UD14_HUMAN
ID UD14_HUMAN Reviewed; 534 AA.
AC P22310; B2R937; B8K288; Q5DT00;
DT 01-AUG-1991, integrated into UniProtKB/Swiss-Prot.
DT 01-AUG-1991, sequence version 1.
DT 03-AUG-2022, entry version 210.
DE RecName: Full=UDP-glucuronosyltransferase 1A4 {ECO:0000303|PubMed:24641623};
DE Short=UGT1A4;
DE EC=2.4.1.17 {ECO:0000269|PubMed:18177842, ECO:0000269|PubMed:24641623};
DE AltName: Full=Bilirubin-specific UDPGT isozyme 2;
DE Short=hUG-BR2;
DE AltName: Full=UDP-glucuronosyltransferase 1-4;
DE Short=UDPGT 1-4;
DE Short=UGT1*4;
DE Short=UGT1-04;
DE Short=UGT1.4;
DE AltName: Full=UDP-glucuronosyltransferase 1-D;
DE Short=UGT-1D;
DE Short=UGT1D;
DE Flags: Precursor;
GN Name=UGT1A4 {ECO:0000312|HGNC:HGNC:12536}; Synonyms=GNT1, UGT1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
RC TISSUE=Liver;
RX PubMed=1898728; DOI=10.1016/s0021-9258(17)35280-8;
RA Ritter J.K., Crawford J.M., Owens I.S.;
RT "Cloning of two human liver bilirubin UDP-glucuronosyltransferase cDNAs
RT with expression in COS-1 cells.";
RL J. Biol. Chem. 266:1043-1047(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND TISSUE SPECIFICITY (ISOFORM 1).
RX PubMed=1339448; DOI=10.1016/s0021-9258(19)50724-4;
RA Ritter J.K., Chen F., Sheen Y.Y., Tran H.M., Kimura S., Yeatman M.T.,
RA Owens I.S.;
RT "A novel complex locus UGT1 encodes human bilirubin, phenol, and other UDP-
RT glucuronosyltransferase isozymes with identical carboxyl termini.";
RL J. Biol. Chem. 267:3257-3261(1992).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=11434514; DOI=10.1097/00008571-200106000-00011;
RA Gong Q.H., Cho J.W., Huang T., Potter C., Gholami N., Basu N.K., Kubota S.,
RA Carvalho S., Pennington M.W., Owens I.S., Popescu N.C.;
RT "Thirteen UDP-glucuronosyltransferase genes are encoded at the human UGT1
RT gene complex locus.";
RL Pharmacogenetics 11:357-368(2001).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=14672974; DOI=10.1101/gr.1225204;
RA Zhang T., Haws P., Wu Q.;
RT "Multiple variable first exons: a mechanism for cell- and tissue-specific
RT gene regulation.";
RL Genome Res. 14:79-89(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT VAL-48.
RC TISSUE=Liver;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RA Guillemette C., Levesque E., Girard H., Bernard O.;
RL Submitted (JAN-2006) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT 4.";
RL Nature 434:724-731(2005).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [10]
RP FUNCTION (ISOFORM 2), ALTERNATIVE SPLICING, AND TISSUE SPECIFICITY
RP (ISOFORMS 1 AND 2).
RX PubMed=18004212; DOI=10.1097/fpc.0b013e3282f1f118;
RA Girard H., Levesque E., Bellemare J., Journault K., Caillier B.,
RA Guillemette C.;
RT "Genetic diversity at the UGT1 locus is amplified by a novel 3' alternative
RT splicing mechanism leading to nine additional UGT1A proteins that act as
RT regulators of glucuronidation activity.";
RL Pharmacogenet. Genomics 17:1077-1089(2007).
RN [11]
RP SUBUNIT, AND SUBCELLULAR LOCATION.
