Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8L6EGI)

• DOT Name: Branched-chain-amino-acid aminotransferase, mitochondrial (BCAT2)
• Synonyms: BCAT(m); EC 2.6.1.42; Placental protein 18; PP18
• Gene Name: BCAT2
• Related Disease: Hypervalinemia and hyperleucine-isoleucinemia
• UniProt ID: BCAT2_HUMAN
• PDB ID: 1EKF; 1EKP; 1EKV; 1KT8; 1KTA; 2A1H; 2HDK; 2HG8; 2HGW; 2HGX; 2HHF; 5BWR; 5BWT; 5BWU; 5BWV; 5BWW; 5BWX; 5CR5; 5HNE; 5I5S; 5I5T; 5I5U; 5I5V; 5I5W; 5I5X; 5I5Y; 5I60; 5MPR; 6PRX
• EC Number: 2.6.1.42
• Pfam ID: PF01063
• Sequence:
  MAAAALGQIWARKLLSVPWLLCGPRRYASSSFKAADLQLEMTQKPHKKPGPGEPLVFGKT
  FTDHMLMVEWNDKGWGQPRIQPFQNLTLHPASSSLHYSLQLFEGMKAFKGKDQQVRLFRP
  WLNMDRMLRSAMRLCLPSFDKLELLECIRRLIEVDKDWVPDAAGTSLYVRPVLIGNEPSL
  GVSQPTRALLFVILCPVGAYFPGGSVTPVSLLADPAFIRAWVGGVGNYKLGGNYGPTVLV
  QQEALKRGCEQVLWLYGPDHQLTEVGTMNIFVYWTHEDGVLELVTPPLNGVILPGVVRQS
  LLDMAQTWGEFRVVERTITMKQLLRALEEGRVREVFGSGTACQVCPVHRILYKDRNLHIP
  TMENGPELILRFQKELKEIQYGIRAHEWMFPV
• Function: Catalyzes the first reaction in the catabolism of the essential branched chain amino acids leucine, isoleucine, and valine. May also function as a transporter of branched chain alpha-keto acids.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway:
  Cysteine and methionine metabolism (hsa00270)
  Valine, leucine and isoleucine degradation (hsa00280)
  Valine, leucine and isoleucine biosynthesis (hsa00290)
  Pantothe.te and CoA biosynthesis (hsa00770)
  Metabolic pathways (hsa01100)
  2-Oxocarboxylic acid metabolism (hsa01210)
  Biosynthesis of amino acids (hsa01230)
  Biosynthesis of cofactors (hsa01240)
• Reactome Pathway: Branched-chain amino acid catabolism (R-HSA-70895)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypervalinemia and hyperleucine-isoleucinemia	DISRFO1R	Definitive	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Branched-chain-amino-acid aminotransferase, mitochondrial (BCAT2).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Branched-chain-amino-acid aminotransferase, mitochondrial (BCAT2).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Branched-chain-amino-acid aminotransferase, mitochondrial (BCAT2).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Branched-chain-amino-acid aminotransferase, mitochondrial (BCAT2).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Branched-chain-amino-acid aminotransferase, mitochondrial (BCAT2).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Branched-chain-amino-acid aminotransferase, mitochondrial (BCAT2).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Branched-chain-amino-acid aminotransferase, mitochondrial (BCAT2).	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Branched-chain-amino-acid aminotransferase, mitochondrial (BCAT2).	[9]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Branched-chain-amino-acid aminotransferase, mitochondrial (BCAT2).	[10]
Cidofovir	DMA13GD	Approved	Cidofovir increases the expression of Branched-chain-amino-acid aminotransferase, mitochondrial (BCAT2).	[5]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Branched-chain-amino-acid aminotransferase, mitochondrial (BCAT2).	[5]
Mifepristone	DMGZQEF	Approved	Mifepristone decreases the expression of Branched-chain-amino-acid aminotransferase, mitochondrial (BCAT2).	[11]
Clodronate	DM9Y6X7	Approved	Clodronate increases the expression of Branched-chain-amino-acid aminotransferase, mitochondrial (BCAT2).	[5]
Ibuprofen	DM8VCBE	Approved	Ibuprofen increases the expression of Branched-chain-amino-acid aminotransferase, mitochondrial (BCAT2).	[5]
Haloperidol	DM96SE0	Approved	Haloperidol decreases the expression of Branched-chain-amino-acid aminotransferase, mitochondrial (BCAT2).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Branched-chain-amino-acid aminotransferase, mitochondrial (BCAT2).	[13]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Branched-chain-amino-acid aminotransferase, mitochondrial (BCAT2).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Branched-chain-amino-acid aminotransferase, mitochondrial (BCAT2).	[15]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] 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.
• [3] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [4] 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.
• [5] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [6] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [7] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [8] Endoplasmic reticulum stress contributes to arsenic trioxide-induced intrinsic apoptosis in human umbilical and bone marrow mesenchymal stem cells. Environ Toxicol. 2016 Mar;31(3):314-28.
• [9] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [10] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [11] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [12] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [13] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [14] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [15] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.