Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6WZPWV)

• DOT Name: 2-amino-3-ketobutyrate coenzyme A ligase, mitochondrial (GCAT)
• Synonyms: AKB ligase; EC 2.3.1.29; Aminoacetone synthase; Glycine acetyltransferase
• Gene Name: GCAT
• Related Disease:
  Advanced cancer
  Lung cancer
  Lung carcinoma
• UniProt ID: KBL_HUMAN
• EC Number: 2.3.1.29
• Pfam ID: PF00155
• Sequence:
  MWPGNAWRAALFWVPRGRRAQSALAQLRGILEGELEGIRGAGTWKSERVITSRQGPHIRV
  DGVSGGILNFCANNYLGLSSHPEVIQAGLQALEEFGAGLSSVRFICGTQSIHKNLEAKIA
  RFHQREDAILYPSCYDANAGLFEALLTPEDAVLSDELNHASIIDGIRLCKAHKYRYRHLD
  MADLEAKLQEAQKHRLRLVATDGAFSMDGDIAPLQEICCLASRYGALVFMDECHATGFLG
  PTGRGTDELLGVMDQVTIINSTLGKALGGASGGYTTGPGPLVSLLRQRARPYLFSNSLPP
  AVVGCASKALDLLMGSNTIVQSMAAKTQRFRSKMEAAGFTISGASHPICPVMLGDARLAS
  RMADDMLKRGIFVIGFSYPVVPKGKARIRVQISAVHSEEDIDRCVEAFVEVGRLHGALP
• Function: Pyridoxal phosphate (PLP) dependent enzyme, which catalyzes the cleavage of 2-amino-3-oxobutanoate to glycine and acetyl-CoA.
• Tissue Specificity: Strongly expressed in heart, brain, liver and pancreas. Also found in lung.
• KEGG Pathway:
  Glycine, serine and threonine metabolism (hsa00260)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Threonine catabolism (R-HSA-8849175)
• BioCyc Pathway: MetaCyc:HS01980-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Lung cancer	DISCM4YA	moderate	Genetic Variation	[2]
Lung carcinoma	DISTR26C	moderate	Genetic Variation	[2]

15 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 2-amino-3-ketobutyrate coenzyme A ligase, mitochondrial (GCAT).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of 2-amino-3-ketobutyrate coenzyme A ligase, mitochondrial (GCAT).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of 2-amino-3-ketobutyrate coenzyme A ligase, mitochondrial (GCAT).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of 2-amino-3-ketobutyrate coenzyme A ligase, mitochondrial (GCAT).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of 2-amino-3-ketobutyrate coenzyme A ligase, mitochondrial (GCAT).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of 2-amino-3-ketobutyrate coenzyme A ligase, mitochondrial (GCAT).	[8]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of 2-amino-3-ketobutyrate coenzyme A ligase, mitochondrial (GCAT).	[9]
Selenium	DM25CGV	Approved	Selenium increases the expression of 2-amino-3-ketobutyrate coenzyme A ligase, mitochondrial (GCAT).	[10]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of 2-amino-3-ketobutyrate coenzyme A ligase, mitochondrial (GCAT).	[11]
Fenofibrate	DMFKXDY	Approved	Fenofibrate decreases the expression of 2-amino-3-ketobutyrate coenzyme A ligase, mitochondrial (GCAT).	[12]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of 2-amino-3-ketobutyrate coenzyme A ligase, mitochondrial (GCAT).	[9]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of 2-amino-3-ketobutyrate coenzyme A ligase, mitochondrial (GCAT).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of 2-amino-3-ketobutyrate coenzyme A ligase, mitochondrial (GCAT).	[13]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of 2-amino-3-ketobutyrate coenzyme A ligase, mitochondrial (GCAT).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of 2-amino-3-ketobutyrate coenzyme A ligase, mitochondrial (GCAT).	[9]

References

• [1] Effect of four genes (ALDH1, NRF1, JAM and KBL) on proliferation arrest in a non-small cell bronchopulmonary cancer line.Anticancer Res. 2002 Jul-Aug;22(4):2229-35.
• [2] Correlation between survivin genetic polymorphisms and lung cancer susceptibility.Int J Clin Exp Pathol. 2015 Jun 1;8(6):7426-30. eCollection 2015.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [6] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [7] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [10] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [11] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [12] 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.
• [13] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [14] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.