UGT1A9

UGT1A9
Identifiers
Aliases	UGT1A9 , HLUGP4, LUGP4, UDPGT, UDPGT 1-9, UGT-1I, UGT1-09, UGT1-9, UGT1.9, UGT1AI, UGT1I, UGT1A9S, UDP glucuronosyltransferase family 1 member A9
External IDs	OMIM: 606434; MGI: 3580642; HomoloGene: 133281; GeneCards: UGT1A9; OMA:UGT1A9 - orthologs
Gene location (Human)
Chr.	Chromosome 2 (human)
End	233,773,300 bp
Gene location (Mouse)
Chr.	Chromosome 1 (mouse)
End	88,146,726 bp
RNA expression pattern
	Top expressed in
	right lobe of liver; ; renal cortex; ; human kidney; ; mucosa of transverse colon; ; rectum; ; urinary bladder; ; olfactory zone of nasal mucosa; ; duodenum; ; body of stomach; ; islet of Langerhans;
	Top expressed in
	renal cortex; ; nephron; ; proximal tubule; ; renal medulla; ; human kidney; ; hair; ; renal pelvis; ; metanephros; ; lateral recess; ; right kidney;
	More reference expression data
	n/a
Gene ontology
Molecular function	transferase activity ; enzyme inhibitor activity ; retinoic acid binding ; hexosyltransferase activity ; protein homodimerization activity ; glycosyltransferase activity ; glucuronosyltransferase activity ; protein heterodimerization activity ; enzyme binding ; UDP-glycosyltransferase activity ;
Cellular component	integral component of membrane ; endoplasmic reticulum membrane ; membrane ; intracellular membrane-bounded organelle ; endoplasmic reticulum ;
Biological process	retinoic acid metabolic process ; negative regulation of cellular glucuronidation ; cellular glucuronidation ; flavonoid glucuronidation ; xenobiotic glucuronidation ; flavone metabolic process ; xenobiotic metabolic process ; negative regulation of glucuronosyltransferase activity ; negative regulation of fatty acid metabolic process ; regulation of lipid metabolic process ; metabolism ;
	Sources:Amigo / QuickGO
Orthologs
	54600
	394430
	ENSG00000241119
	ENSMUSG00000090165
	O60656
	n/a
	NM_021027
	NM_201641
	NP_066307
	n/a
	Wikidata
View/Edit Human	View/Edit Mouse

Last updated September 22, 2024

UDP-glucuronosyltransferase 1-9 is an enzyme that in humans is encoded by the UGT1A9 gene.^[5]^[6]^[7]^[8]

Function

This gene encodes a UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, bilirubin, hormones, and drugs, into water-soluble, excretable metabolites. This gene is part of a complex locus that encodes several UDP-glucuronosyltransferases. The locus includes thirteen unique alternate first exons followed by four common exons. Four of the alternate first exons are considered pseudogenes. Each of the remaining nine 5′ exons may be spliced to the four common exons, resulting in nine proteins with different N-termini and identical C-termini. Each first exon encodes the substrate binding site, and is regulated by its own promoter. The enzyme encoded by this gene is active on phenols.^[8]

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles.^{[§ 1]}

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|alt=Irinotecan Pathway edit]]

Irinotecan Pathway edit

↑ The interactive pathway map can be edited at WikiPathways: "IrinotecanPathway_WP229".

Medicinal Chemistry Case Studies

During hit optimization of HSD17B13 inhibitors significant glucuronidation of the phenol moiety was observed in vitro and in vivo.^[9] UGT phenotyping revealed UGT1A9 as main contributor for glucuronidation. In addition, tissue distribution as well as bile excretion studies were performed.

Related Research Articles

<span class="mw-page-title-main">Gilbert's syndrome</span> Medical condition

Gilbert syndrome (GS) is a syndrome in which the liver of affected individuals processes bilirubin more slowly than the majority. Many people never have symptoms. Occasionally jaundice may occur.

Glucuronidation is often involved in drug metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids. These linkages involve glycosidic bonds.

<span class="mw-page-title-main">Irinotecan</span> Cancer medication

Irinotecan, sold under the brand name Camptosar among others, is an anti-cancer medication used to treat colon cancer and small cell lung cancer. For colon cancer it is used either alone or with fluorouracil. For small cell lung cancer it is used with cisplatin. It is given intravenously.

<span class="mw-page-title-main">Glucuronosyltransferase</span> Class of enzymes

Uridine 5'-diphospho-glucuronosyltransferase is a microsomal glycosyltransferase that catalyzes the transfer of the glucuronic acid component of UDP-glucuronic acid to a small hydrophobic molecule. This is a glucuronidation reaction.

