Details of Drug-Metabolizing Enzyme (DME)

General Information of Drug-Metabolizing Enzyme (DME) (ID: DELOY3P)

• DME Name: UDP-glucuronosyltransferase 1A4 (UGT1A4)
• Synonyms: UDP-glucuronosyltransferase family 1 member A4; UDP-glucuronosyltransferase 1-D; UDP-glucuronosyltransferase 1-4; Bilirubin-specific UDPGT isozyme 2; UDPGT 1-4; UGT-1D; UGT1*4; UGT1-04; UGT1.4; UGT1A4; UGT1D; hUG-BR2
• Gene Name: UGT1A4
• UniProt ID: UD14_HUMAN
• INTEDE ID: DME0048
• Gene ID: 54657
• EC Number:
  EC: 2.4.1.17
  Transferase
  Glycosyltransferases
  Hexosyltransferase
  EC: 2.4.1.17
• Lineage:
  Species: Homo sapiens
  Kingdom: Metazoa
  Phylum: Chordata
  Class: Mammalia
  Order: Primates
  Family: Hominidae
  Genus: Homo
  Species: Homo sapiens
• Sequence:
  MARGLQVPLPRLATGLLLLLSVQPWAESGKVLVVPTDGSPWLSMREALRELHARGHQAVV
  LTPEVNMHIKEEKFFTLTAYAVPWTQKEFDRVTLGYTQGFFETEHLLKRYSRSMAIMNNV
  SLALHRCCVELLHNEALIRHLNATSFDVVLTDPVNLCGAVLAKYLSIPAVFFWRYIPCDL
  DFKGTQCPNPSSYIPKLLTTNSDHMTFLQRVKNMLYPLALSYICHTFSAPYASLASELFQ
  REVSVVDLVSYASVWLFRGDFVMDYPRPIMPNMVFIGGINCANGKPLSQEFEAYINASGE
  HGIVVFSLGSMVSEIPEKKAMAIADALGKIPQTVLWRYTGTRPSNLANNTILVKWLPQND
  LLGHPMTRAFITHAGSHGVYESICNGVPMVMMPLFGDQMDNAKRMETKGAGVTLNVLEMT
  SEDLENALKAVINDKSYKENIMRLSSLHKDRPVEPLDLAVFWVEFVMRHKGAPHLRPAAH
  DLTWYQYHSLDVIGFLLAVVLTVAFITFKCCAYGYRKCLGKKGRVKKAHKSKTH
• Function: This enzyme glucuronidates bilirubin IX-alpha to form both the IX-alpha-C8 and IX-alpha-C12 monoconjugates and diconjugate.
• KEGG Pathway:
  Ascorbate and aldarate metabolism (hsa00053)
  Chemical carcinogenesis (hsa05204)
  Drug metabolism - cytochrome P450 (hsa00982)
  Drug metabolism - other enzymes (hsa00983)
  Metabolic pathways (hsa01100)
  Metabolism of xenobiotics by cytochrome P450 (hsa00980)
  Pentose and glucuronate interconversions (hsa00040)
  Porphyrin and chlorophyll metabolism (hsa00860)
  Retinol metabolism (hsa00830)
  Steroid hormone biosynthesis (hsa00140)
• Reactome Pathway:
  Glucuronidation (R-HSA-156588)
  Heme degradation (R-HSA-189483)
  Defective UGT1A4 causes hyperbilirubinemia (R-HSA-5579016)

Molecular Interaction Atlas (MIA) of This DME

6 Approved Drug(s) Metabolized by This DME

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Anastrozole	DMNP60F	Breast cancer	2C60-2C65	Approved	[]
Calcitriol	DM8ZVJ7	Congenital alopecia	LC30	Approved	[1]
Ketotifen	DM74XKS	Allergic conjunctivitis	9A60.02	Approved	[]
Lamotrigine	DM8SXYG	Bipolar disorder	6A60	Approved	[2]
Lorlatinib	DMICDLV	Non-small-cell lung cancer	2C25.Y	Approved	[3]
Rilpivirine	DMJ0QOW	Human immunodeficiency virus infection	1C62	Approved	[4]

2 Clinical Trial Drug(s) Metabolized by This DME

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Bevirimat	DML2D8Q	Human immunodeficiency virus infection	1C62	Phase 2	[5]
LM-94	DMW3QGJ	N. A.	N. A.	Phase 1/2	[6]

1 Investigative Drug(s) Metabolized by This DME

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
UDP-glucuronic acid	DMW16X2	Discovery agent	N.A.	Investigative	[6]

Experimental Enzyme Kinetic Data of Drugs

Drug Name	Indication	Highest Status	Kinetic Data	REF
UDP-glucuronic acid	Discovery agent [N.A.]	Investigative	Km = 0.00025 microM	[6]
Calcitriol	Congenital alopecia [LC30]	Approved	Km = 0.0073 microM	[1]

References

• [1] Identification of human UDP-glucuronosyltransferases catalyzing hepatic 1alpha,25-dihydroxyvitamin D3 conjugation. Biochem Pharmacol. 2008 Mar 1;75(5):1240-50.
• [2] Studies on induction of lamotrigine metabolism in transgenic UGT1 mice. Xenobiotica. 2009 Nov;39(11):826-35.
• [3] FDA label of Lorlatinib. The 2020 official website of the U.S. Food and Drug Administration.
• [4] Human biotransformation of the nonnucleoside reverse transcriptase inhibitor rilpivirine and a cross-species metabolism comparison. Antimicrob Agents Chemother. 2013 Oct;57(10):5067-79.
• [5] Bevirimat: a novel maturation inhibitor for the treatment of HIV-1 infection. Antivir Chem Chemother. 2008;19(3):107-13.
• [6] Identification of aspartic acid and histidine residues mediating the reaction mechanism and the substrate specificity of the human UDP-glucuronosyltransferases 1A. J Biol Chem. 2007 Dec 14;282(50):36514-24.