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Im SB, Song HN, Jeong TK, Kim N, Kim K, Park SJ, Oh BH. Cryo-EM Structure of Human Hyaluronidase PH-20. Proteins 2025; 93:1067-1073. [PMID: 39722545 DOI: 10.1002/prot.26788] [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: 10/14/2024] [Revised: 12/08/2024] [Accepted: 12/16/2024] [Indexed: 12/28/2024]
Abstract
PH-20 is a specific type of hyaluronidase that plays a critical role in the fertilization process by facilitating the initial binding of sperm to the glycoprotein layer surrounding the oocyte and subsequently breaking down hyaluronic acid polymers in the cumulus cell layer. PH-20 contains an epidermal growth factor (EGF)-like domain, which may be involved in the recognition of the glycoprotein layer in addition to the catalytic domain. Herein, we report the structure of human PH-20 determined by cryogenic electron microscopy. Comparative analyses of the PH-20 structure with two other available hyaluronidase structures reveal a general similarity in the central catalytic domains, including the conservation of catalytically essential residues at the equivalent spatial positions. However, unique difference is found in the EGF-like domain, characterized by a longer sequence that is likely to form a flexibly anchored β-hairpin containing a disulfide bond.
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Affiliation(s)
- Seong-Bin Im
- Department of Biological Sciences, KAIST Institute for the Biocentury, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
| | | | - Tae-Kyeong Jeong
- Department of Biological Sciences, KAIST Institute for the Biocentury, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
| | - Nayun Kim
- Department of Biological Sciences, KAIST Institute for the Biocentury, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
| | | | | | - Byung-Ha Oh
- Department of Biological Sciences, KAIST Institute for the Biocentury, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
- Graduate Program of Engineering Biology, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
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Chen X, Wang Y, Li H, Deng Y, Giang C, Song A, Liu Y, Wang QA, Zhu Y. Hyaluronan Mediates Cold-Induced Adipose Tissue Beiging. Cells 2024; 13:1233. [PMID: 39120264 PMCID: PMC11311271 DOI: 10.3390/cells13151233] [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: 05/30/2024] [Revised: 07/17/2024] [Accepted: 07/19/2024] [Indexed: 08/10/2024] Open
Abstract
Adipose tissue beiging refers to the process by which beige adipocytes emerge in classical white adipose tissue depots. Beige adipocytes dissipate chemical energy and secrete adipokines, such as classical brown adipocytes, to improve systemic metabolism, which is beneficial for people with obesity and metabolic diseases. Cold exposure and β3-adrenergic receptor (AR) agonist treatment are two commonly used stimuli for increasing beige adipocytes in mice; however, their underlying biological processes are different. Transcriptional analysis of inguinal white adipose tissue (iWAT) has revealed that changes in extracellular matrix (ECM) pathway genes are specific to cold exposure. Hyaluronic acid (HA), a non-sulfated linear polysaccharide produced by nearly all cells, is one of the most common components of ECM. We found that cold exposure significantly increased iWAT HA levels, whereas the β3-AR agonist CL316,243 did not. Increasing HA levels in iWAT by Has2 overexpression significantly increases cold-induced adipose tissue beiging; in contrast, decreasing HA by Spam1 overexpression, which encodes a hyaluronidase that digests HA, significantly decreases cold-induced iWAT beiging. All these data implicate a role of HA in promoting adipose tissue beiging, which is unique to cold exposure. Given the failure of β3-AR agonists in clinical trials for obesity and metabolic diseases, increasing HA could serve as a new approach for recruiting more beige adipocytes to combat metabolic diseases.
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Affiliation(s)
- Xi Chen
- USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Yifan Wang
- Department of Molecular Endocrinology, Diabetes and Metabolism Institute, City of Hope Medical Center, Duarte, CA 91010, USA
| | - Huiqiao Li
- USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Yanru Deng
- USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Charlise Giang
- USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Anying Song
- Department of Molecular Endocrinology, Diabetes and Metabolism Institute, City of Hope Medical Center, Duarte, CA 91010, USA
| | - Yu’e Liu
- Tongji University Cancer Center, School of Medicine, Tongji University, Shanghai 200092, China
| | - Qiong A. Wang
- Department of Molecular Endocrinology, Diabetes and Metabolism Institute, City of Hope Medical Center, Duarte, CA 91010, USA
| | - Yi Zhu
- USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
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Bhattacharyya M, Jariyal H, Srivastava A. Hyaluronic acid: More than a carrier, having an overpowering extracellular and intracellular impact on cancer. Carbohydr Polym 2023; 317:121081. [PMID: 37364954 DOI: 10.1016/j.carbpol.2023.121081] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 05/23/2023] [Accepted: 05/29/2023] [Indexed: 06/28/2023]
Abstract
Hyaluronic acid (HA), also named hyaluronan, is an omnipresent component of the tissue microenvironment. It is extensively used to formulate targeted drug delivery systems for cancer. Although HA itself has pivotal influences in various cancers, its calibers are somewhat neglected when using it as delivering platform to treat cancer. In the last decade, multiple studies revealed roles of HA in cancer cell proliferation, invasion, apoptosis, and dormancy through pathways like mitogen-activated protein kinase-extracellular signal-regulated kinase (MAPK/ERK), P38, and nuclear factor kappa-light chain-enhancer of activated B cells (NFκB). A more fascinating fact is that the distinct molecular weight (MW) of HA exerts disparate effects on the same type of cancer. Its overwhelming use in cancer therapy and other therapeutic products make collective research on the sundry impact of it on various types of cancer, an essential aspect to be considered in all of these domains. Even the development of new therapies against cancer needed meticulous studies on HA because of its divergence of activity based on MW. This review will provide painstaking insight into the extracellular and intracellular bioactivity of HA, its modified forms, and its MW in cancers, which may improve the management of cancer.
