UGDH_HUMAN
ID UGDH_HUMAN Reviewed; 494 AA.
AC O60701; B3KUU2; B4DN25; O60589;
DT 15-DEC-1998, integrated into UniProtKB/Swiss-Prot.
DT 01-AUG-1998, sequence version 1.
DT 03-AUG-2022, entry version 200.
DE RecName: Full=UDP-glucose 6-dehydrogenase;
DE Short=UDP-Glc dehydrogenase;
DE Short=UDP-GlcDH;
DE Short=UDPGDH;
DE EC=1.1.1.22 {ECO:0000269|PubMed:21502315, ECO:0000269|PubMed:22123821, ECO:0000269|PubMed:23106432, ECO:0000269|PubMed:25478983, ECO:0000269|PubMed:27966912, ECO:0000269|PubMed:30420606, ECO:0000269|PubMed:30457329};
GN Name=UGDH;
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 [MRNA] (ISOFORM 1), AND TISSUE SPECIFICITY.
RC TISSUE=Placenta;
RX PubMed=9737970; DOI=10.1074/jbc.273.39.25117;
RA Spicer A.P., Kaback L.A., Smith T.J., Seldin M.F.;
RT "Molecular cloning and characterization of the human and mouse UDP-glucose
RT dehydrogenase genes.";
RL J. Biol. Chem. 273:25117-25124(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND TISSUE SPECIFICITY.
RC TISSUE=Liver;
RX PubMed=9850599;
RA Peng H.L., Lou M.D., Chang M.L., Chang H.Y.;
RT "cDNA cloning and expression analysis of the human UDPglucose
RT dehydrogenase.";
RL Proc. Natl. Sci. Counc. Repub. China, B, Life Sci. 22:166-172(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Chang M.L., Chang H.Y., Peng H.L.;
RT "Characterization of human gene encoding UDP-glucose dehydrogenase.";
RL Submitted (FEB-2000) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2 AND 3).
RC TISSUE=Thymus;
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 [5]
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 [6]
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 [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Skin;
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 [8]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 214-388 (ISOFORM 1/2/3).
RA Raghuram V., Foskett J.K.;
RL Submitted (FEB-1998) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-107, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C.,
RA Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [11]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-476, AND IDENTIFICATION BY
RP 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 [13] {ECO:0007744|PDB:3PRJ, ECO:0007744|PDB:3PTZ}
RP X-RAY CRYSTALLOGRAPHY (2.50 ANGSTROMS) IN COMPLEX WITH NAD AND
RP UDP-ALPHA-D-XYLOSE, SUBUNIT, ACTIVITY REGULATION, AND DOMAIN.
RX PubMed=21595445; DOI=10.1021/bi2005637;
RA Kadirvelraj R., Sennett N.C., Polizzi S.J., Weitzel S., Wood Z.A.;
RT "Role of packing defects in the evolution of allostery and induced fit in
RT human UDP-glucose dehydrogenase.";
RL Biochemistry 50:5780-5789(2011).
RN [14] {ECO:0007744|PDB:3TF5}
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS), CATALYTIC ACTIVITY, FUNCTION,
RP SUBUNIT, PATHWAY, ACTIVITY REGULATION, ALLOSTERIC REGULATION, DOMAIN, AND
RP MUTAGENESIS OF VAL-132.
RX PubMed=21961565; DOI=10.1021/bi201381e;
RA Sennett N.C., Kadirvelraj R., Wood Z.A.;
RT "Conformational flexibility in the allosteric regulation of human UDP-
RT alpha-D-glucose 6-dehydrogenase.";
RL Biochemistry 50:9651-9663(2011).
RN [15] {ECO:0007744|PDB:2Q3E, ECO:0007744|PDB:2QG4, ECO:0007744|PDB:3ITK}
RP X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 1-466 IN COMPLEX WITH NAD;
RP UDP-GLUCOSE AND UDP-GLUCURONATE, FUNCTION, CATALYTIC ACTIVITY, PATHWAY,
RP SUBUNIT, ACTIVE SITE, DOMAIN, AND MUTAGENESIS OF THR-131 AND CYS-276.
RX PubMed=21502315; DOI=10.1074/jbc.m111.234682;
RA Egger S., Chaikuad A., Kavanagh K.L., Oppermann U., Nidetzky B.;
RT "Structure and mechanism of human UDP-glucose 6-dehydrogenase.";
RL J. Biol. Chem. 286:23877-23887(2011).
RN [16] {ECO:0007744|PDB:3TDK}
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 1-487 IN COMPLEX WITH UDP-GLUCOSE,
RP SUBUNIT, AND ACTIVE SITE.
RX PubMed=21984906; DOI=10.1371/journal.pone.0025226;
RA Rajakannan V., Lee H.S., Chong S.H., Ryu H.B., Bae J.Y., Whang E.Y.,
RA Huh J.W., Cho S.W., Kang L.W., Choe H., Robinson R.C.;
RT "Structural basis of cooperativity in human UDP-glucose dehydrogenase.";
RL PLoS ONE 6:E25226-E25226(2011).
RN [17] {ECO:0007744|PDB:4EDF}
RP X-RAY CRYSTALLOGRAPHY (2.08 ANGSTROMS) IN COMPLEX WITH UDP-GLUCOSE,
RP CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, PATHWAY, FUNCTION,
RP SUBUNIT, AND MUTAGENESIS OF LYS-94.
RX PubMed=23106432; DOI=10.1021/bi301067w;
RA Sennett N.C., Kadirvelraj R., Wood Z.A.;
RT "Cofactor binding triggers a molecular switch to allosterically activate
RT human UDP-alpha-D-glucose 6-dehydrogenase.";
RL Biochemistry 51:9364-9374(2012).
RN [18] {ECO:0007744|PDB:3KHU}
RP X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) OF 1-466 IN COMPLEX WITH
RP UDP-ALPHA-D-GLUCOSE, CATALYTIC ACTIVITY, FUNCTION, PATHWAY, SUBUNIT, ACTIVE
RP SITE, AND MUTAGENESIS OF GLU-161; LYS-220 AND ASP-280.
