Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8OSVYU)

• DOT Name: 2-oxoisovalerate dehydrogenase subunit beta, mitochondrial (BCKDHB)
• Synonyms: EC 1.2.4.4; Branched-chain alpha-keto acid dehydrogenase E1 component beta chain; BCKDE1B; BCKDH E1-beta
• Gene Name: BCKDHB
• Related Disease:
  Maple syrup urine disease
  Maple syrup urine disease type 1B
  Advanced cancer
  Coeliac disease
  Hepatitis B virus infection
  Hepatocellular carcinoma
  Neoplasm
  Pancreatic cancer
  Systemic lupus erythematosus
  Thyroid gland undifferentiated (anaplastic) carcinoma
  Adenovirus infection
  Female hypogonadism
  Classic maple syrup urine disease
  Intermediate maple syrup urine disease
  Intermittent maple syrup urine disease
  Thiamine-responsive maple syrup urine disease
• UniProt ID: ODBB_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: PF02779 ; PF02780
• Sequence:
  MAVVAAAAGWLLRLRAAGAEGHWRRLPGAGLARGFLHPAATVEDAAQRRQVAHFTFQPDP
  EPREYGQTQKMNLFQSVTSALDNSLAKDPTAVIFGEDVAFGGVFRCTVGLRDKYGKDRVF
  NTPLCEQGIVGFGIGIAVTGATAIAEIQFADYIFPAFDQIVNEAAKYRYRSGDLFNCGSL
  TIRSPWGCVGHGALYHSQSPEAFFAHCPGIKVVIPRSPFQAKGLLLSCIEDKNPCIFFEP
  KILYRAAAEEVPIEPYNIPLSQAEVIQEGSDVTLVAWGTQVHVIREVASMAKEKLGVSCE
  VIDLRTIIPWDVDTICKSVIKTGRLLISHEAPLTGGFASEISSTVQEECFLNLEAPISRV
  CGYDTPFPHIFEPFYIPDKWKCYDALRKMINY
• Function: Together with BCKDHA 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-12006

Molecular Interaction Atlas (MIA) of This DOT

16 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 1B	DISGPKK3	Definitive	Autosomal recessive	[2]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[3]
Coeliac disease	DISIY60C	Strong	Biomarker	[4]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[6]
Neoplasm	DISZKGEW	Strong	Altered Expression	[7]
Pancreatic cancer	DISJC981	Strong	Biomarker	[8]
Systemic lupus erythematosus	DISI1SZ7	Strong	Posttranslational Modification	[9]
Thyroid gland undifferentiated (anaplastic) carcinoma	DISYBB1W	Strong	Biomarker	[10]
Adenovirus infection	DISUYSBZ	moderate	Biomarker	[11]
Female hypogonadism	DISWASB4	moderate	Genetic Variation	[12]
Classic maple syrup urine disease	DIS848CW	Supportive	Autosomal recessive	[13]
Intermediate maple syrup urine disease	DIS5SRXS	Supportive	Autosomal recessive	[13]
Intermittent maple syrup urine disease	DISJEHB2	Supportive	Autosomal recessive	[13]
Thiamine-responsive maple syrup urine disease	DISEL4MR	Supportive	Autosomal recessive	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Chlorothiazide	DMLHESP	Approved	2-oxoisovalerate dehydrogenase subunit beta, mitochondrial (BCKDHB) increases the Metabolic disorder ADR of Chlorothiazide.	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of 2-oxoisovalerate dehydrogenase subunit beta, mitochondrial (BCKDHB).	[14]

13 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 2-oxoisovalerate dehydrogenase subunit beta, mitochondrial (BCKDHB).	[15]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of 2-oxoisovalerate dehydrogenase subunit beta, mitochondrial (BCKDHB).	[16]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of 2-oxoisovalerate dehydrogenase subunit beta, mitochondrial (BCKDHB).	[17]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of 2-oxoisovalerate dehydrogenase subunit beta, mitochondrial (BCKDHB).	[18]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of 2-oxoisovalerate dehydrogenase subunit beta, mitochondrial (BCKDHB).	[19]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of 2-oxoisovalerate dehydrogenase subunit beta, mitochondrial (BCKDHB).	[20]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of 2-oxoisovalerate dehydrogenase subunit beta, mitochondrial (BCKDHB).	[21]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of 2-oxoisovalerate dehydrogenase subunit beta, mitochondrial (BCKDHB).	[22]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of 2-oxoisovalerate dehydrogenase subunit beta, mitochondrial (BCKDHB).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of 2-oxoisovalerate dehydrogenase subunit beta, mitochondrial (BCKDHB).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of 2-oxoisovalerate dehydrogenase subunit beta, mitochondrial (BCKDHB).	[25]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of 2-oxoisovalerate dehydrogenase subunit beta, mitochondrial (BCKDHB).	[26]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of 2-oxoisovalerate dehydrogenase subunit beta, mitochondrial (BCKDHB).	[27]

References

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