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Affiliation(s)
- Medha Bhattacharyya
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research-Ahmedabad, Gandhinagar, Gujarat, India
| | - Heena Jariyal
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research-Ahmedabad, Gandhinagar, Gujarat, India
| | - Akshay Srivastava
- Department of Medical Device, National Institute of Pharmaceutical Education and Research-Ahmedabad, Gandhinagar, Gujarat, India.
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Lafont S, Achouri Y, Cardinal M, Roels T, de Ville de Goyet C, Behets C, Manicourt D. Knockout of hyaluronidase Spam1 reduces age-related bone and cartilage changes in mouse knee. Morphologie 2020; 104:151-157. [PMID: 32224028 DOI: 10.1016/j.morpho.2020.03.001] [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: 12/23/2019] [Revised: 02/11/2020] [Accepted: 03/02/2020] [Indexed: 06/10/2023]
Abstract
OBJECTIVE To investigate the role of Spam1 hyaluronidase in age-related bone and cartilage changes in the mouse knee. DESIGN Spam1-/- and WT mice were euthanised at different ages from 10 to 52 weeks. The right hindlimbs were dissected, scanned with peripheral Quantitative Computed Tomography (pQCT) and then decalcified for histological analysis (modified Mankin score). In other mice, cartilages of both tibiae were sampled at 10, 30 and 52 weeks of age for RNA extraction and qPCR analysis. We assessed the expression of hyaluronidases Hyal1 and Hyal2, hyaluronan synthase HAS2, extracellular matrix proteases Mmp13 and Adamts-5, and type 2 collagen. RESULTS Spam1-/- mice did not exhibit specific morphological characters up to 52 weeks of age. From 20 weeks, the proximal tibia of Spam1-/- mice had a significantly lower bone mineral density than WT mice. At 52 weeks, the modified Mankin score was significantly lower in Spam1-/- than WT mice. Spam1-/- chondrocytes expressed significantly less Hyal2 than WT ones at all ages and less Mmp13 at 52 weeks. Through all the experiment, the Hyal1 expression of Spam1-/- chondrocytes remained similar as that of WT chondrocytes. CONCLUSION Spam1 knockout reduced significantly cartilage degradation in mouse knee whereas the chondrocyte expression of Hyal 1, Hyal 2 and Mmp13 was modified, suggesting a role of this hyaluronidase in cartilage metabolism.
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Affiliation(s)
- S Lafont
- Pole of Morphology-Institut de recherche expérimentale et Clinique - Université Catholique de Louvain, Brussels, Belgium.
| | - Y Achouri
- Institut de Duve, Université catholique de Louvain, Brussels, Belgium
| | - M Cardinal
- Pole of Morphology-Institut de recherche expérimentale et Clinique - Université Catholique de Louvain, Brussels, Belgium
| | - T Roels
- Pole of Morphology-Institut de recherche expérimentale et Clinique - Université Catholique de Louvain, Brussels, Belgium
| | - C de Ville de Goyet
- Pole of Morphology-Institut de recherche expérimentale et Clinique - Université Catholique de Louvain, Brussels, Belgium
| | - C Behets
- Pole of Morphology-Institut de recherche expérimentale et Clinique - Université Catholique de Louvain, Brussels, Belgium
| | - D Manicourt
- Pole of Systemic and Inflammatory Rheumatic Diseases-Institut de recherche expérimentale et Clinique - Université Catholique de Louvain, Brussels, Belgium
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Su W, Matsumoto S, Banine F, Srivastava T, Dean J, Foster S, Pham P, Hammond B, Peters A, Girish KS, Rangappa KS, Basappa S, Jose J, Hennebold JD, Murphy MJ, Bennett-Toomey J, Back SA, Sherman LS. A modified flavonoid accelerates oligodendrocyte maturation and functional remyelination. Glia 2020; 68:263-279. [PMID: 31490574 PMCID: PMC8693768 DOI: 10.1002/glia.23715] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Revised: 08/06/2019] [Accepted: 08/15/2019] [Indexed: 12/19/2022]
Abstract
Myelination delay and remyelination failure following insults to the central nervous system (CNS) impede axonal conduction and lead to motor, sensory and cognitive impairments. Both myelination and remyelination are often inhibited or delayed due to the failure of oligodendrocyte progenitor cells (OPCs) to mature into myelinating oligodendrocytes (OLs). Digestion products of the glycosaminoglycan hyaluronan (HA) have been implicated in blocking OPC maturation, but how these digestion products are generated is unclear. We tested the possibility that hyaluronidase activity is directly linked to the inhibition of OPC maturation by developing a novel modified flavonoid that functions as a hyaluronidase inhibitor. This compound, called S3, blocks some but not all hyaluronidases and only inhibits matrix metalloproteinase activity at high concentrations. We find that S3 reverses HA-mediated inhibition of OPC maturation in vitro, an effect that can be overcome by excess recombinant hyaluronidase. Furthermore, we find that hyaluronidase inhibition by S3 accelerates OPC maturation in an in vitro model of perinatal white matter injury. Finally, blocking hyaluronidase activity with S3 promotes functional remyelination in mice with lysolecithin-induced demyelinating corpus callosum lesions. All together, these findings support the notion that hyaluronidase activity originating from OPCs in CNS lesions is sufficient to prevent OPC maturation, which delays myelination or blocks remyelination. These data also indicate that modified flavonoids can act as selective inhibitors of hyaluronidase activity and can promote OPC maturation, making them excellent candidates to accelerate myelination or promote remyelination following perinatal and adult CNS insults.