Thiopurine methyltransferase or thiopurine S-methyltransferase (TPMT) is an enzyme that in humans is encoded by the TPMT gene. A pseudogene for this locus is located on chromosome 18q.

UDP-glucuronosyltransferase 1-1 also known as UGT-1A is an enzyme that in humans is encoded by the UGT1A1 gene.

UGT2B7 (UDP-Glucuronosyltransferase-2B7) is a phase II metabolism isoenzyme found to be active in the liver, kidneys, epithelial cells of the lower gastrointestinal tract and also has been reported in the brain. In humans, UDP-Glucuronosyltransferase-2B7 is encoded by the UGT2B7 gene.

<span class="mw-page-title-main">SN-38</span> Chemical compound

SN-38 is an antineoplastic drug. It is the active metabolite of irinotecan but has 1000 times more activity than irinotecan itself. In vitro cytotoxicity assays show that the potency of SN-38 relative to irinotecan varies from 2- to 2000-fold.

UDP-glucuronosyltransferase 1-6 is an enzyme that in humans is encoded by the UGT1A6 gene.

UDP-glucuronosyltransferase 1-10 is an enzyme that in humans is encoded by the UGT1A10 gene.

UDP-glucuronosyltransferase 2B15 is an enzyme that in humans is encoded by the UGT2B15 gene.

UDP-glucuronosyltransferase 1-3 is an enzyme that in humans is encoded by the UGT1A3 gene.

UDP-glucuronosyltransferase 1-4 is an enzyme that in humans is encoded by the UGT1A4 gene.

UDP glucuronosyltransferase 2 family, polypeptide B4, also known as UGT2B4, is an enzyme that in humans is encoded by the UGT2B4 gene.

UDP-glucuronosyltransferase 2B17 is an enzyme that in humans is encoded by the UGT2B17 gene.

UDP glucuronosyltransferase 1 family, polypeptide A cluster (UGT1A) is a human gene locus which includes several UDP glucuronosyltransferases.

UDP-glucuronosyltransferase 1-5 is an enzyme that in humans is encoded by the UGT1A5 gene.

UDP-glucuronosyltransferase 1-8 is an enzyme that in humans is encoded by the UGT1A8 gene.

UDP glucuronosyltransferase 2 family, polypeptide B1, also known as UGT2B1, is an enzyme that in humans is encoded by the UGT2B1 gene.

UDP glucuronosyltransferase 1 family, polypeptide A7 is a protein that in humans is encoded by the UGT1A7 gene.

References

1 2 3 GRCh38: Ensembl release 89: ENSG00000241119 – Ensembl, May 2017
1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000090165 – Ensembl, May 2017
↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
↑ Wooster R, Sutherland L, Ebner T, Clarke D, Da Cruz e Silva O, Burchell B (September 1991). "Cloning and stable expression of a new member of the human liver phenol/bilirubin: UDP-glucuronosyltransferase cDNA family". Biochem. J. 278 (2): 465–9. doi:10.1042/bj2780465. PMC 1151367 . PMID 1910331.
↑ Mackenzie PI, Owens IS, Burchell B, Bock KW, Bairoch A, Belanger A, Fournel-Gigleux S, Green M, Hum DW, Iyanagi T, Lancet D, Louisot P, Magdalou J, Chowdhury JR, Ritter JK, Schachter H, Tephly TR, Tipton KF, Nebert DW (Oct 1997). "The UDP glycosyltransferase gene superfamily: recommended nomenclature update based on evolutionary divergence". Pharmacogenetics. 7 (4): 255–69. doi:10.1097/00008571-199708000-00001. PMID 9295054.
↑ Ritter JK, Chen F, Sheen YY, Tran HM, Kimura S, Yeatman MT, Owens IS (Mar 1992). "A novel complex locus UGT1 encodes human bilirubin, phenol, and other UDP-glucuronosyltransferase isozymes with identical carboxyl termini". J Biol Chem. 267 (5): 3257–61. doi: 10.1016/S0021-9258(19)50724-4 . PMID 1339448.
1 2 "Entrez Gene: UGT1A9 UDP glucuronosyltransferase 1 family, polypeptide A9".
↑ Thamm S, Willwacher MK, Aspnes GE, Bretschneider T, Brown NF, Buschbom-Helmke S, Fox T, Gargano EM, Grabowski D, Hoenke C, Matera D, Mueck K, Peters S, Reindl S, Riether D, Schmid M, Tautermann CS, Teitelbaum AM, Trünkle C, Veser T, Winter M, Wortmann L (2023). "Discovery of a Novel Potent and Selective HSD17B13 Inhibitor, BI-3231, a Well-Characterized Chemical Probe Available for Open Science". Journal of Medicinal Chemistry. 66 (4): 2832–2850. doi:10.1021/acs.jmedchem.2c01884. PMC 9969402 . PMID 36727857.

