Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0LHOZB)

• DOT Name: 2-oxoisovalerate dehydrogenase subunit alpha, mitochondrial (BCKDHA)
• Synonyms: EC 1.2.4.4; Branched-chain alpha-keto acid dehydrogenase E1 component alpha chain; BCKDE1A; BCKDH E1-alpha
• Gene Name: BCKDHA
• Related Disease:
  Maple syrup urine disease
  Maple syrup urine disease type 1A
  Arthritis
  Bacillary dysentery
  Crohn disease
  Stroke
  Trichohepatoenteric syndrome
  Ulcerative colitis
  Fetal growth restriction
  Classic maple syrup urine disease
  Intermediate maple syrup urine disease
  Intermittent maple syrup urine disease
  Thiamine-responsive maple syrup urine disease
• UniProt ID: ODBA_HUMAN
• PDB ID: 1DTW; 1OLS; 1OLU; 1OLX; 1U5B; 1V11; 1V16; 1V1M; 1V1R; 1WCI; 1X7W; 1X7X; 1X7Y; 1X7Z; 1X80; 2BEU; 2BEV; 2BEW; 2BFB; 2BFC; 2BFD; 2BFE; 2BFF; 2J9F
• EC Number: 1.2.4.4
• Pfam ID: PF00676
• Sequence:
  MAVAIAAARVWRLNRGLSQAALLLLRQPGARGLARSHPPRQQQQFSSLDDKPQFPGASAE
  FIDKLEFIQPNVISGIPIYRVMDRQGQIINPSEDPHLPKEKVLKLYKSMTLLNTMDRILY
  ESQRQGRISFYMTNYGEEGTHVGSAAALDNTDLVFGQYREAGVLMYRDYPLELFMAQCYG
  NISDLGKGRQMPVHYGCKERHFVTISSPLATQIPQAVGAAYAAKRANANRVVICYFGEGA
  ASEGDAHAGFNFAATLECPIIFFCRNNGYAISTPTSEQYRGDGIAARGPGYGIMSIRVDG
  NDVFAVYNATKEARRRAVAENQPFLIEAMTYRIGHHSTSDDSSAYRSVDEVNYWDKQDHP
  ISRLRHYLLSQGWWDEEQEKAWRKQSRRKVMEAFEQAERKPKPNPNLLFSDVYQEMPAQL
  RKQQESLARHLQTYGEHYPLDHFDK
• Function: Together with BCKDHB forms the heterotetrameric E1 subunit of the mitochondrial branched-chain alpha-ketoacid dehydrogenase (BCKD) complex. The BCKD complex catalyzes the multi-step oxidative decarboxylation of alpha-ketoacids derived from the branched-chain amino-acids valine, leucine and isoleucine producing CO2 and acyl-CoA which is subsequently utilized to produce energy. The E1 subunit catalyzes the first step with the decarboxylation of the alpha-ketoacid forming an enzyme-product intermediate. A reductive acylation mediated by the lipoylamide cofactor of E2 extracts the acyl group from the E1 active site for the next step of the reaction.
• KEGG Pathway:
  Valine, leucine and isoleucine degradation (hsa00280)
  Propanoate metabolism (hsa00640)
  Lipoic acid metabolism (hsa00785)
  Metabolic pathways (hsa01100)
  2-Oxocarboxylic acid metabolism (hsa01210)
• Reactome Pathway:
  Branched-chain amino acid catabolism (R-HSA-70895)
  Glyoxylate metabolism and glycine degradation (R-HSA-389661)
• BioCyc Pathway: MetaCyc:MONOMER-12005

