ID HMDH_HUMAN Reviewed; 888 AA. AC P04035; B7Z3Y9; Q8N190; DT 01-NOV-1986, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1986, sequence version 1. DT 27-MAR-2024, entry version 247. DE RecName: Full=3-hydroxy-3-methylglutaryl-coenzyme A reductase; DE Short=HMG-CoA reductase; DE EC=1.1.1.34 {ECO:0000269|PubMed:21357570, ECO:0000269|PubMed:2991281, ECO:0000269|PubMed:36745799, ECO:0000269|PubMed:6995544}; GN Name=HMGCR {ECO:0000312|HGNC:HGNC:5006}; 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), FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=2991281; DOI=10.1016/s0021-9258(17)39242-6; RA Luskey K.L., Stevens B.; RT "Human 3-hydroxy-3-methylglutaryl coenzyme A reductase. Conserved domains RT responsible for catalytic activity and sterol-regulated degradation."; RL J. Biol. Chem. 260:10271-10277(1985). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RA Nakajima T., Iwaki K., Hamakubo T., Kodama T., Emi M.; RT "Human HMG-CoA reductase gene."; RL Submitted (JUN-2000) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RA Rieder M.J., da Ponte S.H., Kuldanek S.A., Rajkumar N., Smith J.D., RA Toth E.J., Nickerson D.A.; RL Submitted (JUN-2003) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3). RC TISSUE=Thalamus; 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=15372022; DOI=10.1038/nature02919; RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S., RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M., RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S., RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M., RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T., Gomez M., RA Gonzales E., Goodstein D., Grigoriev I., Groza M., Hammon N., Hawkins T., RA Haydu L., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., RA Lopez F., Lou Y., Martinez D., Medina C., Morgan J., Nandkeshwar R., RA Noonan J.P., Pitluck S., Pollard M., Predki P., Priest J., Ramirez L., RA Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., Thayer N., RA Tice H., Tsai M., Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., RA Dickson M., Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., RA Rokhsar D.S., Richardson P., Lucas S.M., Myers R.M., Rubin E.M.; RT "The DNA sequence and comparative analysis of human chromosome 5."; RL Nature 431:268-274(2004). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Blood; 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 [7] RP ACTIVITY REGULATION, CATALYTIC ACTIVITY, AND FUNCTION. RX PubMed=6995544; RA Brown M.S., Goldstein J.L.; RT "Multivalent feedback regulation of HMG CoA reductase, a control mechanism RT coordinating isoprenoid synthesis and cell growth."; RL J. Lipid Res. 21:505-517(1980). RN [8] RP INTERACTION WITH INSIG1, AND UBIQUITINATION. RX PubMed=12535518; DOI=10.1016/s1097-2765(02)00822-5; RA Sever N., Yang T., Brown M.S., Goldstein J.L., DeBose-Boyd R.A.; RT "Accelerated degradation of HMG CoA reductase mediated by binding of insig- RT 1 to its sterol-sensing domain."; RL Mol. Cell 11:25-33(2003). RN [9] RP SUBCELLULAR LOCATION. RX PubMed=17180682; DOI=10.1007/s00418-006-0254-6; RA Kovacs W.J., Tape K.N., Shackelford J.E., Duan X., Kasumov T., RA Kelleher J.K., Brunengraber H., Krisans S.K.; RT "Localization of the pre-squalene segment of the isoprenoid biosynthetic RT pathway in mammalian peroxisomes."; RL Histochem. Cell Biol. 127:273-290(2007). RN [10] RP INTERACTION WITH INSIG1, UBIQUITINATION AT LYS-89 AND LYS-248, RP GLYCOSYLATION, AND MUTAGENESIS OF 75-TYR--TYR-77; LYS-89 AND LYS-248. RX PubMed=19458199; DOI=10.1091/mbc.e08-09-0953; RA Leichner G.S., Avner R., Harats D., Roitelman J.; RT "Dislocation of HMG-CoA reductase and Insig-1, two polytopic endoplasmic RT reticulum proteins, en route to proteasomal degradation."; RL Mol. Biol. Cell 20:3330-3341(2009). RN [11] RP UBIQUITINATION. RX PubMed=21778231; DOI=10.1074/jbc.m111.278036; RA Leichner G.S., Avner R., Harats D., Roitelman J.; RT "Metabolically regulated endoplasmic reticulum-associated degradation of 3- RT hydroxy-3-methylglutaryl-CoA reductase: evidence for requirement of a RT geranylgeranylated protein."; RL J. Biol. Chem. 286:32150-32161(2011). RN [12] RP CATALYTIC ACTIVITY, FUNCTION, ACTIVITY REGULATION, AND MUTAGENESIS OF RP GLY-807. RX PubMed=21357570; DOI=10.1194/jlr.m011817; RA Cuccioloni M., Mozzicafreddo M., Spina M., Tran C.N., Falconi M., RA Eleuteri A.M., Angeletti M.; RT "Epigallocatechin-3-gallate potently inhibits the in vitro activity of RT hydroxy-3-methyl-glutaryl-CoA reductase."; RL J. Lipid Res. 52:897-907(2011). RN [13] RP UBIQUITINATION. RX PubMed=22143767; DOI=10.1073/pnas.1112831108; RA Jo Y., Lee P.C., Sguigna P.V., DeBose-Boyd R.A.; RT "Sterol-induced degradation of HMG CoA reductase depends on interplay of RT two Insigs and two ubiquitin ligases, gp78 and Trc8."; RL Proc. Natl. Acad. Sci. U.S.A. 108:20503-20508(2011). RN [14] RP TISSUE SPECIFICITY (ISOFORMS 1; 2 AND 3), AND ALTERNATIVE SPLICING. RX PubMed=22989091; DOI=10.1186/1471-2199-13-29; RA Stormo C., Kringen M.K., Grimholt R.M., Berg J.P., Piehler A.P.; RT "A novel 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) splice RT variant with an alternative exon 1 potentially encoding an extended N- RT terminus."; RL BMC Mol. Biol. 13:29-29(2012). RN [15] RP INTERACTION WITH UBIAD1. RX PubMed=23169578; DOI=10.1002/humu.22230; RA Nickerson M.L., Bosley A.D., Weiss J.S., Kostiha B.N., Hirota Y., RA Brandt W., Esposito D., Kinoshita S., Wessjohann L., Morham S.G., RA Andresson T., Kruth H.S., Okano T., Dean M.; RT "The UBIAD1 prenyltransferase links menaquione-4 synthesis to cholesterol RT metabolic enzymes."; RL Hum. Mutat. 34:317-329(2013). RN [16] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-504, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [17] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-872, 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 [18] RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 422-888, AND SUBUNIT. RX PubMed=10698924; DOI=10.1093/emboj/19.5.819; RA Istvan E.S., Palnitkar M., Buchanan S.K., Deisenhofer J.; RT "Crystal structure of the catalytic portion of human HMG-CoA reductase: RT insights into regulation of activity and catalysis."; RL EMBO J. 19:819-830(2000). RN [19] RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 422-888 IN COMPLEX WITH COENZYME A RP AND NADP. RX PubMed=11349148; DOI=10.1126/science.1059344; RA Istvan E.S., Deisenhofer J.; RT "Structural mechanism for statin inhibition of HMG-CoA reductase."; RL Science 292:1160-1164(2001). RN [20] RP X-RAY CRYSTALLOGRAPHY (2.39 ANGSTROMS) OF 441-875 IN COMPLEX WITH RP STATIN-BASED INHIBITORS. RX PubMed=18540668; DOI=10.1021/jm7015057; RA Sarver R.W., Bills E., Bolton G., Bratton L.D., Caspers N.L., Dunbar J.B., RA Harris M.S., Hutchings R.H., Kennedy R.M., Larsen S.D., Pavlovsky A., RA Pfefferkorn J.A., Bainbridge G.; RT "Thermodynamic and structure guided design of statin based inhibitors of 3- RT hydroxy-3-methylglutaryl coenzyme A reductase."; RL J. Med. Chem. 51:3804-3813(2008). RN [21] RP VARIANT VAL-638. RX PubMed=10391209; DOI=10.1038/10290; RA Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N., RA Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L., RA Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q., RA Lander E.S.; RT "Characterization of single-nucleotide polymorphisms in coding regions of RT human genes."; RL Nat. Genet. 