RX PubMed=17179145; DOI=10.1074/jbc.m609417200;
RA Operana T.N., Tukey R.H.;
RT "Oligomerization of the UDP-glucuronosyltransferase 1A proteins: homo- and
RT heterodimerization analysis by fluorescence resonance energy transfer and
RT co-immunoprecipitation.";
RL J. Biol. Chem. 282:4821-4829(2007).
RN [12]
RP FUNCTION (ISOFORM 1), CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES,
RP AND SUBSTRATE SPECIFICITY.
RX PubMed=18177842; DOI=10.1016/j.bcp.2007.11.008;
RA Hashizume T., Xu Y., Mohutsky M.A., Alberts J., Hadden C., Kalhorn T.F.,
RA Isoherranen N., Shuhart M.C., Thummel K.E.;
RT "Identification of human UDP-glucuronosyltransferases catalyzing hepatic
RT 1alpha,25-dihydroxyvitamin D3 conjugation.";
RL Biochem. Pharmacol. 75:1240-1250(2008).
RN [13]
RP BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=18719240; DOI=10.1124/dmd.108.022731;
RA Itaeaho K., Mackenzie P.I., Ikushiro S., Miners J.O., Finel M.;
RT "The configuration of the 17-hydroxy group variably influences the
RT glucuronidation of beta-estradiol and epiestradiol by human UDP-
RT glucuronosyltransferases.";
RL Drug Metab. Dispos. 36:2307-2315(2008).
RN [14]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-142 AND ASN-348.
RC TISSUE=Liver;
RX PubMed=19159218; DOI=10.1021/pr8008012;
RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT "Glycoproteomics analysis of human liver tissue by combination of multiple
RT enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
RN [15]
RP FUNCTION (ISOFORM 2), AND SUBUNIT.
RX PubMed=20610558; DOI=10.1124/dmd.110.034835;
RA Bellemare J., Rouleau M., Girard H., Harvey M., Guillemette C.;
RT "Alternatively spliced products of the UGT1A gene interact with the
RT enzymatically active proteins to inhibit glucuronosyltransferase activity
RT in vitro.";
RL Drug Metab. Dispos. 38:1785-1789(2010).
RN [16]
RP BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=23288867; DOI=10.1124/dmd.112.049072;
RA Sneitz N., Vahermo M., Mosorin J., Laakkonen L., Poirier D., Finel M.;
RT "Regiospecificity and stereospecificity of human UDP-
RT glucuronosyltransferases in the glucuronidation of estriol, 16-epiestriol,
RT 17-epiestriol, and 13-epiestradiol.";
RL Drug Metab. Dispos. 41:582-591(2013).
RN [17]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [18]
RP VARIANTS THR-24 AND VAL-48.
RX PubMed=19204906; DOI=10.1002/humu.20946;
RA Menard V., Girard H., Harvey M., Perusse L., Guillemette C.;
RT "Analysis of inherited genetic variations at the UGT1 locus in the French-
RT Canadian population.";
RL Hum. Mutat. 30:677-687(2009).
RN [19]
RP FUNCTION (ISOFORM 1), CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES,
RP AND VARIANT VAL-48.
RX PubMed=24641623; DOI=10.1210/en.2013-2013;
RA Wang Z., Wong T., Hashizume T., Dickmann L.Z., Scian M., Koszewski N.J.,
RA Goff J.P., Horst R.L., Chaudhry A.S., Schuetz E.G., Thummel K.E.;
RT "Human UGT1A4 and UGT1A3 conjugate 25-hydroxyvitamin D3: metabolite
RT structure, kinetics, inducibility, and interindividual variability.";
RL Endocrinology 155:2052-2063(2014).
CC -!- FUNCTION: [Isoform 1]: UDP-glucuronosyltransferase (UGT) that catalyzes
CC phase II biotransformation reactions in which lipophilic substrates are
CC conjugated with glucuronic acid to increase the metabolite's water
CC solubility, thereby facilitating excretion into either the urine or
CC bile (PubMed:18177842, PubMed:24641623). Essential for the elimination
CC and detoxification of drugs, xenobiotics and endogenous compounds
CC (PubMed:18177842). Involved in the glucuronidation of calcidiol, which
CC is the major circulating form of vitamin D3 essential for the
CC regulation of calcium and phosphate homeostasis (PubMed:24641623). Also
CC glucuronidates the biologically active form of vitamin D3, calcitriol,
CC probably leading to its biliary transport and intestinal reabsorption
CC (PubMed:18177842). {ECO:0000269|PubMed:18177842,
CC ECO:0000269|PubMed:24641623}.