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Affiliation(s)
- Weiping Su
- Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, USA
| | - Steven Matsumoto
- Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, USA
- Integrative Biosciences Department, School Dentistry, Oregon Health & Science University, USA
| | - Fatima Banine
- Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, USA
| | | | - Justin Dean
- Department of Physiology, Faculty of Medical and Health Sciences, University of Auckland, New Zealand
| | - Scott Foster
- Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, USA
| | - Peter Pham
- Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, USA
| | - Brian Hammond
- Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, USA
| | - Alec Peters
- Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, USA
| | - Kesturu S. Girish
- Department of Studies and Research in Biochemistry, Tumkur University, Tumakuru, India
| | | | - Salundi Basappa
- Department of Studies in Organic Chemistry, University of Mysore, Manasagangotri, Mysuru, India
| | - Joachim Jose
- Institute of Pharmaceutical and Medicinal Chemistry, Phytochemistry, PharmaCampus, Westfälische Wilhelms-Universität Münster, Münster, Germany
| | - Jon D. Hennebold
- Division of Reproductive & Developmental Sciences, Oregon National Primate Research Center, Oregon Health & Science University, USA
| | - Melinda J. Murphy
- Division of Reproductive & Developmental Sciences, Oregon National Primate Research Center, Oregon Health & Science University, USA
| | - Jill Bennett-Toomey
- Division of Reproductive & Developmental Sciences, Oregon National Primate Research Center, Oregon Health & Science University, USA
| | - Stephen A. Back
- Department of Pediatrics, Oregon Health & Science University, USA
- Department of Neurology, Oregon Health & Science University, USA
| | - Larry S. Sherman
- Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, USA
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, USA
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Silva F, Huang Y, Yang V, Mu X, Shi Q, Antunes A. Transcriptomic Characterization of the South American Freshwater Stingray Potamotrygon motoro Venom Apparatus. Toxins (Basel) 2018; 10:E544. [PMID: 30567320 PMCID: PMC6315956 DOI: 10.3390/toxins10120544] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Revised: 12/14/2018] [Accepted: 12/14/2018] [Indexed: 01/16/2023] Open
Abstract
Venomous animals are found through a wide taxonomic range including cartilaginous fish such as the freshwater stingray Potamotrygon motoro occurring in South America, which can injure people and cause venom-related symptoms. Ensuring the efficacy of drug development to treat stingray injuries can be assisted by the knowledge of the venom composition. Here we performed a detailed transcriptomic characterization of the venom gland of the South American freshwater stingray Potamotrygon motoro. The transcripts retrieved showed 418 hits to venom components (comparably to 426 and 396 hits in other two Potamotrygon species), with high expression levels of hyaluronidase, cystatin and calglandulin along with hits uniquely found in P. motoro such as DELTA-alicitoxin-Pse1b, Augerpeptide hhe53 and PI-actitoxin-Aeq3a. We also identified undescribed molecules with extremely high expression values with sequence similarity to the SE-cephalotoxin and Rapunzel genes. Comparative analyses showed that despite being closely related, there may be significant variation among the venoms of freshwater stingrays, highlighting the importance of considering elicit care in handling different envenomation cases. Since hyaluronidase represents a major component of fish venom, we have performed phylogenetic and selective pressure analyses of this gene/protein across all fish with the available information. Results indicated an independent recruitment of the hyaluronidase into the stingray venom relative to that of venomous bony fish. The hyaluronidase residues were found to be mostly under negative selection, but 18 sites showed evidence of diversifying positive selection (P < 0.05). Our data provides new insight into stingray venom variation, composition, and selective pressure in hyaluronidase.
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Affiliation(s)
- Filipe Silva
- CIIMAR/CIMAR, Interdisciplinary Centre of Marine and Environmental Research, University of Porto, Av. General Norton de Matos, s/n, 4450-208 Porto, Portugal.
- Department of Biology, Faculty of Sciences, University of Porto, Rua do Campo Alegre, s/n, 4169-007 Porto, Portugal.
| | - Yu Huang
- Shenzhen Key Lab of Marine Genomics, Guangdong Provincial Key Lab of Molecular Breeding in Marine Economic Animals, BGI Academy of Marine Sciences, Shenzhen 518083, China.
- BGI Education Center, University of Chinese Academy of Sciences, Shenzhen 518083, China.
| | - Vítor Yang
- CIIMAR/CIMAR, Interdisciplinary Centre of Marine and Environmental Research, University of Porto, Av. General Norton de Matos, s/n, 4450-208 Porto, Portugal.
