Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTO6QUTM)

• DOT Name: Alanine--glyoxylate aminotransferase 2, mitochondrial (AGXT2)
• Synonyms: AGT 2; EC 2.6.1.44; (R)-3-amino-2-methylpropionate--pyruvate transaminase; EC 2.6.1.40; Beta-ALAAT II; Beta-alanine-pyruvate aminotransferase; EC 2.6.1.18; D-3-aminoisobutyrate-pyruvate aminotransferase; D-AIBAT; D-beta-aminoisobutyrate-pyruvate aminotransferase
• Gene Name: AGXT2
• Related Disease:
  Arteriosclerosis
  Atherosclerosis
  Atrial fibrillation
  Chronic kidney disease
  Congestive heart failure
  High blood pressure
  Inborn error of metabolism
  Intermittent claudication
  Myocardial ischemia
  Nephropathy
  Non-insulin dependent diabetes
  Rheumatoid arthritis
  Coronary atherosclerosis
  Coronary heart disease
  Type-1/2 diabetes
• UniProt ID: AGT2_HUMAN
• EC Number: 2.6.1.18; 2.6.1.40; 2.6.1.44
• Pfam ID: PF00202
• Sequence:
  MTLIWRHLLRPLCLVTSAPRILEMHPFLSLGTSRTSVTKLSLHTKPRMPPCDFMPERYQS
  LGYNRVLEIHKEHLSPVVTAYFQKPLLLHQGHMEWLFDAEGSRYLDFFSGIVTVSVGHCH
  PKVNAVAQKQLGRLWHTSTVFFHPPMHEYAEKLAALLPEPLKVIFLVNSGSEANELAMLM
  ARAHSNNIDIISFRGAYHGCSPYTLGLTNVGTYKMELPGGTGCQPTMCPDVFRGPWGGSH
  CRDSPVQTIRKCSCAPDCCQAKDQYIEQFKDTLSTSVAKSIAGFFAEPIQGVNGVVQYPK
  GFLKEAFELVRARGGVCIADEVQTGFGRLGSHFWGFQTHDVLPDIVTMAKGIGNGFPMAA
  VITTPEIAKSLAKCLQHFNTFGGNPMACAIGSAVLEVIKEENLQENSQEVGTYMLLKFAK
  LRDEFEIVGDVRGKGLMIGIEMVQDKISCRPLPREEVNQIHEDCKHMGLLVGRGSIFSQT
  FRIAPSMCITKPEVDFAVEVFRSALTQHMERRAK
• Function: Multifunctional aminotransferase with a broad substrate specifcity. Catalyzes the conversion of glyoxylate to glycine using alanine as the amino donor. Catalyzes metabolism of not L- but the D-isomer of D-beta-aminoisobutyric acid to generate 2-methyl-3-oxopropanoate and alanine. Catalyzes the transfer of the amino group from beta-alanine to pyruvate to yield L-alanine and 3-oxopropanoate. Can metabolize NG-monomethyl-L-arginine (NMMA), asymmetric NG,NG-dimethyl-L-arginine (ADMA) and symmetric NG,N'G-dimethyl-L-arginine (SDMA). ADMA is a potent inhibitor of nitric-oxide (NO) synthase, and this activity provides mechanism through which the kidney regulates blood pressure.
• Tissue Specificity: Expressed in the convoluted tubule in the kidney and in the liver hepatocytes (at protein level).
• KEGG Pathway:
  Alanine, aspartate and glutamate metabolism (hsa00250)
  Glycine, serine and threonine metabolism (hsa00260)
  Cysteine and methionine metabolism (hsa00270)
  Valine, leucine and isoleucine degradation (hsa00280)
  Metabolic pathways (hsa01100)
  2-Oxocarboxylic acid metabolism (hsa01210)
• Reactome Pathway:
  Pyrimidine catabolism (R-HSA-73621)
  Glyoxylate metabolism and glycine degradation (R-HSA-389661)
• BioCyc Pathway: MetaCyc:HS03685-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arteriosclerosis	DISK5QGC	Strong	Genetic Variation	[1]
Atherosclerosis	DISMN9J3	Strong	Genetic Variation	[1]
Atrial fibrillation	DIS15W6U	Strong	Biomarker	[2]
Chronic kidney disease	DISW82R7	Strong	Altered Expression	[3]
Congestive heart failure	DIS32MEA	Strong	Genetic Variation	[4]
High blood pressure	DISY2OHH	Strong	Biomarker	[1]
Inborn error of metabolism	DISO5FAY	Strong	Biomarker	[5]
Intermittent claudication	DISGY3B0	Strong	Genetic Variation	[6]
Myocardial ischemia	DISFTVXF	Strong	Biomarker	[7]
Nephropathy	DISXWP4P	Strong	Genetic Variation	[4]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Altered Expression	[8]
Rheumatoid arthritis	DISTSB4J	moderate	Biomarker	[9]
Coronary atherosclerosis	DISKNDYU	Limited	Genetic Variation	[10]
Coronary heart disease	DIS5OIP1	Limited	Genetic Variation	[10]
Type-1/2 diabetes	DISIUHAP	Limited	Genetic Variation	[11]