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Maple syrup urine disease	DIS61XRH	Definitive	Autosomal recessive	[1]
Maple syrup urine disease type 1A	DIS0P5DC	Definitive	Autosomal recessive	[2]
Arthritis	DIST1YEL	Strong	Biomarker	[3]
Bacillary dysentery	DISFZHKN	Strong	Genetic Variation	[4]
Crohn disease	DIS2C5Q8	Strong	Biomarker	[5]
Stroke	DISX6UHX	Strong	Biomarker	[6]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Biomarker	[7]
Ulcerative colitis	DIS8K27O	Strong	Biomarker	[5]
Fetal growth restriction	DIS5WEJ5	moderate	Biomarker	[8]
Classic maple syrup urine disease	DIS848CW	Supportive	Autosomal recessive	[9]
Intermediate maple syrup urine disease	DIS5SRXS	Supportive	Autosomal recessive	[9]
Intermittent maple syrup urine disease	DISJEHB2	Supportive	Autosomal recessive	[9]
Thiamine-responsive maple syrup urine disease	DISEL4MR	Supportive	Autosomal recessive	[9]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Topotecan	DMP6G8T	Approved	2-oxoisovalerate dehydrogenase subunit alpha, mitochondrial (BCKDHA) affects the response to substance of Topotecan.	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of 2-oxoisovalerate dehydrogenase subunit alpha, mitochondrial (BCKDHA).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of 2-oxoisovalerate dehydrogenase subunit alpha, mitochondrial (BCKDHA).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of 2-oxoisovalerate dehydrogenase subunit alpha, mitochondrial (BCKDHA).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of 2-oxoisovalerate dehydrogenase subunit alpha, mitochondrial (BCKDHA).	[13]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of 2-oxoisovalerate dehydrogenase subunit alpha, mitochondrial (BCKDHA).	[15]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of 2-oxoisovalerate dehydrogenase subunit alpha, mitochondrial (BCKDHA).	[10]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of 2-oxoisovalerate dehydrogenase subunit alpha, mitochondrial (BCKDHA).	[16]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of 2-oxoisovalerate dehydrogenase subunit alpha, mitochondrial (BCKDHA).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of 2-oxoisovalerate dehydrogenase subunit alpha, mitochondrial (BCKDHA).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of 2-oxoisovalerate dehydrogenase subunit alpha, mitochondrial (BCKDHA).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin increases the phosphorylation of 2-oxoisovalerate dehydrogenase subunit alpha, mitochondrial (BCKDHA).	[14]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of 2-oxoisovalerate dehydrogenase subunit alpha, mitochondrial (BCKDHA).	[14]

References

• [1] Molecular genetic basis of maple syrup urine disease in a family with two defective alleles for branched chain acyltransferase and localization of the gene to human chromosome 1. Am J Hum Genet. 1991 Feb;48(2):342-50.
• [2] 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.
• [3] Monosodium urate crystal interleukin-1 release is dependent on Toll-like receptor 4 and transient receptor potential V1 activation.Rheumatology (Oxford). 2020 Jan 1;59(1):233-242. doi: 10.1093/rheumatology/kez259.
• [4] Shigella hijacks the glomulin-cIAPs-inflammasome axis to promote inflammation.EMBO Rep. 2018 Jan;19(1):89-101. doi: 10.15252/embr.201643841. Epub 2017 Nov 30.
• [5] Activation of NLRP3 Inflammasome in Inflammatory Bowel Disease: Differences Between Crohn's Disease and Ulcerative Colitis.Dig Dis Sci. 2017 Sep;62(9):2348-2356. doi: 10.1007/s10620-017-4609-8. Epub 2017 May 18.
• [6] Telemedicine Can Replace the Neurologist on a Mobile Stroke Unit.Stroke. 2017 Feb;48(2):493-496. doi: 10.1161/STROKEAHA.116.015363. Epub 2017 Jan 12.
• [7] ABRO1 promotes NLRP3 inflammasome activation through regulation of NLRP3 deubiquitination.EMBO J. 2019 Mar 15;38(6):e100376. doi: 10.15252/embj.2018100376. Epub 2019 Feb 20.
• [8] Uric Acid Crystals Induce Placental Inflammation and Alter Trophoblast Function via an IL-1-Dependent Pathway: Implications for Fetal Growth Restriction.J Immunol. 2017 Jan 1;198(1):443-451. doi: 10.4049/jimmunol.1601179. Epub 2016 Nov 30.
• [9] Maple Syrup Urine Disease. 2006 Jan 30 [updated 2020 Apr 23]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [10] 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.
• [11] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [12] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [13] 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.
• [14] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [15] 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.
• [16] Multi-level gene expression profiles affected by thymidylate synthase and 5-fluorouracil in colon cancer. BMC Genomics. 2006 Apr 3;7:68. doi: 10.1186/1471-2164-7-68.
• [17] Quantitative proteomics and transcriptomics addressing the estrogen receptor subtype-mediated effects in T47D breast cancer cells exposed to the phytoestrogen genistein. Mol Cell Proteomics. 2011 Jan;10(1):M110.002170.
• [18] 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.
• [19] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [20] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.