RX PubMed=22123821; DOI=10.1074/jbc.m111.313015;
RA Egger S., Chaikuad A., Klimacek M., Kavanagh K.L., Oppermann U.,
RA Nidetzky B.;
RT "Structural and kinetic evidence that catalytic reaction of human UDP-
RT glucose 6-dehydrogenase involves covalent thiohemiacetal and thioester
RT enzyme intermediates.";
RL J. Biol. Chem. 287:2119-2129(2012).
RN [19] {ECO:0007744|PDB:4RJT}
RP X-RAY CRYSTALLOGRAPHY (2.70 ANGSTROMS), CATALYTIC ACTIVITY, FUNCTION,
RP PATHWAY, ACTIVITY REGULATION, SUBUNIT, DOMAIN, MUTAGENESIS OF LYS-94 AND
RP 323-PHE--THR-325, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=25478983; DOI=10.1021/bi500594x;
RA Kadirvelraj R., Custer G.S., Keul N.D., Sennett N.C., Sidlo A.M.,
RA Walsh R.M. Jr., Wood Z.A.;
RT "Hysteresis in human UDP-glucose dehydrogenase is due to a restrained
RT hexameric structure that favors feedback inhibition.";
RL Biochemistry 53:8043-8051(2014).
RN [20] {ECO:0007744|PDB:5TJH}
RP X-RAY CRYSTALLOGRAPHY (2.05 ANGSTROMS) OF MUTANT MET-136 IN COMPLEX WITH
RP UDP-ALPHA-D-GLUCOSE, FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION,
RP BIOPHYSICOCHEMICAL PROPERTIES, PATHWAY, SUBUNIT, DOMAIN, AND MUTAGENESIS OF
RP ALA-136.
RX PubMed=27966912; DOI=10.1021/acs.biochem.6b01044;
RA Beattie N.R., Keul N.D., Sidlo A.M., Wood Z.A.;
RT "Allostery and Hysteresis Are Coupled in Human UDP-Glucose Dehydrogenase.";
RL Biochemistry 56:202-211(2017).
RN [21] {ECO:0007744|PDB:5VR8, ECO:0007744|PDB:5W4X}
RP X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) IN COMPLEX WITH UDP-XYLOSE,
RP CATALYTIC ACTIVITY, FUNCTION, SUBUNIT, PATHWAY, AND MUTAGENESIS OF ALA-136;
RP 323-PHE--THR-325 AND 465-LYS--VAL-494.
RX PubMed=30420606; DOI=10.1038/s41586-018-0699-5;
RA Keul N.D., Oruganty K., Schaper Bergman E.T., Beattie N.R., McDonald W.E.,
RA Kadirvelraj R., Gross M.L., Phillips R.S., Harvey S.C., Wood Z.A.;
RT "The entropic force generated by intrinsically disordered segments tunes
RT protein function.";
RL Nature 563:584-588(2018).
RN [22] {ECO:0007744|PDB:6C4J, ECO:0007744|PDB:6C4K}
RP X-RAY CRYSTALLOGRAPHY (2.53 ANGSTROMS) IN COMPLEX WITH UDP-GLUCOSE AND NAD,
RP FUNCTION, CATALYTIC ACTIVITY, PATHWAY, ACTIVITY REGULATION, SUBUNIT,
RP DOMAIN, MUTAGENESIS OF ALA-104, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=30457329; DOI=10.1021/acs.biochem.8b00497;
RA Beattie N.R., Pioso B., Sidlo A.M., Keul N.D., Wood Z.A.;
RT "Hysteresis and Allostery in Human UDP-Glucose Dehydrogenase Require a
RT Flexible Protein Core.";
RL Biochemistry 57:6848-6859(2018).
RN [23]
RP VARIANTS DEE84 CYS-14; THR-24; THR-42; VAL-44; 65-ARG--VAL-494 DEL; ALA-72;
RP THR-82; THR-116; 155-GLN--VAL-494 DEL; ALA-175; ASP-217; THR-255; ARG-271;
RP ILE-303; VAL-306; GLN-317; 356-TYR--VAL-494 DEL; CYS-367; TRP-393; SER-410;
RP TRP-442; HIS-443 AND ARG-449, CHARACTERIZATION OF VARIANTS DEE84 VAL-44 AND
RP THR-82, INVOLVEMENT IN DEE84, FUNCTION, CATALYTIC ACTIVITY, AND SUBUNIT.
RX PubMed=32001716; DOI=10.1038/s41467-020-14360-7;
RA Hengel H., Bosso-Lefevre C., Grady G., Szenker-Ravi E., Li H., Pierce S.,
RA Lebigot E., Tan T.T., Eio M.Y., Narayanan G., Utami K.H., Yau M.,
RA Handal N., Deigendesch W., Keimer R., Marzouqa H.M., Gunay-Aygun M.,
RA Muriello M.J., Verhelst H., Weckhuysen S., Mahida S., Naidu S.,
RA Thomas T.G., Lim J.Y., Tan E.S., Haye D., Willemsen M.A.A.P., Oegema R.,
RA Mitchell W.G., Pierson T.M., Andrews M.V., Willing M.C., Rodan L.H.,
RA Barakat T.S., van Slegtenhorst M., Gavrilova R.H., Martinelli D.,
RA Gilboa T., Tamim A.M., Hashem M.O., Al-Sayed M.D., Abdulrahim M.M.,
RA Al-Owain M., Awaji A., Mahmoud A.A.H., Faqeih E.A., Asmari A.A.,
RA Algain S.M., Jad L.A., Aldhalaan H.M., Helbig I., Koolen D.A., Riess A.,
RA Kraegeloh-Mann I., Bauer P., Gulsuner S., Stamberger H., Ng A.Y.J.,
RA Tang S., Tohari S., Keren B., Schultz-Rogers L.E., Klee E.W., Barresi S.,
RA Tartaglia M., Mor-Shaked H., Maddirevula S., Begtrup A., Telegrafi A.,
RA Pfundt R., Schuele R., Ciruna B., Bonnard C., Pouladi M.A., Stewart J.C.,
RA Claridge-Chang A., Lefeber D.J., Alkuraya F.S., Mathuru A.S., Venkatesh B.,
RA Barycki J.J., Simpson M.A., Jamuar S.S., Schoels L., Reversade B.;
RT "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive
RT developmental epileptic encephalopathy.";
RL Nat. Commun. 11:595-595(2020).