- Department of Biology, Faculty of Sciences, University of Porto, Rua do Campo Alegre, s/n, 4169-007 Porto, Portugal.
| | - Xidong Mu
- Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Key Laboratory of Recreational Fisheries, Ministry of Agriculture, Guangdong Engineering Technology Research Center for Advanced Recreational Fisheries, Guangzhou 510380, China.
| | - Qiong Shi
- Shenzhen Key Lab of Marine Genomics, Guangdong Provincial Key Lab of Molecular Breeding in Marine Economic Animals, BGI Academy of Marine Sciences, Shenzhen 518083, China.
- BGI Education Center, University of Chinese Academy of Sciences, Shenzhen 518083, China.
| | - Agostinho Antunes
- CIIMAR/CIMAR, Interdisciplinary Centre of Marine and Environmental Research, University of Porto, Av. General Norton de Matos, s/n, 4450-208 Porto, Portugal.
- Department of Biology, Faculty of Sciences, University of Porto, Rua do Campo Alegre, s/n, 4169-007 Porto, Portugal.
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Fouladi-Nashta AA, Raheem KA, Marei WF, Ghafari F, Hartshorne GM. Regulation and roles of the hyaluronan system in mammalian reproduction. Reproduction 2017; 153:R43-R58. [PMID: 27799626 DOI: 10.1530/rep-16-0240] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Revised: 10/14/2016] [Accepted: 10/26/2016] [Indexed: 01/04/2025]
Abstract
Hyaluronan (HA) is a non-sulphated glycosaminoglycan polymer naturally occurring in many tissues and fluids of mammals, including the reproductive system. Its biosynthesis by HA synthase (HAS1-3) and catabolism by hyaluronidases (HYALs) are affected by ovarian steroid hormones. Depending upon its molecular size, HA functions both as a structural component of tissues in the form of high-molecular-weight HA or as a signalling molecule in the form of small HA molecules or HA fragments with effects mediated through interaction with its specific cell-membrane receptors. HA is produced by oocytes and embryos and in various segments of the reproductive system. This review provides information about the expression and function of members of the HA system, including HAS, HYALs and HA receptors. We examine their role in various processes from folliculogenesis through oocyte maturation, fertilisation and early embryo development, to pregnancy and cervical dilation, as well as its application in assisted reproduction technologies. Particular emphasis has been placed upon the role of the HA system in pre-implantation embryo development and embryo implantation, for which we propose a hypothetical sequential model.
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Affiliation(s)
- Ali A Fouladi-Nashta
- Royal Veterinary CollegeReproduction Research Group, Hawkshead Campus, Hatfield, UK
| | - Kabir A Raheem
- Royal Veterinary CollegeReproduction Research Group, Hawkshead Campus, Hatfield, UK
- Department of Veterinary Surgery and TheriogenologyMichael Okpara University of Agriculture, Umudike, Nigeria
| | - Waleed F Marei
- Royal Veterinary CollegeReproduction Research Group, Hawkshead Campus, Hatfield, UK
- Department of TheriogenologyFaculty of Veterinary Medicine, Cairo University, Giza, Egypt
| | - Fataneh Ghafari
- Royal Veterinary CollegeReproduction Research Group, Hawkshead Campus, Hatfield, UK
| | - Geraldine M Hartshorne
- Warwick Medical SchoolUniversity of Warwick, Coventry, UK and Centre for Reproductive Medicine, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK
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Cheon YP, Kim CH. Impact of glycosylation on the unimpaired functions of the sperm. Clin Exp Reprod Med 2015; 42:77-85. [PMID: 26473106 PMCID: PMC4604297 DOI: 10.5653/cerm.2015.42.3.77] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2015] [Revised: 09/20/2015] [Accepted: 09/20/2015] [Indexed: 12/24/2022] Open
Abstract
One of the key factors of early development is the specification of competence between the oocyte and the sperm, which occurs during gametogenesis. However, the starting point, growth, and maturation for acquiring competence during spermatogenesis and oogenesis in mammals are very different. Spermatogenesis includes spermiogenesis, but such a metamorphosis is not observed during oogenesis. Glycosylation, a ubiquitous modification, is a preliminary requisite for distribution of the structural and functional components of spermatids for metamorphosis. In addition, glycosylation using epididymal or female genital secretory glycans is an important process for the sperm maturation, the acquisition of the potential for fertilization, and the acceleration of early embryo development. However, nonemzymatic unexpected covalent bonding of a carbohydrate and malglycosylation can result in falling fertility rates as shown in the diabetic male. So far, glycosylation during spermatogenesis and the dynamics of the plasma membrane in the process of capacitation and fertilization have been evaluated, and a powerful role of glycosylation in spermatogenesis and early development is also suggested by structural bioinformatics, functional genomics, and functional proteomics. Further understanding of glycosylation is needed to provide a better understanding of fertilization and embryo development and for the development of new diagnostic and therapeutic tools for infertility.
