and used for de novo CGA biosynthesis. An influx transporter of 3-dehydroshikimic acid (DHS)/shikimic acid (SA), ShiA, was introduced into the QA module-a DHS auxotroph. The QA module proportion in the polyculture and CGA production were found to be dependent on ShiA expression, providing an alternative approach for controlling microbial community composition. The polyculture strategy avoids metabolic flux competition in the biosynthesis of two CGA precursors, CA and QA, and allows production improvement by balancing module proportions. The performance of this polyculture approach was superior to that of previously reported approaches of de novo CGA production.
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Affiliation(s)
- Shizhong Li
- CAS Key Laboratory of Microbial Physiological and Metabolic Engineering, State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Chaoning Liang
- CAS Key Laboratory of Microbial Physiological and Metabolic Engineering, State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
| | - Guoxia Liu
- CAS Key Laboratory of Microbial Physiological and Metabolic Engineering, State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
| | - Jian-Ming Jin
- Beijing Key Laboratory of Plant Resources Research and Development, Beijing Technology and Business University, Beijing 100048, China
| | - Yong Tao
- CAS Key Laboratory of Microbial Physiological and Metabolic Engineering, State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
| | - Shuang-Yan Tang
- CAS Key Laboratory of Microbial Physiological and Metabolic Engineering, State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
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40
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Xu Y, Li Y, Li L, Zhang L, Ding Z, Shi G. Reductase-catalyzed tetrahydrobiopterin regeneration alleviates the anti-competitive inhibition of tyrosine hydroxylation by 7,8-dihydrobiopterin. Catal Sci Technol 2021. [DOI: 10.1039/d0cy01958e] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
l-Tyrosine hydroxylation by tyrosine hydroxylase is a significant reaction for preparing many nutraceutical and pharmaceutical chemicals.
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Affiliation(s)
- Yinbiao Xu
- Key Laboratory of Industrial Biotechnology
- Ministry of Education
- School of Biotechnology
- Jiangnan University
- Wuxi
| | - Youran Li
- Key Laboratory of Industrial Biotechnology
- Ministry of Education
- School of Biotechnology
- Jiangnan University
- Wuxi
| | - Leyun Li
- Key Laboratory of Industrial Biotechnology
- Ministry of Education
- School of Biotechnology
- Jiangnan University
- Wuxi
| | - Liang Zhang
- Key Laboratory of Industrial Biotechnology
- Ministry of Education
- School of Biotechnology
- Jiangnan University
- Wuxi
| | - Zhongyang Ding
- Key Laboratory of Industrial Biotechnology
- Ministry of Education
- School of Biotechnology
- Jiangnan University
- Wuxi
| | - Guiyang Shi
- Key Laboratory of Industrial Biotechnology
- Ministry of Education
- School of Biotechnology
- Jiangnan University
- Wuxi
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41
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Bounegru AV, Apetrei C. Voltamperometric Sensors and Biosensors Based on Carbon Nanomaterials Used for Detecting Caffeic Acid-A Review. Int J Mol Sci 2020; 21:E9275. [PMID: 33291758 PMCID: PMC7730703 DOI: 10.3390/ijms21239275] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 12/01/2020] [Accepted: 12/02/2020] [Indexed: 12/11/2022] Open
Abstract
Caffeic acid is one of the most important hydroxycinnamic acids found in various foods and plant products. It has multiple beneficial effects in the human body such as antioxidant, antibacterial, anti-inflammatory, and antineoplastic. Since overdoses of caffeic acid may have negative effects, the quality and quantity of this acid in foods, pharmaceuticals, food supplements, etc., needs to be accurately determined. The present paper analyzes the most representative scientific papers published mostly in the last 10 years which describe the development and characterization of voltamperometric sensors or biosensors based on carbon nanomaterials and/or enzyme commonly used for detecting caffeic acid and a series of methods which may improve the performance characteristics of such sensors.