8 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Alanine--glyoxylate aminotransferase 2, mitochondrial (AGXT2).	[12]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Alanine--glyoxylate aminotransferase 2, mitochondrial (AGXT2).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Alanine--glyoxylate aminotransferase 2, mitochondrial (AGXT2).	[14]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Alanine--glyoxylate aminotransferase 2, mitochondrial (AGXT2).	[13]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Alanine--glyoxylate aminotransferase 2, mitochondrial (AGXT2).	[15]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Alanine--glyoxylate aminotransferase 2, mitochondrial (AGXT2).	[15]
Fenofibrate	DMFKXDY	Approved	Fenofibrate decreases the expression of Alanine--glyoxylate aminotransferase 2, mitochondrial (AGXT2).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Alanine--glyoxylate aminotransferase 2, mitochondrial (AGXT2).	[17]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Alanine--glyoxylate aminotransferase 2, mitochondrial (AGXT2).	[16]

References

• [1] Missense variants of the alanine: glyoxylate aminotransferase 2 gene correlated with carotid atherosclerosis in the Japanese population.J Biol Regul Homeost Agents. 2014 Oct-Dec;28(4):605-14.
• [2] Associations of functional alanine-glyoxylate aminotransferase 2 gene variants with atrial fibrillation and ischemic stroke.Sci Rep. 2016 Mar 17;6:23207. doi: 10.1038/srep23207.
• [3] L-Homoarginine and its AGXT2-metabolite GOCA in chronic kidney disease as markers for clinical status and prognosis.Amino Acids. 2018 Oct;50(10):1347-1356. doi: 10.1007/s00726-018-2610-y. Epub 2018 Jul 7.
• [4] AGXT2 rs37369 polymorphism predicts the renal function in patients with chronic heart failure.Gene. 2017 Dec 30;637:145-151. doi: 10.1016/j.gene.2017.09.038. Epub 2017 Sep 21.
• [5] A genome-wide association study of metabolic traits in human urine.Nat Genet. 2011 Jun;43(6):565-9. doi: 10.1038/ng.837. Epub 2011 May 15.
• [6] Genetic and environmental determinants of dimethylarginines and association with cardiovascular disease in patients with type 2 diabetes.Diabetes Care. 2014;37(3):846-54. doi: 10.2337/dc13-0546. Epub 2013 Nov 1.
• [7] Effect of l-arginine, asymmetric dimethylarginine, and symmetric dimethylarginine on ischemic heart disease risk: A Mendelian randomization study.Am Heart J. 2016 Dec;182:54-61. doi: 10.1016/j.ahj.2016.07.021. Epub 2016 Aug 26.
• [8] Diabetes-linked transcription factor HNF4 regulates metabolism of endogenous methylarginines and -aminoisobutyric acid by controlling expression of alanine-glyoxylate aminotransferase 2.Sci Rep. 2016 Oct 18;6:35503. doi: 10.1038/srep35503.
• [9] Genetic regulation of dimethylarginines and endothelial dysfunction in rheumatoid arthritis.Amino Acids. 2019 Jul;51(7):983-990. doi: 10.1007/s00726-019-02740-3. Epub 2019 May 6.
• [10] AGXT2 and DDAH-1 genetic variants are highly correlated with serum ADMA and SDMA levels and with incidence of coronary artery disease in Egyptians.Mol Biol Rep. 2018 Dec;45(6):2411-2419. doi: 10.1007/s11033-018-4407-1. Epub 2018 Oct 3.
• [11] Association of the AGXT2 V140I polymorphism with risk for coronary heart disease in a Chinese population.J Atheroscler Thromb. 2014;21(10):1022-30. doi: 10.5551/jat.23077. Epub 2014 May 16.
• [12] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [13] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [14] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [15] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [16] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [17] Involvement of the Endocrine-Disrupting Chemical Bisphenol A (BPA) in Human Placentation. J Clin Med. 2020 Feb 3;9(2):405. doi: 10.3390/jcm9020405.