CC -!- FUNCTION: Catalyzes the formation of UDP-alpha-D-glucuronate, a
CC constituent of complex glycosaminoglycans (PubMed:21961565,
CC PubMed:21502315, PubMed:23106432, PubMed:22123821, PubMed:25478983,
CC PubMed:27966912, PubMed:30420606, PubMed:30457329). Required for the
CC biosynthesis of chondroitin sulfate and heparan sulfate. Required for
CC embryonic development via its role in the biosynthesis of
CC glycosaminoglycans (By similarity). Required for proper brain and
CC neuronal development (PubMed:32001716). {ECO:0000250|UniProtKB:O70475,
CC ECO:0000269|PubMed:21502315, ECO:0000269|PubMed:21961565,
CC ECO:0000269|PubMed:22123821, ECO:0000269|PubMed:23106432,
CC ECO:0000269|PubMed:25478983, ECO:0000269|PubMed:27966912,
CC ECO:0000269|PubMed:30420606, ECO:0000269|PubMed:30457329,
CC ECO:0000269|PubMed:32001716}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + 2 NAD(+) + UDP-alpha-D-glucose = 3 H(+) + 2 NADH + UDP-
CC alpha-D-glucuronate; Xref=Rhea:RHEA:23596, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945,
CC ChEBI:CHEBI:58052, ChEBI:CHEBI:58885; EC=1.1.1.22;
CC Evidence={ECO:0000269|PubMed:21502315, ECO:0000269|PubMed:21961565,
CC ECO:0000269|PubMed:22123821, ECO:0000269|PubMed:23106432,
CC ECO:0000269|PubMed:25478983, ECO:0000269|PubMed:27966912,
CC ECO:0000269|PubMed:30420606, ECO:0000269|PubMed:30457329,
CC ECO:0000269|PubMed:32001716};
CC -!- ACTIVITY REGULATION: UDP-alpha-D-xylose (UDX) acts as a feedback
CC inhibitor. It binds at the same site as the substrate, but functions as
CC allosteric inhibitor by triggering a conformation change that disrupts
CC the active hexameric ring structure and gives rise to an inactive,
CC horseshoe-shaped hexamer. {ECO:0000269|PubMed:21595445,
CC ECO:0000269|PubMed:21961565, ECO:0000269|PubMed:25478983,
CC ECO:0000269|PubMed:27966912, ECO:0000269|PubMed:30457329}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=9.7 uM for UDP-glucose {ECO:0000269|PubMed:27966912};
CC KM=7.6 uM for UDP-glucose {ECO:0000269|PubMed:30457329};
CC KM=25 uM for UDP-glucose {ECO:0000269|PubMed:23106432};
CC KM=780 uM for NAD {ECO:0000269|PubMed:27966912};
CC KM=1160 uM for NAD(+) {ECO:0000269|PubMed:30457329};
CC KM=384 uM for NAD(+) {ECO:0000269|PubMed:23106432};
CC Note=kcat is 0.55 sec(-1) with UDP-glucose as substrate.
CC {ECO:0000269|PubMed:27966912};
CC pH dependence:
CC Optimum pH is 8.6. {ECO:0000269|PubMed:25478983};
CC -!- PATHWAY: Nucleotide-sugar biosynthesis; UDP-alpha-D-glucuronate
CC biosynthesis; UDP-alpha-D-glucuronate from UDP-alpha-D-glucose: step
CC 1/1. {ECO:0000269|PubMed:21502315, ECO:0000269|PubMed:21961565,
CC ECO:0000269|PubMed:22123821, ECO:0000269|PubMed:23106432,
CC ECO:0000269|PubMed:25478983, ECO:0000269|PubMed:27966912,
CC ECO:0000269|PubMed:30420606, ECO:0000269|PubMed:30457329}.
CC -!- SUBUNIT: Homohexamer. {ECO:0000269|PubMed:21502315,
CC ECO:0000269|PubMed:21595445, ECO:0000269|PubMed:21961565,
CC ECO:0000269|PubMed:21984906, ECO:0000269|PubMed:22123821,
CC ECO:0000269|PubMed:23106432, ECO:0000269|PubMed:25478983,
CC ECO:0000269|PubMed:27966912, ECO:0000269|PubMed:30420606,
CC ECO:0000269|PubMed:30457329, ECO:0000269|PubMed:32001716}.
CC -!- INTERACTION:
CC O60701; O60701: UGDH; NbExp=4; IntAct=EBI-353006, EBI-353006;
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=O60701-1; Sequence=Displayed;
CC Name=2;
CC IsoId=O60701-2; Sequence=VSP_042550;
CC Name=3;
CC IsoId=O60701-3; Sequence=VSP_046234;
CC -!- TISSUE SPECIFICITY: Detected in heart, placenta, liver, pancreas,
CC spleen, thymus, prostate, ovary, small intestine and colon
CC (PubMed:9737970). Widely expressed (PubMed:9737970).
CC {ECO:0000269|PubMed:9737970, ECO:0000269|PubMed:9850599}.
CC -!- DOMAIN: The protein goes through several conformation states during the
CC reaction cycle, giving rise to hysteresis. In the initial state, the
CC ligand-free protein is in an inactive conformation (E*). Substrate
CC binding triggers a change to the active conformation (E). UDP-xylose
CC binding triggers the transition to a distinct, inhibited conformation.
CC The presence of an intrinsically disordered C-terminus promotes a more
CC dynamic protein structure and favors a conformation with high affinity
CC for UPD-xylose. {ECO:0000269|PubMed:30457329}.
CC -!- DOMAIN: The allosteric switch region moves by about 5 Angstroms when
CC UDP-xylose is bound, and occupies part of the UDP-glucose binding site.
CC At the same time it promotes domain movements that disrupt the active
CC hexameric ring structure and lead to the formation of a horseshoe-
CC shaped, inactive hexamer. {ECO:0000269|PubMed:21502315,
CC ECO:0000269|PubMed:21595445, ECO:0000269|PubMed:21961565,
CC ECO:0000269|PubMed:25478983, ECO:0000269|PubMed:27966912,
CC ECO:0000269|PubMed:30457329}.