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Affiliation(s)
| | - Constantin Apetrei
- Department of Chemistry, Physics and Environment, Faculty of Sciences and Environment, “Dunărea de Jos” University of Galaţi, 47 Domnească Street, 800008 Galaţi, Romania;
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Liang W, Xiong T, Wang X, Deng H, Bai Y, Fan TP, Zheng X, Cai Y. A novel feruloyl esterase with high rosmarinic acid hydrolysis activity from Bacillus pumilus W3. Int J Biol Macromol 2020; 161:525-530. [PMID: 32531366 DOI: 10.1016/j.ijbiomac.2020.06.038] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 05/29/2020] [Accepted: 06/04/2020] [Indexed: 11/16/2022]
Abstract
A novel feruloyl esterase (BpFae12) with rosmarinic acid (RA) hydrolysis activity was isolated from Bacillus pumilus W3 and expressed in Escherichia coli BL21 (DE3). With RA as a substrate, the optimal pH and temperature of BpFae12 were pH 8.0 and 50 °C, respectively. The specific enzyme activity was 12.8 U·mg-1. BpFae12 showed the highest activity and substrate affinity toward RA (Vmax of 13.13 U·mg-1, Km of 0.41 mM). Moreover, it also presented strong hydrolysis performance against chlorogenic acid (190.17 U·mg-1). RA was effectively Hydrolyzed into more bioactive caffeic acid and 3,4-dihydroxyphenyllactic acid by BpFae12, which have potential applications in the food industry.
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Affiliation(s)
- Weiyue Liang
- The Key Laboratory of Industrial Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China
| | - Tianzhen Xiong
- The Key Laboratory of Industrial Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China
| | - Xiaomei Wang
- The Key Laboratory of Industrial Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China
| | - Huaxiang Deng
- The Key Laboratory of Industrial Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China
| | - Yajun Bai
- College of Life Sciences, Northwest University, Xi'an, Shanxi 710069, China
| | - Tai-Ping Fan
- Department of Pharmacology, University of Cambridge, Cambridge CB2 1T, UK
| | - Xiaohui Zheng
- College of Life Sciences, Northwest University, Xi'an, Shanxi 710069, China.
| | - Yujie Cai
- The Key Laboratory of Industrial Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China.
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Babaei M, Borja Zamfir GM, Chen X, Christensen HB, Kristensen M, Nielsen J, Borodina I. Metabolic Engineering of Saccharomyces cerevisiae for Rosmarinic Acid Production. ACS Synth Biol 2020; 9:1978-1988. [PMID: 32589831 PMCID: PMC8961883 DOI: 10.1021/acssynbio.0c00048] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Indexed: 02/08/2023]
Abstract
Rosmarinic acid is a hydroxycinnamic acid ester commonly found in the Boraginaceae and Lamiaceae plant families. It exhibits various biological activities, including antioxidant, anti-inflammatory, antibacterial, antiallergic, and antiviral properties. Rosmarinic acid is used as a food and cosmetic ingredient, and several pharmaceutical applications have been suggested as well. Rosmarinic acid is currently produced by extraction from plants or chemical synthesis; however, due to limited availability of the plant sources and the complexity of the chemical synthesis method, there is an increasing interest in producing this compound by microbial fermentation. In this study, we aimed to produce rosmarinic acid by engineered baker's yeast Saccharomyces cerevisiae. Multiple biosynthetic pathway variants, carrying only plant genes or a combination of plant and Escherichia coli genes, were implemented using a full factorial design of experiment. Through analysis of variances, the effect of each enzyme variant (factors), together with possible interactions between these factors, was assessed. The best pathway variant produced 2.95 ± 0.08 mg/L rosmarinic acid in mineral medium with glucose as the sole carbon source. Increasing the copy number of rosmarinic acid biosynthetic genes increased the titer to 5.93 ± 0.06 mg/L. The study shows the feasibility of producing rosmarinic acid by yeast fermentation.
