Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTN90HDQ)

• DOT Name: UDP-glucuronosyltransferase 1A5
• Synonyms: UGT1A5; EC 2.4.1.17; UDP-glucuronosyltransferase 1-5; UDPGT 1-5; UGT1*5; UGT1-05; UGT1.5; UDP-glucuronosyltransferase 1-E; UGT-1E; UGT1E
• Gene Name: UGT1A5
• UniProt ID: UD15_HUMAN
• EC Number: 2.4.1.17
• Pfam ID: PF00201
• Sequence:
  MATGLQVPLPQLATGLLLLLSVQPWAESGKVLVVPTDGSHWLSMREALRDLHARGHQVVV
  LTLEVNMYIKEENFFTLTTYAISWTQDEFDRLLLGHTQSFFETEHLLMKFSRRMAIMNNM
  SLIIHRSCVELLHNEALIRHLHATSFDVVLTDPFHLCAAVLAKYLSIPAVFFLRNIPCDL
  DFKGTQCPNPSSYIPRLLTTNSDHMTFLQRVKNMLYPLALSYLCHAVSAPYASLASELFQ
  REVSVVDLVSHASVWLFRGDFVMDYPRPIMPNMVFIGGINCANGKPLSQEFEAYINASGE
  HGIVVFSLGSMVSEIPEKKAMAIADALGKIPQTVLWRYTGTRPSNLANNTILVKWLPQND
  LLGHPMTRAFITHAGSHGVYESICNGVPMVMMPLFGDQMDNAKRMETKGAGVTLNVLEMT
  SEDLENALKAVINDKSYKENIMRLSSLHKDRPVEPLDLAVFWVEFVMRHKGAPHLRPAAH
  DLTWYQYHSLDVIGFLLAVVLTVAFITFKCCAYGYRKCLGKKGRVKKAHKSKTH
• Function: [Isoform 1]: UDP-glucuronosyltransferase (UGT) that catalyzes phase II biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase the metabolite's water solubility, thereby facilitating excretion into either the urine or bile. Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds. Involved in the glucuronidation of the AGTR1 angiotensin receptor antagonist zolarsatan, a drug which can inhibit the effect of angiotensin II ; [Isoform 2]: Lacks UGT glucuronidation activity but acts as a negative regulator of isoform 1.
• Tissue Specificity: Isoform 1 and isoform 2 are expressed in colon and small intestine. Neither isoform is expressed in liver, kidney or esophagus.
• KEGG Pathway:
  Pentose and glucuro.te interconversions (hsa00040)
  Ascorbate and aldarate metabolism (hsa00053)
  Steroid hormone biosynthesis (hsa00140)
  Retinol metabolism (hsa00830)
  Porphyrin metabolism (hsa00860)
  Metabolism of xenobiotics by cytochrome P450 (hsa00980)
  Drug metabolism - cytochrome P450 (hsa00982)
  Drug metabolism - other enzymes (hsa00983)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
  Bile secretion (hsa04976)
  Chemical carcinogenesis - D. adducts (hsa05204)
  Chemical carcinogenesis - receptor activation (hsa05207)
• Reactome Pathway:
  Aspirin ADME (R-HSA-9749641)
  Glucuronidation (R-HSA-156588)

Molecular Interaction Atlas (MIA) of This DOT

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 UDP-glucuronosyltransferase 1A5.	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Omeprazole	DM471KJ	Approved	Omeprazole increases the expression of UDP-glucuronosyltransferase 1A5.	[2]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of UDP-glucuronosyltransferase 1A5.	[3]
pregnenolone-16alpha-carbonitrile	DM0LW7G	Investigative	pregnenolone-16alpha-carbonitrile increases the expression of UDP-glucuronosyltransferase 1A5.	[4]

References

• [1] 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.
• [2] Use of mRNA expression to detect the induction of drug metabolising enzymes in rat and human hepatocytes. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):86-96.
• [3] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [4] Tissue-specific, inducible, and hormonal control of the human UDP-glucuronosyltransferase-1 (UGT1) locus. J Biol Chem. 2005 Nov 11;280(45):37547-57.