CC -!- DISEASE: Developmental and epileptic encephalopathy 84 (DEE84)
CC [MIM:618792]: A form of epileptic encephalopathy, a heterogeneous group
CC of severe early-onset epilepsies characterized by refractory seizures,
CC neurodevelopmental impairment, and poor prognosis. Development is
CC normal prior to seizure onset, after which cognitive and motor delays
CC become apparent. DEE84 is an autosomal recessive form characterized by
CC onset of refractory seizures in the first months of life.
CC {ECO:0000269|PubMed:32001716}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the UDP-glucose/GDP-mannose dehydrogenase
CC family. {ECO:0000305}.
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DR EMBL; AF061016; AAC36095.1; -; mRNA.
DR EMBL; AJ007702; CAA07609.1; -; mRNA.
DR EMBL; AJ272274; CAB75891.1; -; Genomic_DNA.
DR EMBL; AJ272275; CAB75891.1; JOINED; Genomic_DNA.
DR EMBL; AJ272276; CAB75891.1; JOINED; Genomic_DNA.
DR EMBL; AJ272277; CAB75891.1; JOINED; Genomic_DNA.
DR EMBL; AJ272278; CAB75891.1; JOINED; Genomic_DNA.
DR EMBL; AJ272279; CAB75891.1; JOINED; Genomic_DNA.
DR EMBL; AJ272280; CAB75891.1; JOINED; Genomic_DNA.
DR EMBL; AJ272281; CAB75891.1; JOINED; Genomic_DNA.
DR EMBL; AK097930; BAG53554.1; -; mRNA.
DR EMBL; AK297737; BAG60087.1; -; mRNA.
DR EMBL; AC021148; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471069; EAW92937.1; -; Genomic_DNA.
DR EMBL; BC022781; AAH22781.1; -; mRNA.
DR EMBL; AF049126; AAC05135.1; -; mRNA.
DR CCDS; CCDS3455.1; -. [O60701-1]
DR CCDS; CCDS54757.1; -. [O60701-3]
DR CCDS; CCDS54758.1; -. [O60701-2]
DR PIR; JE0353; JE0353.
DR RefSeq; NP_001171629.1; NM_001184700.1. [O60701-2]
DR RefSeq; NP_001171630.1; NM_001184701.1. [O60701-3]
DR RefSeq; NP_003350.1; NM_003359.3. [O60701-1]
DR PDB; 2Q3E; X-ray; 2.00 A; A/B/C/D/E/F/G/H/I/J/K/L=1-466.
DR PDB; 2QG4; X-ray; 2.10 A; A/B/C/D/E/F/G/H=1-466.
DR PDB; 3ITK; X-ray; 2.40 A; A/B/C/D/E/F=1-466.
DR PDB; 3KHU; X-ray; 2.30 A; A/B/C/D/E/F=1-466.
DR PDB; 3PRJ; X-ray; 3.10 A; A/B/C/D/E/F=1-494.
DR PDB; 3PTZ; X-ray; 2.50 A; A/B/C/D/E/F=1-494.
DR PDB; 3TDK; X-ray; 2.80 A; A/B/C/D/E/F/G/H/I/J/K/L=1-487.
DR PDB; 3TF5; X-ray; 2.30 A; A/B/C=1-494.
DR PDB; 4EDF; X-ray; 2.08 A; A/B/C/D=1-494.
DR PDB; 4RJT; X-ray; 2.70 A; A/B/C=1-494.
DR PDB; 5TJH; X-ray; 2.05 A; A/B/C/D/E/F=1-494.
DR PDB; 5VR8; X-ray; 2.00 A; A/B/C/D/E/F=1-494.
DR PDB; 5W4X; X-ray; 2.65 A; A/B/C=1-466.
DR PDB; 6C4J; X-ray; 2.53 A; A/B/C/D/E/F/G/H/I/J/K/L=1-494.
DR PDB; 6C4K; X-ray; 2.65 A; A/B/C=1-494.
DR PDB; 6C58; X-ray; 2.20 A; A/B/C/D/E/F=1-494.
DR PDB; 6C5A; X-ray; 2.30 A; A/B/C/D/E/F=1-494.
DR PDB; 6C5Z; X-ray; 2.95 A; A/B/C/D/E/F=1-494.
DR PDBsum; 2Q3E; -.
DR PDBsum; 2QG4; -.
DR PDBsum; 3ITK; -.
DR PDBsum; 3KHU; -.
DR PDBsum; 3PRJ; -.
DR PDBsum; 3PTZ; -.
DR PDBsum; 3TDK; -.
DR PDBsum; 3TF5; -.
DR PDBsum; 4EDF; -.
DR PDBsum; 4RJT; -.
DR PDBsum; 5TJH; -.
DR PDBsum; 5VR8; -.
DR PDBsum; 5W4X; -.
DR PDBsum; 6C4J; -.
DR PDBsum; 6C4K; -.
DR PDBsum; 6C58; -.
DR PDBsum; 6C5A; -.
DR PDBsum; 6C5Z; -.
DR AlphaFoldDB; O60701; -.
DR SMR; O60701; -.
DR BioGRID; 113205; 70.
DR IntAct; O60701; 15.
DR MINT; O60701; -.
DR STRING; 9606.ENSP00000319501; -.
DR DrugBank; DB09130; Copper.
DR DrugBank; DB00157; NADH.
DR GlyGen; O60701; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; O60701; -.
DR MetOSite; O60701; -.
DR PhosphoSitePlus; O60701; -.
DR SwissPalm; O60701; -.
DR BioMuta; UGDH; -.
DR REPRODUCTION-2DPAGE; O60701; -.
DR EPD; O60701; -.
DR jPOST; O60701; -.
DR MassIVE; O60701; -.
DR MaxQB; O60701; -.
DR PaxDb; O60701; -.
DR PeptideAtlas; O60701; -.
DR PRIDE; O60701; -.
DR ProteomicsDB; 4666; -.
DR ProteomicsDB; 49530; -. [O60701-1]
DR ProteomicsDB; 49531; -. [O60701-2]
DR Antibodypedia; 23464; 330 antibodies from 31 providers.
DR DNASU; 7358; -.