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Affiliation(s)
- Yong-Pil Cheon
- Division of Developmental Biology and Physiology, School of Biosciences and Chemistry, Sungshin Women's University, Seoul, Korea
| | - Chung-Hoon Kim
- Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea
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9
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Affiliation(s)
- Min Liu
- Department of Life Science and Graduate Institute of Biotechnology, Chinese Culture University, Taipei, Republic of China
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10
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Triggs-Raine B, Natowicz MR. Biology of hyaluronan: Insights from genetic disorders of hyaluronan metabolism. World J Biol Chem 2015; 6:110-120. [PMID: 26322170 PMCID: PMC4549756 DOI: 10.4331/wjbc.v6.i3.110] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2015] [Revised: 05/08/2015] [Accepted: 07/17/2015] [Indexed: 02/05/2023] Open
Abstract
Hyaluronan is a rapidly turned over component of the vertebrate extracellular matrix. Its levels are determined, in part, by the hyaluronan synthases, HAS1, HAS2, and HAS3, and three hyaluronidases, HYAL1, HYAL2 and HYAL3. Hyaluronan binding proteins also regulate hyaluronan levels although their involvement is less well understood. To date, two genetic disorders of hyaluronan metabolism have been reported in humans: HYAL1 deficiency (Mucopolysaccharidosis IX) in four individuals with joint pathology as the predominant phenotypic finding and HAS2 deficiency in a single person having cardiac pathology. However, inherited disorders and induced mutations affecting hyaluronan metabolism have been characterized in other species. Overproduction of hyaluronan by HAS2 results in skin folding and thickening in shar-pei dogs and the naked mole rat, whereas a complete deficiency of HAS2 causes embryonic lethality in mice due to cardiac defects. Deficiencies of murine HAS1 and HAS3 result in a predisposition to seizures. Like humans, mice with HYAL1 deficiency exhibit joint pathology. Mice lacking HYAL2 have variably penetrant developmental defects, including skeletal and cardiac anomalies. Thus, based on mutant animal models, a partial deficiency of HAS2 or HYAL2 might be compatible with survival in humans, while complete deficiencies of HAS1, HAS3, and HYAL3 may yet be recognized.
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11
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Schmaus A, Bauer J, Sleeman JP. Sugars in the microenvironment: the sticky problem of HA turnover in tumors. Cancer Metastasis Rev 2015; 33:1059-79. [PMID: 25324146 DOI: 10.1007/s10555-014-9532-2] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The properties and behavior of tumor cells are closely regulated by their microenvironment. Accordingly, stromal cells and extracellular matrix components can have a pronounced effect on cancer initiation, growth, and progression. The linear glycosaminoglycan hyaluronan (HA) is a major component of the extracellular matrix. Altered synthesis and degradation of HA in the tumor context has been implicated in many aspects of tumor biology. In particular, the accumulation of small HA oligosaccharides (sHA) in the tumor interstitial space may play a decisive role, due to the ability of sHA to activate a number of biological processes that are not modulated by high molecular weight (HMW)-HA. In this article, we review the normal physiological role and metabolism of HA and then survey the evidence implicating HA in tumor growth and progression, focusing in particular on the potential contribution of sHA to these processes.
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Affiliation(s)
- Anja Schmaus
- Institut für Toxikologie und Genetik, Karlsruhe Institute for Technology (KIT), Campus Nord, Postfach 3640, 76021, Karlsruhe, Germany
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12
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Ghosh S, Hoselton SA, Dorsam GP, Schuh JM. Hyaluronan fragments as mediators of inflammation in allergic pulmonary disease. Immunobiology 2014; 220:575-88. [PMID: 25582403 DOI: 10.1016/j.imbio.2014.12.005] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2014] [Revised: 12/10/2014] [Accepted: 12/15/2014] [Indexed: 12/22/2022]
Abstract
Asthma is frequently caused and/or exacerbated by sensitization to allergens, which are ubiquitous in many indoor and outdoor environments. Severe asthma is characterized by airway hyperresponsiveness and bronchial constriction in response to an inhaled allergen, leading to a disease course that is often very difficult to treat with standard asthma therapies. As a result of interactions among inflammatory cells, structural cells, and the intercellular matrix of the allergic lung, patients with sensitization to allergens may experience a greater degree of tissue injury followed by airway wall remodeling and progressive, accumulated pulmonary dysfunction as part of the disease sequela. In addition, turnover of extracellular matrix (ECM) components is a hallmark of tissue injury and repair. This review focuses on the role of the glycosaminoglycan hyaluronan (HA), a component of the ECM, in pulmonary injury and repair with an emphasis on allergic asthma. Both the synthesis and degradation of the ECM are critical contributors to tissue repair and remodeling. Fragmented HA accumulates during tissue injury and functions in ways distinct from the larger native polymer. There is gathering evidence that HA degradation products are active participants in stimulating the expression of inflammatory genes in a variety of immune cells at the injury site. In this review, we will consider recent advances in the understanding of the mechanisms that are associated with HA accumulation and inflammatory cell recruitment in the asthmatic lung.
