Details of Drug-Metabolizing Enzyme (DME)

General Information of Drug-Metabolizing Enzyme (DME) (ID: DESD26P)

• DME Name: UDP-glucuronosyltransferase 1A6 (UGT1A6)
• Synonyms: UDP-glucuronosyltransferase family 1 member A6; UDP-glucuronosyltransferase 1-F; UDP-glucuronosyltransferase 1-6; Phenol-metabolizing UDP-glucuronosyltransferase; UDPGT 1-6; UGT-1F; UGT1*6; UGT1-06; UGT1.6; UGT1A6; UGT1F
• Gene Name: UGT1A6
• UniProt ID: UD16_HUMAN
• INTEDE ID: DME0072
• Gene ID: 54578
• 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:
  MACLLRSFQRISAGVFFLALWGMVVGDKLLVVPQDGSHWLSMKDIVEVLSDRGHEIVVVV
  PEVNLLLKESKYYTRKIYPVPYDQEELKNRYQSFGNNHFAERSFLTAPQTEYRNNMIVIG
  LYFINCQSLLQDRDTLNFFKESKFDALFTDPALPCGVILAEYLGLPSVYLFRGFPCSLEH
  TFSRSPDPVSYIPRCYTKFSDHMTFSQRVANFLVNLLEPYLFYCLFSKYEELASAVLKRD
  VDIITLYQKVSVWLLRYDFVLEYPRPVMPNMVFIGGINCKKRKDLSQEFEAYINASGEHG
  IVVFSLGSMVSEIPEKKAMAIADALGKIPQTVLWRYTGTRPSNLANNTILVKWLPQNDLL
  GHPMTRAFITHAGSHGVYESICNGVPMVMMPLFGDQMDNAKRMETKGAGVTLNVLEMTSE
  DLENALKAVINDKSYKENIMRLSSLHKDRPVEPLDLAVFWVEFVMRHKGAPHLRPAAHDL
  TWYQYHSLDVIGFLLAVVLTVAFITFKCCAYGYRKCLGKKGRVKKAHKSKTH
• Function: This enzyme has specificity for phenols.
• 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)

Molecular Interaction Atlas (MIA) of This DME

8 Approved Drug(s) Metabolized by This DME

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Acetaminophen	DMUIE76	Allergic rhinitis	CA08.0	Approved	[1]
Aspirin	DM672AH	Acute coronary syndrome	BA41	Approved	[2]
Deferiprone	DMS2M7O	Beta thalassemia	3A50.2	Approved	[3]
Mycophenolate mofetil	DMPQAGE	Hepatosplenic T-cell lymphoma		Approved	[4]
Naproxen	DMZ5RGV	Bursitis		Approved	[5]
Propofol	DMB4OLE	Anaesthesia	9A78.6	Approved	[6]
Troglitazone	DM3VFPD	Diabetic complication	5A2Y	Approved	[7]
Valproate	DMCFE9I	Epilepsy	8A60-8A68	Approved	[8]

3 Clinical Trial Drug(s) Metabolized by This DME

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ANDROSTERONE	DMITJAK	N. A.	N. A.	Phase 3	[9]
BCP-13498	DM2BO9W	N. A.	N. A.	Phase 2	[10]
LM-94	DMW3QGJ	N. A.	N. A.	Phase 1/2	[11]

8 Investigative Drug(s) Metabolized by This DME

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
2-hydroxy-17beta-estradiol	DMM9Z0B	Discovery agent	N.A.	Investigative	[9]
bilirubin	DMI0V4O	Discovery agent	N.A.	Investigative	[9]
BRN-1999480	DMC9Q4D	N. A.	N. A.	Investigative	[9]
Hydroxyestradiol	DMJXQME	N. A.	N. A.	Investigative	[9]
Hydroxyestrone	DMBO7ZD	N. A.	N. A.	Investigative	[9]
Hydroxytryptophol	DMZN3GP	N. A.	N. A.	Investigative	[12]
Hyodeoxycholic acid	DMSIWD0	N. A.	N. A.	Investigative	[9]
UDP-glucuronic acid	DMW16X2	Discovery agent	N.A.	Investigative	[11]

Experimental Enzyme Kinetic Data of Drugs

Drug Name	Indication	Highest Status	Kinetic Data	REF
2-hydroxy-17beta-estradiol	Discovery agent [N.A.]	Investigative	Km = 0.024 microM	[9]
bilirubin	Discovery agent [N.A.]	Investigative	Km = 0.024 microM	[9]
UDP-glucuronic acid	Discovery agent [N.A.]	Investigative	Km = 0.00025 microM	[11]
ANDROSTERONE	N. A.	Phase 3	Km = 0.0066 microM	[9]

References

• [1] UGT1A6 and UGT2B15 polymorphisms and acetaminophen conjugation in response to a randomized, controlled diet of select fruits and vegetables. Drug Metab Dispos. 2011 Sep;39(9):1650-7.
• [2] Polymorphisms of Aspirin-Metabolizing Enzymes CYP2C9, NAT2 and UGT1A6 in Aspirin-Intolerant Urticaria. Allergy Asthma Immunol Res. 2011 Oct;3(4):273-6.
• [3] Deferiprone glucuronidation by human tissues and recombinant UDP glucuronosyltransferase 1A6: an in vitro investigation of genetic and splice variants. Drug Metab Dispos. 2009 Feb;37(2):322-9.
• [4] Characterization of rat intestinal microsomal UDP-glucuronosyltransferase activity toward mycophenolic acid. Drug Metab Dispos. 2006 Sep;34(9):1632-9.
• [5] S-Naproxen and desmethylnaproxen glucuronidation by human liver microsomes and recombinant human UDP-glucuronosyltransferases (UGT): role of UGT2B7 in the elimination of naproxen. Br J Clin Pharmacol. 2005 Oct;60(4):423-33.
• [6] Pharmacokinetics of propofol and extrahepatic UGT1A6 gene expression in anhepatic rats. Pharmacology. 2009;84(4):219-26.
• [7] Troglitazone glucuronidation in human liver and intestine microsomes: high catalytic activity of UGT1A8 and UGT1A10. Drug Metab Dispos. 2002 Dec;30(12):1462-9.
• [8] UDP glucuronosyltransferase (UGT) 1A6 pharmacogenetics: II. Functional impact of the three most common nonsynonymous UGT1A6 polymorphisms (S7A, T181A, and R184S). J Pharmacol Exp Ther. 2005 Jun;313(3):1340-6.
• [9] Structural and functional studies of UDP-glucuronosyltransferases. Drug Metab Rev. 1999 Nov;31(4):817-99.
• [10] Human UGT1A6 pharmacogenetics: identification of a novel SNP, characterization of allele frequencies and functional analysis of recombinant allozymes in human liver tissue and in cultured cells. Pharmacogenetics. 2004 Aug;14(8):487-99.
• [11] 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.
• [12] Evaluation of 5-hydroxytryptophol and other endogenous serotonin (5-hydroxytryptamine) analogs as substrates for UDP-glucuronosyltransferase 1A6. Drug Metab Dispos. 2004 Aug;32(8):862-9.