DR Ensembl; ENST00000316423.11; ENSP00000319501.6; ENSG00000109814.12. [O60701-1]
DR Ensembl; ENST00000501493.6; ENSP00000422909.1; ENSG00000109814.12. [O60701-2]
DR Ensembl; ENST00000506179.5; ENSP00000421757.1; ENSG00000109814.12. [O60701-1]
DR Ensembl; ENST00000507089.5; ENSP00000426560.1; ENSG00000109814.12. [O60701-3]
DR GeneID; 7358; -.
DR KEGG; hsa:7358; -.
DR MANE-Select; ENST00000316423.11; ENSP00000319501.6; NM_003359.4; NP_003350.1.
DR UCSC; uc003guk.3; human. [O60701-1]
DR CTD; 7358; -.
DR DisGeNET; 7358; -.
DR GeneCards; UGDH; -.
DR HGNC; HGNC:12525; UGDH.
DR HPA; ENSG00000109814; Tissue enhanced (liver).
DR MalaCards; UGDH; -.
DR MIM; 603370; gene.
DR MIM; 618792; phenotype.
DR neXtProt; NX_O60701; -.
DR OpenTargets; ENSG00000109814; -.
DR PharmGKB; PA37170; -.
DR VEuPathDB; HostDB:ENSG00000109814; -.
DR eggNOG; KOG2666; Eukaryota.
DR GeneTree; ENSGT00390000015355; -.
DR HOGENOM; CLU_023810_7_2_1; -.
DR InParanoid; O60701; -.
DR OMA; CECLNLP; -.
DR OrthoDB; 915490at2759; -.
DR PhylomeDB; O60701; -.
DR TreeFam; TF105671; -.
DR BRENDA; 1.1.1.22; 2681.
DR PathwayCommons; O60701; -.
DR Reactome; R-HSA-173599; Formation of the active cofactor, UDP-glucuronate.
DR SABIO-RK; O60701; -.
DR SignaLink; O60701; -.
DR UniPathway; UPA00038; UER00491.
DR BioGRID-ORCS; 7358; 23 hits in 1083 CRISPR screens.
DR ChiTaRS; UGDH; human.
DR EvolutionaryTrace; O60701; -.
DR GeneWiki; UGDH; -.
DR GenomeRNAi; 7358; -.
DR Pharos; O60701; Tbio.
DR PRO; PR:O60701; -.
DR Proteomes; UP000005640; Chromosome 4.
DR RNAct; O60701; protein.
DR Bgee; ENSG00000109814; Expressed in colonic mucosa and 195 other tissues.
DR ExpressionAtlas; O60701; baseline and differential.
DR Genevisible; O60701; HS.
DR GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0051287; F:NAD binding; IEA:InterPro.
DR GO; GO:0003979; F:UDP-glucose 6-dehydrogenase activity; IDA:UniProtKB.
DR GO; GO:0005975; P:carbohydrate metabolic process; IEA:UniProtKB-KW.
DR GO; GO:0030206; P:chondroitin sulfate biosynthetic process; ISS:UniProtKB.
DR GO; GO:0001702; P:gastrulation with mouth forming second; ISS:UniProtKB.
DR GO; GO:0006024; P:glycosaminoglycan biosynthetic process; IBA:GO_Central.
DR GO; GO:0015012; P:heparan sulfate proteoglycan biosynthetic process; ISS:UniProtKB.
DR GO; GO:0048666; P:neuron development; IMP:UniProtKB.
DR GO; GO:0034214; P:protein hexamerization; IDA:UniProtKB.
DR GO; GO:0006065; P:UDP-glucuronate biosynthetic process; IDA:UniProtKB.
DR DisProt; DP02338; -.
DR InterPro; IPR008927; 6-PGluconate_DH-like_C_sf.
DR InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR InterPro; IPR017476; UDP-Glc/GDP-Man.
DR InterPro; IPR014027; UDP-Glc/GDP-Man_DH_C.
DR InterPro; IPR036220; UDP-Glc/GDP-Man_DH_C_sf.
DR InterPro; IPR014026; UDP-Glc/GDP-Man_DH_dimer.
DR InterPro; IPR001732; UDP-Glc/GDP-Man_DH_N.
DR InterPro; IPR028356; UDPglc_DH_euk.
DR PANTHER; PTHR11374; PTHR11374; 1.
DR Pfam; PF00984; UDPG_MGDP_dh; 1.
DR Pfam; PF03720; UDPG_MGDP_dh_C; 1.
DR Pfam; PF03721; UDPG_MGDP_dh_N; 1.
DR PIRSF; PIRSF500133; UDPglc_DH_euk; 1.
DR PIRSF; PIRSF000124; UDPglc_GDPman_dh; 1.
DR SMART; SM00984; UDPG_MGDP_dh_C; 1.
DR SUPFAM; SSF48179; SSF48179; 1.
DR SUPFAM; SSF51735; SSF51735; 1.
DR SUPFAM; SSF52413; SSF52413; 1.
DR TIGRFAMs; TIGR03026; NDP-sugDHase; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Allosteric enzyme; Alternative splicing;
KW Carbohydrate metabolism; Disease variant; Epilepsy; NAD; Oxidoreductase;
KW Phosphoprotein; Reference proteome.