CC -!- FUNCTION: [Isoform 2]: Lacks UDP-glucuronosyltransferase (UGT) activity
CC but acts as a negative regulator of isoform 1.
CC {ECO:0000269|PubMed:18004212, ECO:0000269|PubMed:20610558}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=glucuronate acceptor + UDP-alpha-D-glucuronate = acceptor
CC beta-D-glucuronoside + H(+) + UDP; Xref=Rhea:RHEA:21032,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:58052, ChEBI:CHEBI:58223,
CC ChEBI:CHEBI:132367, ChEBI:CHEBI:132368; EC=2.4.1.17;
CC Evidence={ECO:0000269|PubMed:18177842, ECO:0000269|PubMed:24641623};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:21033;
CC Evidence={ECO:0000305|PubMed:18177842, ECO:0000305|PubMed:24641623};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=calcidiol + UDP-alpha-D-glucuronate = calcidiol 25-O-(beta-D-
CC glucuronide) + H(+) + UDP; Xref=Rhea:RHEA:55840, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:17933, ChEBI:CHEBI:58052, ChEBI:CHEBI:58223,
CC ChEBI:CHEBI:139277; Evidence={ECO:0000269|PubMed:24641623};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:55841;
CC Evidence={ECO:0000305|PubMed:24641623};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=calcidiol + UDP-alpha-D-glucuronate = calcidiol 3-O-(beta-D-
CC glucuronide) + H(+) + UDP; Xref=Rhea:RHEA:55844, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:17933, ChEBI:CHEBI:58052, ChEBI:CHEBI:58223,
CC ChEBI:CHEBI:139278; Evidence={ECO:0000269|PubMed:24641623};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:55845;
CC Evidence={ECO:0000305|PubMed:24641623};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=calcitriol + UDP-alpha-D-glucuronate = calcitriol 25-O-(beta-
CC D-glucuronide) + H(+) + UDP; Xref=Rhea:RHEA:55836, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:17823, ChEBI:CHEBI:58052, ChEBI:CHEBI:58223,
CC ChEBI:CHEBI:139274; Evidence={ECO:0000269|PubMed:18177842};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:55837;
CC Evidence={ECO:0000305|PubMed:18177842};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=6.39 uM for calcidiol (when assaying glucuronidation at position
CC 25) {ECO:0000269|PubMed:24641623};
CC KM=2.16 uM for calcidiol (when assaying glucuronidation at position
CC 3) {ECO:0000269|PubMed:24641623};
CC KM=4.19 uM for 5,6-trans-calcidiol (when assaying glucuronidation at
CC position 25) {ECO:0000269|PubMed:24641623};
CC KM=7.3 uM for calcitriol (when assaying glucuronidation at position
CC 25) {ECO:0000269|PubMed:18177842};
CC KM=10.6 uM for 17beta-estradiol/estradiol (when assaying
CC glucuronidation at position 17) {ECO:0000269|PubMed:18719240};
CC KM=21.7 uM for 17alpha-estradiol/epiestradiol (when assaying
CC glucuronidation at position 17) {ECO:0000269|PubMed:18719240};
CC Vmax=7.35 pmol/min/mg enzyme for the formation of calcidiol 25-O-
CC (beta-D-glucuronate) {ECO:0000269|PubMed:24641623};
CC Vmax=0.93 pmol/min/mg enzyme for the formation of calcidiol 3-O-
