Alanine and aspartate aminotransferase and glutamine-cycling pathway: Their roles in pathogenesis of metabolic syndrome

Table 1 Overview about liver aminotransferases alanine and aspartate

ALT or GPT

Catalyzes the reversible transamination1 between alanine and 2-oxoglutarate to form pyruvate and glutamate: L-alanine + 2-oxoglutarate = pyruvate + L-glutamate

ALT has both degradative and biosynthetic roles in the glutamate cycling

ALT participates in cellular nitrogen metabolism and also in liver gluconeogenesis starting with precursors transported from skeletal muscles

ALT is present in tissues including liver, kidney, heart, and skeletal muscle.

AST or GOT

Catalyzes the reversible transamination between L-aspartate and 2-oxoglutarate to form oxaloacetate and glutamate: L-alanine + 2-oxoglutarate

L-aspartate + 2-oxoglutarate = oxaloacetate + L-glutamate

Cytosolic AST (GOT 1 catalyzes the reversible reaction of oxaloacetate and glutamate to form aspartate and 2-oxoglutarate (alpha-ketoglutarate)

AST has two isoforms: cytoplasmatic and mitochondrial

¹Transaminase: A subclass of enzymes that catalyze the transfer of an amino group from a donor (generally an amino acid) to an acceptor (generally 2 keto acid) in a cyclic process using pyridoxal phosphate as a cofactor. ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; GPT: Glutamate pyruvate transaminase; GOT: Glutamate oxaloacetate transaminase.