FT CHAIN 1..494
FT /note="UDP-glucose 6-dehydrogenase"
FT /id="PRO_0000074060"
FT REGION 88..110
FT /note="Disordered"
FT /evidence="ECO:0000305|PubMed:23106432"
FT REGION 129..135
FT /note="Allosteric switch region"
FT /evidence="ECO:0000269|PubMed:21502315,
FT ECO:0000269|PubMed:21595445, ECO:0000269|PubMed:21961565,
FT ECO:0000269|PubMed:25478983, ECO:0000269|PubMed:27966912,
FT ECO:0000269|PubMed:30457329"
FT REGION 321..325
FT /note="Important for formation of active hexamer structure"
FT /evidence="ECO:0000269|PubMed:25478983,
FT ECO:0000305|PubMed:23106432"
FT REGION 466..494
FT /note="Disordered"
FT /evidence="ECO:0000269|PubMed:25478983,
FT ECO:0000269|PubMed:30457329, ECO:0000305|PubMed:23106432"
FT ACT_SITE 161
FT /note="Proton donor/acceptor"
FT /evidence="ECO:0000269|PubMed:22123821"
FT ACT_SITE 220
FT /note="Proton donor/acceptor"
FT /evidence="ECO:0000269|PubMed:22123821"
FT ACT_SITE 276
FT /note="Nucleophile"
FT /evidence="ECO:0000269|PubMed:21502315,
FT ECO:0000269|PubMed:21984906, ECO:0000269|PubMed:22123821"
FT BINDING 11..16
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000269|PubMed:21502315,
FT ECO:0000269|PubMed:21595445, ECO:0000269|PubMed:21984906,
FT ECO:0007744|PDB:2Q3E, ECO:0007744|PDB:2QG4,
FT ECO:0007744|PDB:3PRJ, ECO:0007744|PDB:3PTZ,
FT ECO:0007744|PDB:3TDK"
FT BINDING 36
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000269|PubMed:21502315,
FT ECO:0000269|PubMed:21595445, ECO:0000269|PubMed:21984906,
FT ECO:0007744|PDB:2Q3E, ECO:0007744|PDB:2QG4,
FT ECO:0007744|PDB:3PRJ, ECO:0007744|PDB:3PTZ,
FT ECO:0007744|PDB:3TDK"
FT BINDING 41
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000269|PubMed:21502315,
FT ECO:0000269|PubMed:21595445, ECO:0000269|PubMed:21984906,
FT ECO:0007744|PDB:2Q3E, ECO:0007744|PDB:2QG4,
FT ECO:0007744|PDB:3PRJ, ECO:0007744|PDB:3PTZ,
FT ECO:0007744|PDB:3TDK"
FT BINDING 89..93
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000269|PubMed:21502315,
FT ECO:0000269|PubMed:21595445, ECO:0000269|PubMed:21984906,
FT ECO:0007744|PDB:2Q3E, ECO:0007744|PDB:2QG4,
FT ECO:0007744|PDB:3PRJ, ECO:0007744|PDB:3PTZ,
FT ECO:0007744|PDB:3TDK"
FT BINDING 130..132
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000269|PubMed:21502315,
FT ECO:0000269|PubMed:21595445"
FT BINDING 161..165
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:23106432,
FT ECO:0000305|PubMed:21502315, ECO:0000305|PubMed:21595445,
FT ECO:0007744|PDB:2QG4, ECO:0007744|PDB:3PRJ,
FT ECO:0007744|PDB:3PTZ, ECO:0007744|PDB:4EDF"
FT BINDING 165
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000269|PubMed:21502315,
FT ECO:0007744|PDB:2Q3E, ECO:0007744|PDB:2QG4"
FT BINDING 220..224
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:23106432,
FT ECO:0000305|PubMed:21502315, ECO:0000305|PubMed:21595445,
FT ECO:0007744|PDB:2QG4, ECO:0007744|PDB:3PRJ,
FT ECO:0007744|PDB:3PTZ, ECO:0007744|PDB:4EDF"
FT BINDING 260
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:23106432,
FT ECO:0000269|PubMed:27966912, ECO:0000305|PubMed:21502315,
FT ECO:0000305|PubMed:21595445, ECO:0007744|PDB:2QG4,
FT ECO:0007744|PDB:3PRJ, ECO:0007744|PDB:3PTZ,
FT ECO:0007744|PDB:4EDF, ECO:0007744|PDB:5TJH"
FT BINDING 267..273
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:23106432,
FT ECO:0000305|PubMed:21502315, ECO:0000305|PubMed:21595445,
FT ECO:0007744|PDB:2QG4, ECO:0007744|PDB:3PRJ,
FT ECO:0007744|PDB:3PTZ, ECO:0007744|PDB:4EDF"
FT BINDING 276..279
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000269|PubMed:21502315,
FT ECO:0000269|PubMed:21595445, ECO:0000269|PubMed:21984906,
FT ECO:0007744|PDB:2Q3E, ECO:0007744|PDB:2QG4,
FT ECO:0007744|PDB:3PRJ, ECO:0007744|PDB:3PTZ,
FT ECO:0007744|PDB:3TDK"
FT BINDING 338..339
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:23106432,
FT ECO:0000305|PubMed:21502315, ECO:0000305|PubMed:21595445,
FT ECO:0007744|PDB:2QG4, ECO:0007744|PDB:3PRJ,
FT ECO:0007744|PDB:3PTZ, ECO:0007744|PDB:4EDF"
FT BINDING 346
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000269|PubMed:21502315,
FT ECO:0000269|PubMed:21595445, ECO:0000269|PubMed:21984906,
FT ECO:0000269|PubMed:22123821, ECO:0007744|PDB:2Q3E,
FT ECO:0007744|PDB:2QG4, ECO:0007744|PDB:3PRJ,
FT ECO:0007744|PDB:3PTZ, ECO:0007744|PDB:3TDK"
FT BINDING 442
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:22123821,
FT ECO:0000269|PubMed:23106432, ECO:0000305|PubMed:21502315,
FT ECO:0000305|PubMed:21595445, ECO:0007744|PDB:2QG4,
FT ECO:0007744|PDB:3KHU, ECO:0007744|PDB:3PRJ,
FT ECO:0007744|PDB:3PTZ, ECO:0007744|PDB:4EDF"
FT MOD_RES 107
FT /note="N6-acetyllysine"
FT /evidence="ECO:0007744|PubMed:19608861"
FT MOD_RES 476
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:24275569"
FT VAR_SEQ 1..97
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_046234"
FT VAR_SEQ 89..155
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_042550"
FT VARIANT 14
FT /note="Y -> C (in DEE84)"
FT /evidence="ECO:0000269|PubMed:32001716"
FT /id="VAR_083750"
FT VARIANT 24
FT /note="A -> T (in DEE84; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:32001716"
FT /id="VAR_083751"
FT VARIANT 42
FT /note="I -> T (in DEE84; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:32001716"
FT /id="VAR_083752"
FT VARIANT 44
FT /note="A -> V (in DEE84; severely decreased protein