Innocenti F, Kroetz DL, Schuetz E, et al. (2009). "Comprehensive Pharmacogenetic Analysis of Irinotecan Neutropenia and Pharmacokinetics". J. Clin. Oncol. 27 (16): 2604–14. doi:10.1200/JCO.2008.20.6300. PMC 2690389 . PMID 19349540.
Holmes MV, Shah T, Vickery C, et al. (2009). Luo Y (ed.). "Fulfilling the Promise of Personalized Medicine? Systematic Review and Field Synopsis of Pharmacogenetic Studies". PLOS ONE. 4 (12): e7960. Bibcode:2009PLoSO...4.7960H. doi: 10.1371/journal.pone.0007960 . PMC 2778625 . PMID 19956635.
Prausa SE, Fukuda T, Maseck D, et al. (2009). "UGT genotype may contribute to adverse events following medication with mycophenolate mofetil in pediatric kidney transplant recipients". Clin. Pharmacol. Ther. 85 (5): 495–500. doi:10.1038/clpt.2009.3. PMID 19225446. S2CID 33309241.
Ross CJ, Katzov-Eckert H, Dubé MP, et al. (2009). "Genetic variants in TPMT and COMT are associated with hearing loss in children receiving cisplatin chemotherapy". Nat. Genet. 41 (12): 1345–9. doi:10.1038/ng.478. PMID 19898482. S2CID 21293339.
Korprasertthaworn P, Udomuksorn W, Yoovathaworn K (2009). "Three novel single nucleotide polymorphisms of UGT1A9 in a Thai population". Drug Metab. Pharmacokinet. 24 (5): 482–5. doi:10.2133/dmpk.24.482. PMID 19881262.
Nakajima M, Koga T, Sakai H, et al. (2010). "N-Glycosylation plays a role in protein folding of human UGT1A9". Biochem. Pharmacol. 79 (8): 1165–72. doi:10.1016/j.bcp.2009.11.020. hdl: 2297/23493 . PMID 19951703. S2CID 11013645.
van Schaik RH, van Agteren M, de Fijter JW, et al. (2009). "UGT1A9 -275T>A/-2152C>T polymorphisms correlate with low MPA exposure and acute rejection in MMF/tacrolimus-treated kidney transplant patients". Clin. Pharmacol. Ther. 86 (3): 319–27. doi:10.1038/clpt.2009.83. PMID 19494809. S2CID 21082902.
Sanna S, Busonero F, Maschio A, et al. (2009). "Common variants in the SLCO1B3 locus are associated with bilirubin levels and unconjugated hyperbilirubinemia". Hum. Mol. Genet. 18 (14): 2711–8. doi:10.1093/hmg/ddp203. PMC 2701337 . PMID 19419973.
King CD, Rios GR, Green MD, Tephly TR (2000). "UDP-glucuronosyltransferases". Curr. Drug Metab. 1 (2): 143–61. doi:10.2174/1389200003339171. PMID 11465080.
Sánchez-Fructuoso AI, Maestro ML, Calvo N, et al. (2009). "The prevalence of uridine diphosphate-glucuronosyltransferase 1A9 (UGT1A9) gene promoter region single-nucleotide polymorphisms T-275A and C-2152T and its influence on mycophenolic acid pharmacokinetics in stable renal transplant patients". Transplant. Proc. 41 (6): 2313–6. doi:10.1016/j.transproceed.2009.06.038. PMID 19715905.
Chu XY, Liang Y, Cai X, et al. (2009). "Metabolism and renal elimination of gaboxadol in humans: role of UDP-glucuronosyltransferases and transporters". Pharm. Res. 26 (2): 459–68. doi:10.1007/s11095-008-9799-5. PMID 19082692. S2CID 24490597.
Bock KW, Gschaidmeier H, Heel H, et al. (1999). "Functions and transcriptional regulation of PAH-inducible human UDP-glucuronosyltransferases". Drug Metab. Rev. 31 (2): 411–22. doi:10.1081/DMR-100101927. PMID 10335444.
Saito Y, Sai K, Maekawa K, et al. (2009). "Close association of UGT1A9 IVS1+399C>T with UGT1A1*28, *6, or *60 haplotype and its apparent influence on 7-ethyl-10-hydroxycamptothecin (SN-38) glucuronidation in Japanese". Drug Metab. Dispos. 37 (2): 272–6. doi:10.1124/dmd.108.024208. PMID 18981166. S2CID 2886803.
Tukey RH, Strassburg CP (2000). "Human UDP-glucuronosyltransferases: metabolism, expression, and disease". Annu. Rev. Pharmacol. Toxicol. 40: 581–616. doi:10.1146/annurev.pharmtox.40.1.581. PMID 10836148.
Ménard V, Girard H, Harvey M, et al. (2009). "Analysis of inherited genetic variations at the UGT1 locus in the French-Canadian population". Hum. Mutat. 30 (4): 677–87. doi: 10.1002/humu.20946 . PMID 19204906. S2CID 6235077.
Cecchin E, Innocenti F, D'Andrea M, et al. (2009). "Predictive role of the UGT1A1, UGT1A7, and UGT1A9 genetic variants and their haplotypes on the outcome of metastatic colorectal cancer patients treated with fluorouracil, leucovorin, and irinotecan". J. Clin. Oncol. 27 (15): 2457–65. doi: 10.1200/JCO.2008.19.0314 . PMID 19364970.
Fujiwara R, Nakajima M, Yamamoto T, et al. (2009). "In silico and in vitro approaches to elucidate the thermal stability of human UDP-glucuronosyltransferase (UGT) 1A9". Drug Metab. Pharmacokinet. 24 (3): 235–44. doi:10.2133/dmpk.24.235. PMID 19571435.
Kadakol A, Ghosh SS, Sappal BS, et al. (2000). "Genetic lesions of bilirubin uridine-diphosphoglucuronate glucuronosyltransferase (UGT1A1) causing Crigler-Najjar and Gilbert syndromes: correlation of genotype to phenotype". Hum. Mutat. 16 (4): 297–306. doi:10.1002/1098-1004(200010)16:4<297::AID-HUMU2>3.0.CO;2-Z. PMID 11013440. S2CID 24275067.
Johnson AD, Kavousi M, Smith AV, et al. (2009). "Genome-wide association meta-analysis for total serum bilirubin levels". Hum. Mol. Genet. 18 (14): 2700–10. doi:10.1093/hmg/ddp202. PMC 2701336 . PMID 19414484.