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Affiliation(s)
- Mahsa Babaei
- The
Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kemitorvet Building 220, DK-2800 Kgs. Lyngby, Denmark
| | - Gheorghe M. Borja Zamfir
- The
Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kemitorvet Building 220, DK-2800 Kgs. Lyngby, Denmark
| | - Xiao Chen
- The
Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kemitorvet Building 220, DK-2800 Kgs. Lyngby, Denmark
| | - Hanne Bjerre Christensen
- The
Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kemitorvet Building 220, DK-2800 Kgs. Lyngby, Denmark
| | - Mette Kristensen
- The
Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kemitorvet Building 220, DK-2800 Kgs. Lyngby, Denmark
| | - Jens Nielsen
- The
Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kemitorvet Building 220, DK-2800 Kgs. Lyngby, Denmark
- Department
of Biology and Biological Engineering, Chalmers
University of Technology, 412 96, Gothenburg, Sweden
- BioInnovation
Institute, Ole Måløes
Vej 3, 2200, Copenhagen
N, Denmark
| | - Irina Borodina
- The
Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kemitorvet Building 220, DK-2800 Kgs. Lyngby, Denmark
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Hou Y, Liu X, Li S, Zhang X, Yu S, Zhao GR. Metabolic Engineering of Escherichia coli for de Novo Production of Betaxanthins. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2020; 68:8370-8380. [PMID: 32627549 DOI: 10.1021/acs.jafc.0c02949] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/22/2023]
Abstract
Betalains are emerging natural pigments with high tinctorial strength and stability, physiological activities, and fluorescent properties for potential application in food, cosmetic, and pharmaceutical industries. Betalains including yellow betaxanthins and red betacyanins are mainly restricted in the Caryophyllales plants. To expand the availability of individual betaxanthins, here, we constructed an Escherichia coli BTA6 for de novo biosynthesis of betalamic acid. Using this strain as a monoculture platform, 14 yellow and 2 red betaxanthins were produced by feeding amino acids and amines. Furthermore, we constructed an l-histidine overproducing strain using chromosome engineering to deattenuate regulation and established a coculture system. After optimization of the initial inoculation ratios and fermentation conditions, the compatible and robust coculture system produced 287.69 mg/L of histidine-betaxanthin. This is the first report on de novo production of betaxanthins in engineered E. coli using glucose as a carbon source. Our work highlights the feasibility of microbial cell factories to produce individual betalains.
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Affiliation(s)
- Yanan Hou
- Frontier Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), School of Chemical Engineering and Technology, Tianjin University, Yaguan Road 135, Jinnan District, Tianjin 300350, China
| | - Xue Liu
- Frontier Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), School of Chemical Engineering and Technology, Tianjin University, Yaguan Road 135, Jinnan District, Tianjin 300350, China
| | - Shilin Li
- Frontier Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), School of Chemical Engineering and Technology, Tianjin University, Yaguan Road 135, Jinnan District, Tianjin 300350, China
| | - Xue Zhang
- Frontier Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), School of Chemical Engineering and Technology, Tianjin University, Yaguan Road 135, Jinnan District, Tianjin 300350, China
| | - Sili Yu
- Frontier Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), School of Chemical Engineering and Technology, Tianjin University, Yaguan Road 135, Jinnan District, Tianjin 300350, China
| | - Guang-Rong Zhao
- Frontier Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), School of Chemical Engineering and Technology, Tianjin University, Yaguan Road 135, Jinnan District, Tianjin 300350, China
- SynBio Research Platform, Collaborative Innovation Centre of Chemical Science and Engineering (Tianjin), Tianjin University, Yaguan Road 135, Jinnan District, Tianjin 300350, China
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Stănciuc N, Râpeanu G, Bahrim GE, Aprodu I. The Interaction of Bovine β-Lactoglobulin with Caffeic Acid: From Binding Mechanisms to Functional Complexes. Biomolecules 2020; 10:biom10081096. [PMID: 32718063 PMCID: PMC7464270 DOI: 10.3390/biom10081096] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Revised: 07/17/2020] [Accepted: 07/20/2020] [Indexed: 01/06/2023] Open
Abstract
In this study, the interaction of native and transglutaminase (Tgase) cross-linked β-lactoglobulin (β-LG) with caffeic acid (CA) was examined, aiming to obtain functional composites. Knowledge on the binding affinity and interaction mechanism was provided by performing fluorescence spectroscopy measurements, after heating the native and cross-linked protein at temperatures ranging from 25 to 95 °C. Regardless of the protein aggregation state, a static quenching mechanism of intrinsic fluorescence of β-LG by CA was established. The decrease of the Stern–Volmer constants with the temperature increase indicating the facile dissociation of the weakly bound complexes. The thermodynamic analysis suggested the existence of multiple contact types, such as Van der Waals’ force and hydrogen bonds, between β-LG and CA. Further molecular docking tests indicated the existence of various CA binding sites on the β-LG surface heat-treated at different temperatures. Anyway, regardless of the simulated temperature, the CA-β-LG assemblies appeared to be unstable. Compared to native protein, the CA-β-LG and CA-β-LGTgase complexes (ratio 1:1) exhibited significantly higher antioxidant activity and inhibitory effects on α-glucosidase, α-amylase, and pancreatic lipase, enzymes associated with metabolic syndrome. These findings might help the knowledge-based development of novel food ingredients with valuable biological properties.