FT stability; decreased hexamer formation; severe decrease of
FT UDP-glucose 6-dehydrogenase activity; dbSNP:rs749975104)"
FT /evidence="ECO:0000269|PubMed:32001716"
FT /id="VAR_083753"
FT VARIANT 65..494
FT /note="Missing (in DEE84; dbSNP:rs200059198)"
FT /evidence="ECO:0000269|PubMed:32001716"
FT /id="VAR_083754"
FT VARIANT 72
FT /note="S -> A (in DEE84)"
FT /evidence="ECO:0000269|PubMed:32001716"
FT /id="VAR_083755"
FT VARIANT 82
FT /note="A -> T (in DEE84; decreased function in
FT glycosaminoglycan biosynthetic process in patient cells;
FT severely decreased protein stability; decreased hexamer
FT formation; severe decrease of UDP-glucose 6-dehydrogenase
FT activity)"
FT /evidence="ECO:0000269|PubMed:32001716"
FT /id="VAR_083756"
FT VARIANT 116
FT /note="I -> T (in DEE84; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:32001716"
FT /id="VAR_083757"
FT VARIANT 155..494
FT /note="Missing (in DEE84; dbSNP:rs1381665298)"
FT /evidence="ECO:0000269|PubMed:32001716"
FT /id="VAR_083758"
FT VARIANT 175
FT /note="P -> A (in DEE84; unknown pathological significance;
FT dbSNP:rs756467468)"
FT /evidence="ECO:0000269|PubMed:32001716"
FT /id="VAR_083759"
FT VARIANT 217
FT /note="E -> D (in DEE84; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:32001716"
FT /id="VAR_083760"
FT VARIANT 255
FT /note="I -> T (in DEE84; unknown pathological significance;
FT dbSNP:rs1186496501)"
FT /evidence="ECO:0000269|PubMed:32001716"
FT /id="VAR_083761"
FT VARIANT 271
FT /note="G -> R (in DEE84; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:32001716"
FT /id="VAR_083762"
FT VARIANT 303
FT /note="V -> I (in DEE84; unknown pathological significance;
FT may affect splicing)"
FT /evidence="ECO:0000269|PubMed:32001716"
FT /id="VAR_083763"
FT VARIANT 306
FT /note="M -> V (in DEE84; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:32001716"
FT /id="VAR_083764"
FT VARIANT 317
FT /note="R -> Q (in DEE84; unknown pathological significance;
FT dbSNP:rs775162839)"
FT /evidence="ECO:0000269|PubMed:32001716"
FT /id="VAR_083765"
FT VARIANT 356..494
FT /note="Missing (in DEE84)"
FT /evidence="ECO:0000269|PubMed:32001716"
FT /id="VAR_083766"
FT VARIANT 367
FT /note="Y -> C (in DEE84)"
FT /evidence="ECO:0000269|PubMed:32001716"
FT /id="VAR_083767"
FT VARIANT 393
FT /note="R -> W (in DEE84; unknown pathological significance;
FT dbSNP:rs113094436)"
FT /evidence="ECO:0000269|PubMed:32001716"
FT /id="VAR_083768"
FT VARIANT 410
FT /note="A -> S (in DEE84; unknown pathological significance;
FT dbSNP:rs770456604)"
FT /evidence="ECO:0000269|PubMed:32001716"
FT /id="VAR_083769"
FT VARIANT 442
FT /note="R -> W (in DEE84; unknown pathological significance;
FT dbSNP:rs201894374)"
FT /evidence="ECO:0000269|PubMed:32001716"
FT /id="VAR_083770"
FT VARIANT 443
FT /note="R -> H (in DEE84; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:32001716"
FT /id="VAR_083771"
FT VARIANT 449
FT /note="H -> R (in DEE84; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:32001716"
FT /id="VAR_083772"
FT MUTAGEN 94
FT /note="K->E: Loss of hexamer formation. Causes formation of
FT stable dimers. Strongly reduced affinity for NAD and UDP-
FT glucose, and strongly decreased catalytic efficiency at pH
FT 8.6."
FT /evidence="ECO:0000269|PubMed:23106432,
FT ECO:0000269|PubMed:25478983"
FT MUTAGEN 104
FT /note="A->G: Impairs protein folding. Decreases affinity
FT for UDP-glucose. No effect on inhibition by UDP-xylose. No
FT effect on hysteresis and cooperativity."
FT /evidence="ECO:0000269|PubMed:30457329"
FT MUTAGEN 104
FT /note="A->L: No significant effect on catalytic activity
FT and on affinity for NAD and UDP-glucose. Decreases affinity
FT for the inhibitor UDP-xylose. Disrupts hysteresis and
FT cooperativity."
FT /evidence="ECO:0000269|PubMed:30457329"
FT MUTAGEN 131
FT /note="T->A: Reduced affinity for UDP-glucose, and reduced
FT catalytic efficiency."
FT /evidence="ECO:0000269|PubMed:21502315"
FT MUTAGEN 132
FT /note="Missing: Nearly abolishes enzyme activity.
FT Stabilizes the enzyme in a low-activity hexameric
FT conformation."
FT /evidence="ECO:0000269|PubMed:21961565"
FT MUTAGEN 136
FT /note="A->M: Stabilizes the active conformation of the
FT hexamer. Decreases affinity for UDP-xylose, but not for
FT UDP-glucose. Disrupts hysteresis and cooperativity."
FT /evidence="ECO:0000269|PubMed:27966912,
FT ECO:0000269|PubMed:30457329"
FT MUTAGEN 161
FT /note="E->Q: Abolishes hydrolysis of the covalent
FT intermediate between substrate and the catalytic cysteine
FT residue."
FT /evidence="ECO:0000269|PubMed:22123821"
FT MUTAGEN 220
FT /note="K->A: Loss of ezyme activity."
FT /evidence="ECO:0000269|PubMed:22123821"
FT MUTAGEN 276
FT /note="C->A,S: Loss of enzyme activity."
FT /evidence="ECO:0000269|PubMed:21502315"
FT MUTAGEN 280
FT /note="D->A: Loss of ezyme activity."
FT /evidence="ECO:0000269|PubMed:22123821"
FT MUTAGEN 323..325
FT /note="FNT->TTD: Loss of hexamer formation. Causes
FT formation of stable dimers. Strongly decreased specific
FT activity at pH 8.4."
FT /evidence="ECO:0000269|PubMed:25478983"
FT MUTAGEN 465..494
FT /note="KVSSKRIPYAPSGEIPKFSLQDPPNKKPKV->SSSSSSSSSSSSSSSSSSSS
FT SSSSSSSSSS: No effect on the intrinsically disordered
FT nature of the C-terminus. No effect on affinity for the
FT inhibitor UDP-xylose."