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[WikiPathways-9] The interactive pathway map can be edited at WikiPathways: "IrinotecanPathway_WP229".

[refGRCh38Ensembl-1] 1 2 3 GRCh38: Ensembl release 89: ENSG00000241119 – Ensembl, May 2017

[refGRCm38Ensembl-2] 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000090165 – Ensembl, May 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[pmid1910331-5] Wooster R, Sutherland L, Ebner T, Clarke D, Da Cruz e Silva O, Burchell B (September 1991). "Cloning and stable expression of a new member of the human liver phenol/bilirubin: UDP-glucuronosyltransferase cDNA family". Biochem. J. 278 (2): 465–9. doi:10.1042/bj2780465. PMC 1151367 . PMID 1910331.

[pmid9295054-6] Mackenzie PI, Owens IS, Burchell B, Bock KW, Bairoch A, Belanger A, Fournel-Gigleux S, Green M, Hum DW, Iyanagi T, Lancet D, Louisot P, Magdalou J, Chowdhury JR, Ritter JK, Schachter H, Tephly TR, Tipton KF, Nebert DW (Oct 1997). "The UDP glycosyltransferase gene superfamily: recommended nomenclature update based on evolutionary divergence". Pharmacogenetics. 7 (4): 255–69. doi:10.1097/00008571-199708000-00001. PMID 9295054.

[pmid1339448-7] Ritter JK, Chen F, Sheen YY, Tran HM, Kimura S, Yeatman MT, Owens IS (Mar 1992). "A novel complex locus UGT1 encodes human bilirubin, phenol, and other UDP-glucuronosyltransferase isozymes with identical carboxyl termini". J Biol Chem. 267 (5): 3257–61. doi: 10.1016/S0021-9258(19)50724-4 . PMID 1339448.

[entrez-8] 1 2 "Entrez Gene: UGT1A9 UDP glucuronosyltransferase 1 family, polypeptide A9".

[10] Thamm S, Willwacher MK, Aspnes GE, Bretschneider T, Brown NF, Buschbom-Helmke S, Fox T, Gargano EM, Grabowski D, Hoenke C, Matera D, Mueck K, Peters S, Reindl S, Riether D, Schmid M, Tautermann CS, Teitelbaum AM, Trünkle C, Veser T, Winter M, Wortmann L (2023). "Discovery of a Novel Potent and Selective HSD17B13 Inhibitor, BI-3231, a Well-Characterized Chemical Probe Available for Open Science". Journal of Medicinal Chemistry. 66 (4): 2832–2850. doi:10.1021/acs.jmedchem.2c01884. PMC 9969402 . PMID 36727857.

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