Table 2 Candidate gene list (in bold) and 50 predicted genes by systems biology

Symbol	Description	Score
HNF4A	Hepatocyte nuclear factor 4, alpha [source: HGNC symbol; Acc: 5024]	66.77
IDH2	Isocitrate dehydrogenase 2 (NADP+), mitochondrial [source: HGNC symbol; Acc: 5383]	62.04
IDH1	Isocitrate dehydrogenase 1 (NADP+), soluble [source: HGNC symbol; Acc: 5382]	61.96
GPT	Glutamic-pyruvate transaminase (alanine aminotransferase) [source: HGNC symbol; Acc: 4552]	58.97
GOT1	Glutamic-oxaloacetic transaminase 1, soluble (aspartate aminotransferase 1) [source: HGNC symbol; Acc: 4432]	54.78
GOT2	Glutamic-oxaloacetic transaminase 2, mitochondrial (aspartate aminotransferase 2) [source: HGNC symbol; Acc: 4433]	54.48
IDH3A	Isocitrate dehydrogenase 3 (NAD+) alpha [source: HGNC symbol; Acc: 5384]	2.68
IDH3G	Isocitrate dehydrogenase 3 (NAD+) gamma [source: HGNC symbol; Acc: 5386]	2.6
IDH3B	Isocitrate dehydrogenase 3 (NAD+) beta [source: HGNC symbol; Acc: 5385]	2.56
ALAS1	Aminolevulinate, delta-, synthase 1 [source: HGNC symbol; Acc: 396]	1.57
GOT1L1	Glutamic-oxaloacetic transaminase 1-like 1 [source: HGNC symbol; Acc: 28487]	1.35
ACCSL	1-aminocyclopropane-1-carboxylate synthase homolog (Arabidopsis)(non-functional)-like [source: HGNC symbol; Acc: 34391]	1.14
GPT2	Glutamic pyruvate transaminase (alanine aminotransferase) 2 [source: HGNC symbol; Acc: 18062]	1.03
ACCS	1-aminocyclopropane-1-carboxylate synthase homolog (Arabidopsis)(non-functional) [source: HGNC symbol; Acc: 23989]	0.98
TAT	Tyrosine aminotransferase [source: HGNC symbol; Acc: 11573]	0.93
AADAT	Aminoadipate aminotransferase [source: HGNC symbol; Acc: 17929]	0.88
CCBL1	Cysteine conjugate-beta lyase, cytoplasmic [source: HGNC symbol; Acc: 1564]	0.87
CCBL2	Cysteine conjugate-beta lyase 2 [source: HGNC symbol; Acc: 33238]	0.83
SPTLC3	Serine palmitoyltransferase, long chain base subunit 3 [source: HGNC symbol; Acc: 16253]	0.82
ALAS2	Aminolevulinate, delta-, synthase 2 [source: HGNC symbol; Acc: 397]	0.8
SPTLC2	Serine palmitoyltransferase, long chain base subunit 2 [source: HGNC symbol; Acc: 11278]	0.79
SPTLC1	Serine palmitoyltransferase, long chain base subunit 1 [source: HGNC symbol; Acc: 11277]	0.75
PC	Pyruvate carboxylase [source: HGNC symbol; Acc: 8636]	0.69
SLC2A4	Solute carrier family 2 (facilitated glucose transporter), member 4 [source: HGNC symbol; Acc: 11009]	0.69
GCAT	Glycine C-acetyltransferase [source: HGNC symbol; Acc: 4188]	0.66
RCAN1	Regulator of calcineurin 1 [source: HGNC symbol; Acc: 3040]	0.56
SEPSECS	Sep (O-phosphoserine) tRNA: Sec (selenocysteine) tRNA synthase [source: HGNC symbol; Acc: 30605]	0.56
GLUD1	Glutamate dehydrogenase 1 [source: HGNC symbol; Acc: 4335]	0.55
SHMT2	Serine hydroxymethyltransferase 2 (mitochondrial) [source: HGNC symbol; Acc: 10852]	0.54
CTH	Cystathionase (cystathionine gamma-lyase) [source: HGNC symbol; Acc: 2501]	0.52
AGXT2L2	Alanine-glyoxylate aminotransferase 2-like 2 [source: HGNC symbol; Acc: 28249]	0.49
RCAN2	Regulator of calcineurin 2 [source: HGNC symbol; Acc: 3041]	0.49
AGXT	Alanine-glyoxylate aminotransferase [source: HGNC symbol; Acc: 341]	0.48
GLDC	Glycine dehydrogenase (decarboxylating) [source: HGNC symbol; Acc: 4313]	0.48
GADL1	Glutamate decarboxylase-like 1 [source: HGNC symbol; Acc: 27949]	0.47
PDXDC1	Pyridoxal-dependent decarboxylase domain containing 1 [source: HGNC symbol; Acc: 28995]	0.45
AGXT2	Alanine--glyoxylate aminotransferase 2 [source: HGNC symbol; Acc: 14412]	0.45
GAD2	Glutamate decarboxylase 2 (pancreatic islets and brain, 65 kDa) [source: HGNC symbol; Acc: 4093]	0.43
SCLY	Selenocysteine lyase [source: HGNC symbol; Acc: 18161]	0.43
AGXT2L1	Alanine-glyoxylate aminotransferase 2-like 1 [source: HGNC symbol; Acc: 14404]	0.42
ABAT	4-aminobutyrate aminotransferase [source: HGNC symbol; Acc: 23]	0.42
DDC	Dopa decarboxylase (aromatic L-amino acid decarboxylase) [source: HGNC symbol; Acc: 2719]	0.42
KYNU	Kynureninase [source: HGNC symbol; Acc: 6469]	0.41
OAT	Ornithine aminotransferase [source: HGNC symbol; Acc: 8091]	0.4
SHMT1	Serine hydroxymethyltransferase 1 (soluble) [source: HGNC symbol; Acc: 10850]	0.4
PSAT1	Phosphoserine aminotransferase 1 [source: HGNC symbol; Acc: 19129]	0.39
GAD1	Glutamate decarboxylase 1 (brain, 67 kDa) [source: HGNC symbol; Acc: 4092]	0.38
CSAD	Cysteine sulfinic acid decarboxylase [source: HGNC symbol; Acc: 18966]	0.38
NFS1	NFS1 nitrogen fixation 1 homolog (S. cerevisiae) [source: HGNC symbol; Acc: 15910]	0.38
ACO1	Aconitase 1, soluble [source: HGNC symbol; Acc: 117]	0.37
SGPL1	Sphingosine-1-phosphate lyase 1 [source: HGNC symbol; Acc: 10817]	0.36
HDC	Histidine decarboxylase [source: HGNC symbol; Acc: 4855]	0.36
MOCOS	Molybdenum cofactor sulfurase [source: HGNC symbol; Acc: 18234]	0.31
ZNHIT3	Zinc finger, HIT-type containing 3 [source: HGNC symbol; Acc: 12309]	0.3
COQ9	Coenzyme Q9 homolog (S. cerevisiae) [source: HGNC symbol; Acc: 25302]	0.3
ESRRA	Estrogen-related receptor alpha [source: HGNC symbol; Acc: 3471]	0.3

IDH: Isocitrate dehydrogenases; GPT: Glutamate pyruvate transaminase; GOT: Glutamate oxaloacetate transaminase.