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Affiliation(s)
- Sumit Ghosh
- Department of Veterinary and Microbiological Sciences, North Dakota State University, Fargo, ND 58108, USA.
| | - Scott A Hoselton
- Department of Veterinary and Microbiological Sciences, North Dakota State University, Fargo, ND 58108, USA
| | - Glenn P Dorsam
- Department of Veterinary and Microbiological Sciences, North Dakota State University, Fargo, ND 58108, USA
| | - Jane M Schuh
- Department of Veterinary and Microbiological Sciences, North Dakota State University, Fargo, ND 58108, USA
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Schmaus A, Sleeman JP. Hyaluronidase-1 expression promotes lung metastasis in syngeneic mouse tumor models without affecting accumulation of small hyaluronan oligosaccharides in tumor interstitial fluid. Glycobiology 2014; 25:258-68. [PMID: 25354852 DOI: 10.1093/glycob/cwu106] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Enhanced levels in tumors of hyaluronan, a glycosaminoglycan component of the extracellular matrix, and hyaluronidases such as hyaluronidase-1 (Hyal1) that degrade hyaluronan have both been linked to poor prognosis and metastasis, suggesting that the turnover of hyaluronan might contribute to tumor progression. Small hyaluronan oligosaccharides (sHA) can accumulate in tumor interstitial fluid (TIF), and have been implicated in a number of processes that drive tumor progression, including MMP expression and angiogenesis. The properties of Hyal1 suggest that it might contribute to the degradation of hyaluronan in tumors and the subsequent accumulation of sHA. Accumulation of Hyal1-produced sHA may therefore account for the association between Hyal1 and metastasis. Here we have investigated this hypothesis using mouse syngeneic breast tumor models. Specifically, we modulated Hyal1 expression and activity either in the tumor cells themselves, or in the stromal compartment by using Hyal1 knockout (KO) mice. These approaches did not change sHA levels in TIF, but nevertheless fostered metastasis to the lung in some of the models used in the study. Together, these data suggest that Hyal1 can promote lung metastasis in a manner that is not dependent on altered accumulation of sHA in TIF.
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Affiliation(s)
- Anja Schmaus
- Medical Faculty Mannheim, Centre for Biomedicine and Medical Technology Mannheim (CBTM), University of Heidelberg, Mannheim 68167, Germany Karlsruhe Institute of Technology (KIT), Campus Nord, Institut für Toxikologie und Genetik, Postfach 3640, Karlsruhe 76021, Germany
| | - Jonathan P Sleeman
- Medical Faculty Mannheim, Centre for Biomedicine and Medical Technology Mannheim (CBTM), University of Heidelberg, Mannheim 68167, Germany Karlsruhe Institute of Technology (KIT), Campus Nord, Institut für Toxikologie und Genetik, Postfach 3640, Karlsruhe 76021, Germany
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14
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YUDA Y, KASASHIMA Y, KUWANO A, SATO K, HATTORI S, ARAI K. Active Hyaluronidase 2 Expression in the Granulation Tissue Formed in the Healing Process of Equine Superficial Digital Flexor Tendonitis. J Vet Med Sci 2013; 75:219-23. [DOI: 10.1292/jvms.12-0318] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Affiliation(s)
- Yohei YUDA
- Department of Tissue Physiology, Tokyo University of Agriculture and Technology, 3–5–8 Saiwai-cho, Fuchu, Tokyo 183–8509, Japan
| | - Yoshinori KASASHIMA
- Laboratory of Clinical Science and Pathobiology, Equine Research Institute, Japan Racing Association, 321–4 Togami-cho, Utsunomiya, Tochigi 320–8056, Japan
| | - Atsutoshi KUWANO
- Laboratory of Clinical Science and Pathobiology, Equine Research Institute, Japan Racing Association, 321–4 Togami-cho, Utsunomiya, Tochigi 320–8056, Japan
| | - Kan SATO
- Department of Biological Production, Tokyo University of Agriculture and Technology, 3–5–8 Saiwai-cho, Fuchu, Tokyo 183–8509, Japan
| | - Shunji HATTORI
- Nippi Research Institute of Biomatrix, Nippi Inc., 520–11 Kuwabara, Toride, Ibaraki 302–0017, Japan
| | - Katsuhiko ARAI
- Department of Tissue Physiology, Tokyo University of Agriculture and Technology, 3–5–8 Saiwai-cho, Fuchu, Tokyo 183–8509, Japan
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15
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16
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Abstract
Accumulation and turnover of extracellular matrix components are the hallmarks of tissue injury. Fragmented hyaluronan stimulates the expression of inflammatory genes by a variety of immune cells at the injury site. Hyaluronan binds to a number of cell surface proteins on various cell types. Hyaluronan fragments signal through both Toll-like receptor (TLR) 4 and TLR2 as well as CD44 to stimulate inflammatory genes in inflammatory cells. Hyaluronan is also present on the cell surface of epithelial cells and provides protection against tissue damage from the environment by interacting with TLR2 and TLR4. Hyaluronan and hyaluronan-binding proteins regulate inflammation, tissue injury, and repair through regulating inflammatory cell recruitment, release of inflammatory cytokines, and cell migration. This review focuses on the role of hyaluronan as an immune regulator in human diseases.
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Affiliation(s)
- Dianhua Jiang
- Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, Duke University School of Medicine, Durham, North Carolina 27710, USA.