CC (beta-D-glucuronate) {ECO:0000269|PubMed:24641623};
CC Vmax=0.26 pmol/min/mg enzyme for the formation of 5,6-trans-calcidiol
CC 25-O-(beta-D-glucuronate) {ECO:0000269|PubMed:24641623};
CC Vmax=33.7 pmol/min/mg enzyme for the formation of calcitriol 25-O-
CC (beta-D-glucuronate) {ECO:0000269|PubMed:18177842};
CC Vmax=14 pmol/min/mg enzyme for the formation of 17beta-estradiol 17-
CC O-(beta-D-glucuronate) {ECO:0000269|PubMed:18719240};
CC Vmax=41 pmol/min/mg enzyme for the formation of 17alpha-estradiol 17-
CC O-(beta-D-glucuronate) {ECO:0000269|PubMed:18719240};
CC Vmax=5.5 pmol/min/mg enzyme for the formation of 16alpha,17beta-
CC estriol 16-O-(beta-D-glucuronate) {ECO:0000269|PubMed:23288867};
CC Vmax=4.1 pmol/min/mg enzyme for the formation of 16alpha,17alpha-
CC estriol 16-O-(beta-D-glucuronate) {ECO:0000269|PubMed:23288867};
CC Vmax=1.9 pmol/min/mg enzyme for the formation of 17beta-estradiol 17-
CC O-(beta-D-glucuronate) {ECO:0000269|PubMed:23288867};
CC Vmax=6.1 pmol/min/mg enzyme for the formation of 17alpha-estradiol
CC 17-O-(beta-D-glucuronate) {ECO:0000269|PubMed:23288867};
CC Note=Some kinetic parameters were assessed using commercial enzymes,
CC which may represent a mix of both active and inactive protein forms,
CC and therefore modify the kinetic values.
CC {ECO:0000305|PubMed:18177842, ECO:0000305|PubMed:24641623};
CC -!- SUBUNIT: Homodimer (PubMed:17179145). Homooligomer (Probable).
CC Interacts with UGT1A1, UGT1A3, UGT1A6, UGT1A7, UGT1A8, UGT1A9 and
CC UGT1A10 to form heterodimers (PubMed:17179145). Isoform 1 interacts
CC with isoform 2/i2 suggesting that oligomerization is involved in
CC negative regulation of transferase activity by isoform 2. Isoform 1
CC also interacts with respective i2 isoforms of UGT1A1, UGT1A3, UGT1A6,
CC UGT1A7, UGT1A8, UGT1A9 and UGT1A10 (PubMed:20610558).
CC {ECO:0000269|PubMed:17179145, ECO:0000269|PubMed:20610558,
CC ECO:0000305|PubMed:20610558}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000305|PubMed:17179145}; Single-pass membrane protein
CC {ECO:0000255}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1; Synonyms=i1 {ECO:0000303|PubMed:18004212};
CC IsoId=P22310-1; Sequence=Displayed;
CC Name=2; Synonyms=i2 {ECO:0000303|PubMed:18004212}, UGT1A4s;
CC IsoId=P22310-2; Sequence=VSP_053960;
CC -!- TISSUE SPECIFICITY: [Isoform 1]: Expressed in liver (PubMed:1339448,
CC PubMed:18004212). Expressed in kidney, colon and small intestine
CC (PubMed:18004212). Not expressed in esophagus (PubMed:18004212). Not
CC expressed in skin (PubMed:1339448). {ECO:0000269|PubMed:1339448,
CC ECO:0000269|PubMed:18004212}.
CC -!- TISSUE SPECIFICITY: [Isoform 2]: Expressed in liver, kidney, colon,
CC esophagus and small intestine. {ECO:0000269|PubMed:18004212}.
CC -!- INDUCTION: Induced by phenobarbital. {ECO:0000269|PubMed:1339448}.
CC -!- MISCELLANEOUS: UGT1A4 isoform is part of the UGT1A complex locus which
CC displays alternative use of promoters, first exons and terminal exons.