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Valanciene E, Jonuskiene I, Syrpas M, Augustiniene E, Matulis P, Simonavicius A, Malys N. Advances and Prospects of Phenolic Acids Production, Biorefinery and Analysis. Biomolecules 2020; 10:E874. [PMID: 32517243 PMCID: PMC7356249 DOI: 10.3390/biom10060874] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 05/28/2020] [Accepted: 06/03/2020] [Indexed: 12/20/2022] Open
Abstract
Biotechnological production of phenolic acids is attracting increased interest due to their superior antioxidant activity, as well as other antimicrobial, dietary, and health benefits. As secondary metabolites, primarily found in plants and fungi, they are effective free radical scavengers due to the phenolic group available in their structure. Therefore, phenolic acids are widely utilised by pharmaceutical, food, cosmetic, and chemical industries. A demand for phenolic acids is mostly satisfied by utilising chemically synthesised compounds, with only a low quantity obtained from natural sources. As an alternative to chemical synthesis, environmentally friendly bio-based technologies are necessary for development in large-scale production. One of the most promising sustainable technologies is the utilisation of microbial cell factories for biosynthesis of phenolic acids. In this paper, we perform a systematic comparison of the best known natural sources of phenolic acids. The advances and prospects in the development of microbial cell factories for biosynthesis of these bioactive compounds are discussed in more detail. A special consideration is given to the modern production methods and analytics of phenolic acids.
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Affiliation(s)
| | | | | | | | | | | | - Naglis Malys
- Bioprocess Research Centre, Faculty of Chemical Technology, Kaunas University of Technology, Radvilėnų pl. 19, Kaunas LT-50254, Lithuania; (E.V.); (I.J.); (M.S.); (E.A.); (P.M.); (A.S.)
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Shen YP, Niu FX, Yan ZB, Fong LS, Huang YB, Liu JZ. Recent Advances in Metabolically Engineered Microorganisms for the Production of Aromatic Chemicals Derived From Aromatic Amino Acids. Front Bioeng Biotechnol 2020; 8:407. [PMID: 32432104 PMCID: PMC7214760 DOI: 10.3389/fbioe.2020.00407] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Accepted: 04/14/2020] [Indexed: 12/16/2022] Open
Abstract
Aromatic compounds derived from aromatic amino acids are an important class of diverse chemicals with a wide range of industrial and commercial applications. They are currently produced via petrochemical processes, which are not sustainable and eco-friendly. In the past decades, significant progress has been made in the construction of microbial cell factories capable of effectively converting renewable carbon sources into value-added aromatics. Here, we systematically and comprehensively review the recent advancements in metabolic engineering and synthetic biology in the microbial production of aromatic amino acid derivatives, stilbenes, and benzylisoquinoline alkaloids. The future outlook concerning the engineering of microbial cell factories for the production of aromatic compounds is also discussed.