Table 3 Gene ontology annotation of predicted biological process

Gene ontology annotation	Q value	Genes in network	Genes in genome
Transaminase activity	4.86E-31	14	16
Transferase activity, transferring nitrogenous groups	6.17E-30	14	18
Mitochondrial matrix	3.10E-15	16	220
Cellular amino acid catabolic process	7.40E-15	12	77
Amine catabolic process	1.13E-14	12	81
Dicarboxylic acid metabolic process	1.75E-14	9	24
Cellular amino acid biosynthetic process	5.90E-13	10	54
Carboxylic acid catabolic process	2.55E-12	12	131
2-oxoglutarate metabolic process	2.55E-12	7	13
Organic acid catabolic process	2.55E-12	12	131
Amine biosynthetic process	8.11E-12	10	72
Glutamate metabolic process	1.08E-10	6	10
Carboxylic acid biosynthetic process	4.53E-10	11	154
Organic acid biosynthetic process	4.53E-10	11	154
Small molecule catabolic process	4.87E-10	12	211
Small molecule biosynthetic process	2.21E-9	12	241
Cofactor metabolic process	2.24E-8	10	163
Vitamin B6 binding	9.53E-8	5	12
Glutamine family amino acid metabolic process	9.53E-8	6	27
Cellular aromatic compound metabolic process	9.53E-8	9	135
Pyridoxal phosphate binding	9.53E-8	5	12
Cofactor binding	6.48E-7	7	69
Aromatic amino acid family catabolic process	1.24E-6	5	19
Coenzyme metabolic process	1.46E-6	8	126
Aromatic compound catabolic process	3.14E-6	5	23
Aromatic amino acid family metabolic process	3.14E-6	5	23
Vitamin binding	8.74E-6	5	28
Indolalkylamine catabolic process	1.08E-5	4	11
Indole-containing compound catabolic process	1.08E-5	4	11
Tryptophan catabolic process	1.08E-5	4	11
Tryptophan metabolic process	1.48E-5	4	12
Indolalkylamine metabolic process	1.48E-5	4	12
Indole-containing compound metabolic process	1.48E-5	4	12
Cellular biogenic amine catabolic process	3.93E-5	4	15
Serine family amino acid metabolic process	5.07E-5	4	16
Acetyl-CoA catabolic process	1.23E-4	4	20
Tricarboxylic acid cycle	1.23E-4	4	20
Coenzyme catabolic process	1.23E-4	4	20
Cofactor catabolic process	3.67E-4	4	26
Aerobic respiration	4.88E-4	4	28
Cellular biogenic amine metabolic process	6.98E-4	5	71
Lyase activity	8.37E-4	5	74
Acetyl-CoA metabolic process	1.01E-3	4	34
Transferase activity, transferring acyl groups other than amino-acyl groups	1.41E-3	5	83
Gluconeogenesis	3.05E-3	4	45
Aspartate family amino acid catabolic process	3.67E-3	3	15
Generation of a signal involved in cell-cell signaling	3.67E-3	6	178
Signal release	3.67E-3	6	178
Transferase activity, transferring acyl groups	3.67E-3	5	103
Sulfur amino acid metabolic process	4.26E-3	3	16
Neurotransmitter secretion	5.20E-3	4	53
Hexose biosynthetic process	5.50E-3	4	54
Water-soluble vitamin metabolic process	6.24E-3	4	56
Monosaccharide biosynthetic process	1.04E-2	4	64
Pteridine-containing compound metabolic process	1.05E-2	3	22
Neurotransmitter transport	1.14E-2	4	66
Carbon-carbon lyase activity	1.48E-2	3	25
Aspartate family amino acid metabolic process	1.48E-2	3	25
Regulation of neurotransmitter levels	1.60E-2	4	73
Sphingolipid metabolic process	1.82E-2	4	76
Alcohol biosynthetic process	1.82E-2	4	76
Pigment biosynthetic process	1.96E-2	3	28
Membrane lipid metabolic process	2.35E-2	4	82
Sphingolipid biosynthetic process	2.35E-2	3	30
Cofactor biosynthetic process	2.53E-2	4	84
Membrane lipid biosynthetic process	2.77E-2	3	32
Cellular modified amino acid metabolic process	2.81E-2	4	87
Cellular carbohydrate biosynthetic process	4.06E-2	4	96
Pigment metabolic process	4.80E-2	3	39
Vitamin metabolic process	4.80E-2	4	101

Q value stands for the P value corrected for multiple testing. In addition, number of genes in the network and in the whole genome belonging to the biological process is depicted. The candidate genes are listed in Table 2, which are involved in functional enrichment analysis using the GeneMANIA tool (genemania.org).