CC The locus is defined by 13 first exons, which are alternatively spliced
CC to 3 other common exons and 2 alternative terminal exons 5. From the 27
CC possible mRNA isoforms, 9 produce functionally active polypeptides
CC (UGT1A1, 1A3, 1A4, 1A5, 1A6, 1A7, 1A8, 1A9 and 1A10) called isoforms 1
CC (i1). Use of an alternative exon 5 (5b) as terminal exon is leading to
CC 9 additional alternatively spliced products termed isoforms i2 and
CC which lack transferase activity. {ECO:0000269|PubMed:18004212}.
CC -!- SIMILARITY: Belongs to the UDP-glycosyltransferase family.
CC {ECO:0000305}.
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DR EMBL; M84128; AAA61249.1; -; Genomic_DNA.
DR EMBL; M84124; AAA61247.1; ALT_SEQ; Genomic_DNA.
DR EMBL; M84122; AAA61247.1; JOINED; Genomic_DNA.
DR EMBL; M84123; AAA61247.1; JOINED; Genomic_DNA.
DR EMBL; M57951; AAA63196.1; -; mRNA.
DR EMBL; AF297093; AAG30422.1; -; Genomic_DNA.
DR EMBL; AY435139; AAR95640.1; -; mRNA.
DR EMBL; AK313623; BAG36384.1; -; mRNA.
DR EMBL; DQ364249; ABC96773.1; -; mRNA.
DR EMBL; AC006985; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC114812; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471063; EAW71061.1; -; Genomic_DNA.
DR EMBL; BC139784; AAI39785.1; -; mRNA.
DR CCDS; CCDS33405.1; -. [P22310-1]
DR RefSeq; NP_009051.1; NM_007120.2. [P22310-1]
DR AlphaFoldDB; P22310; -.
DR SMR; P22310; -.
DR BioGRID; 120086; 15.
DR IntAct; P22310; 9.
DR STRING; 9606.ENSP00000362508; -.
DR BindingDB; P22310; -.
DR ChEMBL; CHEMBL3619; -.
DR DrugBank; DB00321; Amitriptyline.
DR DrugBank; DB01217; Anastrozole.
DR DrugBank; DB00714; Apomorphine.
DR DrugBank; DB06216; Asenapine.
DR DrugBank; DB06401; Bazedoxifene.
DR DrugBank; DB00363; Clozapine.
DR DrugBank; DB14635; Curcumin sulfate.
DR DrugBank; DB00924; Cyclobenzaprine.
DR DrugBank; DB00434; Cyproheptadine.
DR DrugBank; DB13874; Enasidenib.
DR DrugBank; DB11827; Ertugliflozin.
DR DrugBank; DB00783; Estradiol.
DR DrugBank; DB00977; Ethinylestradiol.
DR DrugBank; DB04953; Ezogabine.
DR DrugBank; DB11796; Fostemsavir.
DR DrugBank; DB12471; Ibrexafungerp.
DR DrugBank; DB09054; Idelalisib.
DR DrugBank; DB09262; Imidafenacin.
DR DrugBank; DB00920; Ketotifen.
DR DrugBank; DB00555; Lamotrigine.
DR DrugBank; DB06077; Lumateperone.
DR DrugBank; DB09241; Methylene blue.
DR DrugBank; DB00683; Midazolam.
DR DrugBank; DB08804; Nandrolone decanoate.
DR DrugBank; DB00334; Olanzapine.
DR DrugBank; DB11837; Osilodrostat.
DR DrugBank; DB00910; Paricalcitol.
DR DrugBank; DB12978; Pexidartinib.
DR DrugBank; DB00252; Phenytoin.
DR DrugBank; DB00960; Pindolol.
DR DrugBank; DB00794; Primidone.
DR DrugBank; DB00503; Ritonavir.
DR DrugBank; DB12020; Tecovirimat.
DR DrugBank; DB00871; Terbutaline.
DR DrugBank; DB00831; Trifluoperazine.
DR DrugBank; DB00197; Troglitazone.
DR DrugBank; DB00313; Valproic acid.
DR DrugCentral; P22310; -.