FT /evidence="ECO:0000269|PubMed:30457329"
FT MUTAGEN 465..494
FT /note="Missing: Strongly decreases affinity for the
FT inhibitor UDP-xylose."
FT /evidence="ECO:0000269|PubMed:30457329"
FT CONFLICT 338
FT /note="F -> V (in Ref. 8; AAC05135)"
FT /evidence="ECO:0000305"
FT CONFLICT 377
FT /note="V -> A (in Ref. 8; AAC05135)"
FT /evidence="ECO:0000305"
FT STRAND 6..10
FT /evidence="ECO:0007829|PDB:5VR8"
FT STRAND 13..15
FT /evidence="ECO:0007829|PDB:6C4K"
FT HELIX 16..26
FT /evidence="ECO:0007829|PDB:5VR8"
FT STRAND 30..35
FT /evidence="ECO:0007829|PDB:5VR8"
FT HELIX 39..45
FT /evidence="ECO:0007829|PDB:5VR8"
FT STRAND 47..49
FT /evidence="ECO:0007829|PDB:5VR8"
FT HELIX 57..64
FT /evidence="ECO:0007829|PDB:5VR8"
FT TURN 65..67
FT /evidence="ECO:0007829|PDB:5VR8"
FT STRAND 68..73
FT /evidence="ECO:0007829|PDB:5VR8"
FT HELIX 75..81
FT /evidence="ECO:0007829|PDB:5VR8"
FT STRAND 83..87
FT /evidence="ECO:0007829|PDB:5VR8"
FT STRAND 95..97
FT /evidence="ECO:0007829|PDB:5VR8"
FT TURN 98..102
FT /evidence="ECO:0007829|PDB:5VR8"
FT HELIX 107..118
FT /evidence="ECO:0007829|PDB:5VR8"
FT STRAND 122..128
FT /evidence="ECO:0007829|PDB:5VR8"
FT HELIX 136..146
FT /evidence="ECO:0007829|PDB:5VR8"
FT STRAND 153..158
FT /evidence="ECO:0007829|PDB:5VR8"
FT HELIX 168..173
FT /evidence="ECO:0007829|PDB:5VR8"
FT STRAND 178..181
FT /evidence="ECO:0007829|PDB:5VR8"
FT HELIX 186..199
FT /evidence="ECO:0007829|PDB:5VR8"
FT TURN 200..202
FT /evidence="ECO:0007829|PDB:5VR8"
FT HELIX 205..207
FT /evidence="ECO:0007829|PDB:5VR8"
FT STRAND 208..211
FT /evidence="ECO:0007829|PDB:5VR8"
FT HELIX 213..244
FT /evidence="ECO:0007829|PDB:5VR8"
FT HELIX 248..256
FT /evidence="ECO:0007829|PDB:5VR8"
FT TURN 259..261
FT /evidence="ECO:0007829|PDB:5VR8"
FT STRAND 263..265
FT /evidence="ECO:0007829|PDB:5VR8"
FT STRAND 274..276
FT /evidence="ECO:0007829|PDB:2Q3E"
FT HELIX 277..290
FT /evidence="ECO:0007829|PDB:5VR8"
FT HELIX 294..321
FT /evidence="ECO:0007829|PDB:5VR8"
FT TURN 322..324
FT /evidence="ECO:0007829|PDB:5VR8"
FT STRAND 330..334
FT /evidence="ECO:0007829|PDB:5VR8"
FT STRAND 337..339
FT /evidence="ECO:0007829|PDB:5VR8"
FT HELIX 349..358
FT /evidence="ECO:0007829|PDB:5VR8"
FT TURN 359..361
FT /evidence="ECO:0007829|PDB:5VR8"
FT STRAND 363..367
FT /evidence="ECO:0007829|PDB:5VR8"
FT STRAND 369..371
FT /evidence="ECO:0007829|PDB:5VR8"
FT HELIX 373..380
FT /evidence="ECO:0007829|PDB:5VR8"
FT HELIX 389..394
FT /evidence="ECO:0007829|PDB:5VR8"
FT STRAND 395..397
FT /evidence="ECO:0007829|PDB:5VR8"
FT HELIX 401..405
FT /evidence="ECO:0007829|PDB:5VR8"
FT STRAND 409..413
FT /evidence="ECO:0007829|PDB:5VR8"
FT HELIX 418..422
FT /evidence="ECO:0007829|PDB:5VR8"
FT HELIX 425..431
FT /evidence="ECO:0007829|PDB:5VR8"
FT STRAND 437..440
FT /evidence="ECO:0007829|PDB:5VR8"
FT TURN 444..447
FT /evidence="ECO:0007829|PDB:5VR8"
FT HELIX 449..455
FT /evidence="ECO:0007829|PDB:5VR8"
FT STRAND 458..461
FT /evidence="ECO:0007829|PDB:5VR8"
SQ SEQUENCE 494 AA; 55024 MW; 9C9DA5E1227D65CC CRC64;
MFEIKKICCI GAGYVGGPTC SVIAHMCPEI RVTVVDVNES RINAWNSPTL PIYEPGLKEV
VESCRGKNLF FSTNIDDAIK EADLVFISVN TPTKTYGMGK GRAADLKYIE ACARRIVQNS
NGYKIVTEKS TVPVRAAESI RRIFDANTKP NLNLQVLSNP EFLAEGTAIK DLKNPDRVLI
GGDETPEGQR AVQALCAVYE HWVPREKILT TNTWSSELSK LAANAFLAQR ISSINSISAL
CEATGADVEE VATAIGMDQR IGNKFLKASV GFGGSCFQKD VLNLVYLCEA LNLPEVARYW
QQVIDMNDYQ RRRFASRIID SLFNTVTDKK IAILGFAFKK DTGDTRESSS IYISKYLMDE
GAHLHIYDPK VPREQIVVDL SHPGVSEDDQ VSRLVTISKD PYEACDGAHA VVICTEWDMF
KELDYERIHK KMLKPAFIFD GRRVLDGLHN ELQTIGFQIE TIGKKVSSKR IPYAPSGEIP
KFSLQDPPNK KPKV