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17
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Hermo L, Pelletier RM, Cyr DG, Smith CE. Surfing the wave, cycle, life history, and genes/proteins expressed by testicular germ cells. Part 3: developmental changes in spermatid flagellum and cytoplasmic droplet and interaction of sperm with the zona pellucida and egg plasma membrane. Microsc Res Tech 2010; 73:320-63. [PMID: 19941287 DOI: 10.1002/jemt.20784] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Spermiogenesis constitutes the steps involved in the metamorphosis of spermatids into spermatozoa. It involves modification of several organelles in addition to the formation of several structures including the flagellum and cytoplasmic droplet. The flagellum is composed of a neck region and middle, principal, and end pieces. The axoneme composed of nine outer microtubular doublets circularly arranged to form a cylinder around a central pair of microtubules is present throughout the flagellum. The middle and principal pieces each contain specific components such as the mitochondrial sheath and fibrous sheath, respectively, while outer dense fibers are common to both. A plethora of proteins are constituents of each of these structures, with each playing key roles in functions related to the fertility of spermatozoa. At the end of spermiogenesis, a portion of spermatid cytoplasm remains associated with the released spermatozoa, referred to as the cytoplasmic droplet. The latter has as its main feature Golgi saccules, which appear to modify the plasma membrane of spermatozoa as they move down the epididymal duct and hence may be partly involved in male gamete maturation. The end product of spermatogenesis is highly streamlined and motile spermatozoa having a condensed nucleus equipped with an acrosome. Spermatozoa move through the female reproductive tract and eventually penetrate the zona pellucida and bind to the egg plasma membrane. Many proteins have been implicated in the process of fertilization as well as a plethora of proteins involved in the development of spermatids and sperm, and these are high lighted in this review.
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Affiliation(s)
- Louis Hermo
- Department of Anatomy and Cell Biology, Faculty of Medicine, McGill University, Montreal, Quebec, Canada H3A 2B2.
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18
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Kimura M, Kim E, Kang W, Yamashita M, Saigo M, Yamazaki T, Nakanishi T, Kashiwabara SI, Baba T. Functional roles of mouse sperm hyaluronidases, HYAL5 and SPAM1, in fertilization. Biol Reprod 2009; 81:939-47. [PMID: 19605784 DOI: 10.1095/biolreprod.109.078816] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Although sperm entry into the oocyte-cumulus complex and subsequent sperm penetration through the cumulus matrix to reach the oocyte zona pellucida are essential for mammalian fertilization, the molecular mechanism remains controversial. Previously, we have shown that mouse sperm lacking SPAM1 are capable of penetrating the cumulus matrix despite a delayed dispersal of cumulus cells. We also have identified another sperm hyaluronidase, HYAL5, as a candidate enzyme involved in sperm penetration through the cumulus. In the present study, we produced HYAL5-deficient mice to uncover the functional roles of HYAL5 and SPAM1 in fertilization. The HYAL5-deficient mice were fully fertile and yielded normal litter sizes. In vitro fertilization assays demonstrated that HYAL5-deficient epididymal sperm is functionally normal. We thus conclude that HYAL5 may be dispensable for fertilization. Comparative analysis among wild-type, HYAL5-deficient, and SPAM1-deficient epididymal sperm revealed that only SPAM1 is probably involved in sperm penetration through the cumulus matrix. Notably, the loss of SPAM1 resulted in a remarkably increased accumulation of sperm on the surface or outer edge of the cumulus. These data suggest that SPAM1 may function in sperm entry into the cumulus and sperm penetration through the cumulus matrix.
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Affiliation(s)
- Masanori Kimura
- Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba Science City, Ibaraki, Japan
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Reitinger S, Müllegger J, Greiderer B, Nielsen JE, Lepperdinger G. Designed human serum hyaluronidase 1 variant, HYAL1DeltaL, exhibits activity up to pH 5.9. J Biol Chem 2009; 284:19173-7. [PMID: 19478093 DOI: 10.1074/jbc.c109.004358] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Hyaluronidases from diverse species and sources have different pH optima. Distinct mechanisms with regard to dynamic structural changes, which control hyaluronidase activity at varying pH, are unknown. Human serum hyaluronidase 1 (HYAL1) is active solely below pH 5.1. Here we report the design of a HYAL1 variant that degrades hyaluronan up to pH 5.9. Besides highly conserved residues in close proximity of the active site of most hyaluronidases, we identified a bulky loop formation located at the end of the substrate binding crevice of HYAL1 to be crucial for substrate hydrolysis. The stretch between cysteine residues 207 and 221, which normally contains 13 amino acids, could be replaced by a tetrapeptide sequence of alternating glycine serine residues, thereby yielding an active enzyme with an extended binding cleft. This variant exhibited hyaluronan degradation at elevated pH. This is indicative for appropriate substrate binding and proper positioning being decisively affected by sites far off from the active center.