DR SwissLipids; SLP:000001872; -.
DR CAZy; GT1; Glycosyltransferase Family 1.
DR GlyConnect; 1876; 2 N-Linked glycans (1 site).
DR GlyGen; P22310; 4 sites, 2 N-linked glycans (1 site).
DR iPTMnet; P22310; -.
DR PhosphoSitePlus; P22310; -.
DR BioMuta; UGT1A4; -.
DR DMDM; 136731; -.
DR jPOST; P22310; -.
DR MassIVE; P22310; -.
DR MaxQB; P22310; -.
DR PaxDb; P22310; -.
DR PeptideAtlas; P22310; -.
DR PRIDE; P22310; -.
DR ProteomicsDB; 53982; -. [P22310-1]
DR ProteomicsDB; 7279; -.
DR Antibodypedia; 35064; 85 antibodies from 21 providers.
DR DNASU; 54657; -.
DR Ensembl; ENST00000373409.8; ENSP00000362508.4; ENSG00000244474.6. [P22310-1]
DR Ensembl; ENST00000450233.1; ENSP00000408608.1; ENSG00000244474.6. [P22310-2]
DR GeneID; 54657; -.
DR KEGG; hsa:54657; -.
DR MANE-Select; ENST00000373409.8; ENSP00000362508.4; NM_007120.3; NP_009051.1.
DR UCSC; uc002vux.4; human. [P22310-1]
DR CTD; 54657; -.
DR DisGeNET; 54657; -.
DR GeneCards; UGT1A4; -.
DR HGNC; HGNC:12536; UGT1A4.
DR HPA; ENSG00000244474; Tissue enriched (liver).
DR MalaCards; UGT1A4; -.
DR MIM; 606429; gene.
DR neXtProt; NX_P22310; -.
DR OpenTargets; ENSG00000244474; -.
DR PharmGKB; PA37179; -.
DR VEuPathDB; HostDB:ENSG00000244474; -.
DR eggNOG; KOG1192; Eukaryota.
DR GeneTree; ENSGT00940000162976; -.
DR HOGENOM; CLU_012949_1_3_1; -.
DR InParanoid; P22310; -.
DR OMA; WASWICC; -.
DR OrthoDB; 508327at2759; -.
DR PhylomeDB; P22310; -.
DR TreeFam; TF315472; -.
DR BioCyc; MetaCyc:HS11970-MON; -.
DR BRENDA; 2.4.1.17; 2681.
DR PathwayCommons; P22310; -.
DR Reactome; R-HSA-156588; Glucuronidation.
DR Reactome; R-HSA-189483; Heme degradation.
DR Reactome; R-HSA-5579016; Defective UGT1A4 causes hyperbilirubinemia.
DR Reactome; R-HSA-9749641; Aspirin ADME.
DR SABIO-RK; P22310; -.
DR SignaLink; P22310; -.
DR SIGNOR; P22310; -.
DR BioGRID-ORCS; 54657; 8 hits in 950 CRISPR screens.
DR GeneWiki; UGT1A4; -.
DR GenomeRNAi; 54657; -.
DR Pharos; P22310; Tbio.
DR PRO; PR:P22310; -.
DR Proteomes; UP000005640; Chromosome 2.
DR RNAct; P22310; protein.
DR Bgee; ENSG00000244474; Expressed in right lobe of liver and 35 other tissues.
DR Genevisible; P22310; HS.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0019899; F:enzyme binding; IPI:BHF-UCL.
DR GO; GO:0015020; F:glucuronosyltransferase activity; IDA:UniProtKB.
DR GO; GO:0046982; F:protein heterodimerization activity; IPI:BHF-UCL.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:0006789; P:bilirubin conjugation; TAS:Reactome.
DR GO; GO:0052695; P:cellular glucuronidation; IDA:UniProtKB.
DR GO; GO:0042167; P:heme catabolic process; TAS:Reactome.
DR GO; GO:2001030; P:negative regulation of cellular glucuronidation; ISS:BHF-UCL.