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Affiliation(s)
- Yu-Ping Shen
- Guangdong Province Key Laboratory of Improved Variety Reproduction in Aquatic Economic Animals, Biomedical Center, School of Life Sciences, Institute of Synthetic Biology, Sun Yat-sen University, Guangzhou, China
| | - Fu-Xing Niu
- Guangdong Province Key Laboratory of Improved Variety Reproduction in Aquatic Economic Animals, Biomedical Center, School of Life Sciences, Institute of Synthetic Biology, Sun Yat-sen University, Guangzhou, China
| | - Zhi-Bo Yan
- Guangdong Province Key Laboratory of Improved Variety Reproduction in Aquatic Economic Animals, Biomedical Center, School of Life Sciences, Institute of Synthetic Biology, Sun Yat-sen University, Guangzhou, China
| | - Lai San Fong
- Guangdong Province Key Laboratory of Improved Variety Reproduction in Aquatic Economic Animals, Biomedical Center, School of Life Sciences, Institute of Synthetic Biology, Sun Yat-sen University, Guangzhou, China
| | - Yuan-Bin Huang
- Guangdong Province Key Laboratory of Improved Variety Reproduction in Aquatic Economic Animals, Biomedical Center, School of Life Sciences, Institute of Synthetic Biology, Sun Yat-sen University, Guangzhou, China
| | - Jian-Zhong Liu
- Guangdong Province Key Laboratory of Improved Variety Reproduction in Aquatic Economic Animals, Biomedical Center, School of Life Sciences, Institute of Synthetic Biology, Sun Yat-sen University, Guangzhou, China
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Song W, Chen X, Wu J, Xu J, Zhang W, Liu J, Chen J, Liu L. Biocatalytic derivatization of proteinogenic amino acids for fine chemicals. Biotechnol Adv 2020; 40:107496. [DOI: 10.1016/j.biotechadv.2019.107496] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 11/13/2019] [Accepted: 11/18/2019] [Indexed: 01/09/2023]
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Cao M, Gao M, Suástegui M, Mei Y, Shao Z. Building microbial factories for the production of aromatic amino acid pathway derivatives: From commodity chemicals to plant-sourced natural products. Metab Eng 2020; 58:94-132. [DOI: 10.1016/j.ymben.2019.08.008] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 08/03/2019] [Accepted: 08/07/2019] [Indexed: 01/23/2023]
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Braga A, Faria N. Bioprocess Optimization for the Production of Aromatic Compounds With Metabolically Engineered Hosts: Recent Developments and Future Challenges. Front Bioeng Biotechnol 2020; 8:96. [PMID: 32154231 PMCID: PMC7044121 DOI: 10.3389/fbioe.2020.00096] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Accepted: 02/03/2020] [Indexed: 12/18/2022] Open
Abstract
The most common route to produce aromatic chemicals - organic compounds containing at least one benzene ring in their structure - is chemical synthesis. These processes, usually starting from an extracted fossil oil molecule such as benzene, toluene, or xylene, are highly environmentally unfriendly due to the use of non-renewable raw materials, high energy consumption and the usual production of toxic by-products. An alternative way to produce aromatic compounds is extraction from plants. These extractions typically have a low yield and a high purification cost. This motivates the search for alternative platforms to produce aromatic compounds through low-cost and environmentally friendly processes. Microorganisms are able to synthesize aromatic amino acids through the shikimate pathway. The construction of microbial cell factories able to produce the desired molecule from renewable feedstock becomes a promising alternative. This review article focuses on the recent advances in microbial production of aromatic products, with a special emphasis on metabolic engineering strategies, as well as bioprocess optimization. The recent combination of these two techniques has resulted in the development of several alternative processes to produce phenylpropanoids, aromatic alcohols, phenolic aldehydes, and others. Chemical species that were unavailable for human consumption due to the high cost and/or high environmental impact of their production, have now become accessible.
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Affiliation(s)
- Adelaide Braga
- Centre of Biological Engineering, University of Minho, Braga, Portugal
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