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Affiliation(s)
- Stephan Reitinger
- Extracellular Matrix Research Group, Institute for Biomedical Aging Research, Austrian Academy of Sciences, Rennweg 10, A-6020 Innsbruck, Austria
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20
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Williams SA, Stanley P. Oocyte-specific deletion of complex and hybrid N-glycans leads to defects in preovulatory follicle and cumulus mass development. Reproduction 2009; 137:321-31. [PMID: 19028923 PMCID: PMC2788604 DOI: 10.1530/rep-07-0469] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Complex and hybrid N-glycans generated by N-acetylglucosaminyltransferase I (GlcNAcT-I), encoded by Mgat1, affect the functions of glycoproteins. We have previously shown that females with oocyte-specific deletion of a floxed Mgat1 gene using a zona pellucida protein 3 (ZP3)Cre transgene produce fewer pups primarily due to a reduction in ovulation rate. Here, we show that the ovulation rate of mutant females is decreased due to aberrant development of preovulatory follicles. After a superovulatory regime of 48 h pregnant mare's serum (PMSG) and 9 h human chorionic gonadotropin (hCG), mutant ovaries weighed less and contained approximately 60% fewer preovulatory follicles and more atretic and abnormal follicles than controls. Unlike controls, a proportion of mutant follicles underwent premature luteinization. In addition, mutant preovulatory oocytes exhibited gross abnormalities with approximately 36% being blebbed or zona-free. While 97% of wild-type oocytes had a perivitelline space at the preovulatory stage, approximately 54% of mutant oocytes did not. The cumulus mass surrounding mutant oocytes was also smaller with a decreased number of proliferating cells compared with controls, although hyaluronan around mutant oocytes was similar to controls. In addition, cumulus cells surrounding mutant eggs were resistant to removal by either hyaluronidase or incubation with capacitated sperm. Therefore, the absence of complex and hybrid N-glycans on oocyte glycoproteins leads to abnormal folliculogenesis resulting in a decreased ovulation rate.
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Affiliation(s)
| | - Pamela Stanley
- Department of Cell Biology, Albert Einstein College of Medicine, New York, NY-10461, U.S.A
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Baker MA, Hetherington L, Reeves GM, Aitken RJ. The mouse sperm proteome characterized via IPG strip prefractionation and LC-MS/MS identification. Proteomics 2008; 8:1720-30. [PMID: 18340633 DOI: 10.1002/pmic.200701020] [Citation(s) in RCA: 123] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Proteomic profiling of the mouse spermatozoon has generated a unique and valuable inventory of candidates that can be mined for potential contraceptive targets and to further our understanding of the PTMs that regulate the functionality of this highly specialized cell. Here we report the identification of 858 proteins derived from mouse spermatozoa, 23 of which demonstrated testis only expression. The list contained many proteins that are known constituents of murine spermatozoa including Izumo, Spaca 1, 3, and 5, Spam 1, Zonadhesin, Spesp1, Smcp, Spata 6, 18, and 19, Zp3r, Zpbp 1 and 2, Spa17, Spag 6, 16, and 17, CatSper4, Acr, Cylc2, Odf1 and 2, Acrbp, and Acrv1. Certain protein families were highly represented in the proteome. For example, of the 42 gene products classified as proteases, 26 belonged to the 26S-proteasome. Of the many chaperones identified in this proteome, eight proteins with a TCP-1 domain were found, as were seven Rab guanosine triphosphatases. Finally, our list yielded three putative seven-transmembrane proteins, two of which have no known tissue distribution, an extragenomic progesterone receptor and three unique testis-specific kinases all of which may have some potential in the future regulation of male fertility.
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Affiliation(s)
- Mark A Baker
- The ARC Centre of Excellence in Biotechnology and Development, Reproductive Science Group, School of Environmental and Life Sciences, University of Newcastle, NSW, Australia.
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Girish KS, Kemparaju K. The magic glue hyaluronan and its eraser hyaluronidase: a biological overview. Life Sci 2007; 80:1921-43. [PMID: 17408700 DOI: 10.1016/j.lfs.2007.02.037] [Citation(s) in RCA: 457] [Impact Index Per Article: 25.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2006] [Revised: 02/04/2007] [Accepted: 02/19/2007] [Indexed: 01/09/2023]
Abstract
Hyaluronan (HA) is a multifunctional high molecular weight polysaccharide found throughout the animal kingdom, especially in the extracellular matrix (ECM) of soft connective tissues. HA is thought to participate in many biological processes, and its level is markedly elevated during embryogenesis, cell migration, wound healing, malignant transformation, and tissue turnover. The enzymes that degrade HA, hyaluronidases (HAases) are expressed both in prokaryotes and eukaryotes. These enzymes are known to be involved in physiological and pathological processes ranging from fertilization to aging. Hyaluronidase-mediated degradation of HA increases the permeability of connective tissues and decreases the viscosity of body fluids and is also involved in bacterial pathogenesis, the spread of toxins and venoms, acrosomal reaction/ovum fertilization, and cancer progression. Furthermore, these enzymes may promote direct contact between pathogens and the host cell surfaces. Depolymerization of HA also adversely affects the role of ECM and impairs its activity as a reservoir of growth factors, cytokines and various enzymes involved in signal transduction. Inhibition of HA degradation therefore may be crucial in reducing disease progression and spread of venom/toxins and bacterial pathogens. Hyaluronidase inhibitors are potent, ubiquitous regulating agents that are involved in maintaining the balance between the anabolism and catabolism of HA. Hyaluronidase inhibitors could also serve as contraceptives and anti-tumor agents and possibly have antibacterial and anti-venom/toxin activities. Additionally, these molecules can be used as pharmacological tools to study the physiological and pathophysiological role of HA and hyaluronidases.
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Affiliation(s)
- K S Girish
- Department of Biochemistry, University of Mysore, Manasagangothri, Mysore, Karnataka State, 560007, India.
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