DR GO; GO:0045922; P:negative regulation of fatty acid metabolic process; ISS:BHF-UCL.
DR GO; GO:1904224; P:negative regulation of glucuronosyltransferase activity; ISS:BHF-UCL.
DR GO; GO:0070640; P:vitamin D3 metabolic process; IDA:UniProtKB.
DR CDD; cd03784; GT1_Gtf-like; 1.
DR InterPro; IPR002213; UDP_glucos_trans.
DR InterPro; IPR035595; UDP_glycos_trans_CS.
DR Pfam; PF00201; UDPGT; 1.
DR PROSITE; PS00375; UDPGT; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Endoplasmic reticulum; Glycoprotein;
KW Glycosyltransferase; Lipid metabolism; Membrane; Reference proteome;
KW Signal; Transferase; Transmembrane; Transmembrane helix.
FT SIGNAL 1..28
FT /evidence="ECO:0000255"
FT CHAIN 29..534
FT /note="UDP-glucuronosyltransferase 1A4"
FT /id="PRO_0000036003"
FT TRANSMEM 492..508
FT /note="Helical"
FT /evidence="ECO:0000255"
FT CARBOHYD 119
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 142
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:19159218"
FT CARBOHYD 296
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 348
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:19159218"
FT VAR_SEQ 436..534
FT /note="SYKENIMRLSSLHKDRPVEPLDLAVFWVEFVMRHKGAPHLRPAAHDLTWYQY
FT HSLDVIGFLLAVVLTVAFITFKCCAYGYRKCLGKKGRVKKAHKSKTH -> RKKQQSGR
FT QM (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334, ECO:0000303|Ref.6"
FT /id="VSP_053960"
FT VARIANT 11
FT /note="R -> W (in dbSNP:rs3892221)"
FT /id="VAR_059844"
FT VARIANT 24
FT /note="P -> T (in dbSNP:rs6755571)"
FT /evidence="ECO:0000269|PubMed:19204906"
FT /id="VAR_024684"
FT VARIANT 48
FT /note="L -> V (increased glucuronosyltransferase activity
FT towards calcidiol; dbSNP:rs2011425)"
FT /evidence="ECO:0000269|PubMed:14702039,
FT ECO:0000269|PubMed:19204906, ECO:0000269|PubMed:24641623"
FT /id="VAR_058584"
FT VARIANT 68
FT /note="H -> Y (in dbSNP:rs45621441)"
FT /id="VAR_061870"
FT VARIANT 176
FT /note="I -> F (in dbSNP:rs45540231)"
FT /id="VAR_052454"
SQ SEQUENCE 534 AA; 60025 MW; AB745D46F57538BE CRC64;
MARGLQVPLP RLATGLLLLL SVQPWAESGK VLVVPTDGSP WLSMREALRE LHARGHQAVV
LTPEVNMHIK EEKFFTLTAY AVPWTQKEFD RVTLGYTQGF FETEHLLKRY SRSMAIMNNV
SLALHRCCVE LLHNEALIRH LNATSFDVVL TDPVNLCGAV LAKYLSIPAV FFWRYIPCDL
DFKGTQCPNP SSYIPKLLTT NSDHMTFLQR VKNMLYPLAL SYICHTFSAP YASLASELFQ
REVSVVDLVS YASVWLFRGD FVMDYPRPIM PNMVFIGGIN CANGKPLSQE FEAYINASGE
HGIVVFSLGS MVSEIPEKKA MAIADALGKI PQTVLWRYTG TRPSNLANNT ILVKWLPQND
LLGHPMTRAF ITHAGSHGVY ESICNGVPMV MMPLFGDQMD NAKRMETKGA GVTLNVLEMT
SEDLENALKA VINDKSYKEN IMRLSSLHKD RPVEPLDLAV FWVEFVMRHK GAPHLRPAAH
DLTWYQYHSL DVIGFLLAVV LTVAFITFKC CAYGYRKCLG KKGRVKKAHK SKTH