22:231-238(1999). RN [22] RP ERRATUM OF PUBMED:10391209. RA Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N., RA Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L., RA Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q., RA Lander E.S.; RL Nat. Genet. 23:373-373(1999). RN [23] RP POLYMORPHISM. RX PubMed=18193044; DOI=10.1038/ng.75; RA Kathiresan S., Melander O., Guiducci C., Surti A., Burtt N.P., Rieder M.J., RA Cooper G.M., Roos C., Voight B.F., Havulinna A.S., Wahlstrand B., RA Hedner T., Corella D., Tai E.S., Ordovas J.M., Berglund G., Vartiainen E., RA Jousilahti P., Hedblad B., Taskinen M.R., Newton-Cheh C., Salomaa V., RA Peltonen L., Groop L., Altshuler D.M., Orho-Melander M.; RT "Six new loci associated with blood low-density lipoprotein cholesterol, RT high-density lipoprotein cholesterol or triglycerides in humans."; RL Nat. Genet. 40:189-197(2008). RN [24] RP POLYMORPHISM. RX PubMed=18354102; DOI=10.1056/nejmoa0706728; RA Kathiresan S., Melander O., Anevski D., Guiducci C., Burtt N.P., Roos C., RA Hirschhorn J.N., Berglund G., Hedblad B., Groop L., Altshuler D.M., RA Newton-Cheh C., Orho-Melander M.; RT "Polymorphisms associated with cholesterol and risk of cardiovascular RT events."; RL N. Engl. J. Med. 358:1240-1249(2008). RN [25] RP POLYMORPHISM. RX PubMed=20686565; DOI=10.1038/nature09270; RA Teslovich T.M., Musunuru K., Smith A.V., Edmondson A.C., Stylianou I.M., RA Koseki M., Pirruccello J.P., Ripatti S., Chasman D.I., Willer C.J., RA Johansen C.T., Fouchier S.W., Isaacs A., Peloso G.M., Barbalic M., RA Ricketts S.L., Bis J.C., Aulchenko Y.S., Thorleifsson G., Feitosa M.F., RA Chambers J., Orho-Melander M., Melander O., Johnson T., Li X., Guo X., RA Li M., Shin Cho Y., Jin Go M., Jin Kim Y., Lee J.Y., Park T., Kim K., RA Sim X., Twee-Hee Ong R., Croteau-Chonka D.C., Lange L.A., Smith J.D., RA Song K., Hua Zhao J., Yuan X., Luan J., Lamina C., Ziegler A., Zhang W., RA Zee R.Y., Wright A.F., Witteman J.C., Wilson J.F., Willemsen G., RA Wichmann H.E., Whitfield J.B., Waterworth D.M., Wareham N.J., Waeber G., RA Vollenweider P., Voight B.F., Vitart V., Uitterlinden A.G., Uda M., RA Tuomilehto J., Thompson J.R., Tanaka T., Surakka I., Stringham H.M., RA Spector T.D., Soranzo N., Smit J.H., Sinisalo J., Silander K., RA Sijbrands E.J., Scuteri A., Scott J., Schlessinger D., Sanna S., RA Salomaa V., Saharinen J., Sabatti C., Ruokonen A., Rudan I., Rose L.M., RA Roberts R., Rieder M., Psaty B.M., Pramstaller P.P., Pichler I., Perola M., RA Penninx B.W., Pedersen N.L., Pattaro C., Parker A.N., Pare G., Oostra B.A., RA O'Donnell C.J., Nieminen M.S., Nickerson D.A., Montgomery G.W., RA Meitinger T., McPherson R., McCarthy M.I., McArdle W., Masson D., RA Martin N.G., Marroni F., Mangino M., Magnusson P.K., Lucas G., Luben R., RA Loos R.J., Lokki M.L., Lettre G., Langenberg C., Launer L.J., Lakatta E.G., RA Laaksonen R., Kyvik K.O., Kronenberg F., Konig I.R., Khaw K.T., Kaprio J., RA Kaplan L.M., Johansson A., Jarvelin M.R., Janssens A.C., Ingelsson E., RA Igl W., Kees Hovingh G., Hottenga J.J., Hofman A., Hicks A.A., RA Hengstenberg C., Heid I.M., Hayward C., Havulinna A.S., Hastie N.D., RA Harris T.B., Haritunians T., Hall A.S., Gyllensten U., Guiducci C., RA Groop L.C., Gonzalez E., Gieger C., Freimer N.B., Ferrucci L., Erdmann J., RA Elliott P., Ejebe K.G., Doring A., Dominiczak A.F., Demissie S., RA Deloukas P., de Geus E.J., de Faire U., Crawford G., Collins F.S., RA Chen Y.D., Caulfield M.J., Campbell H., Burtt N.P., Bonnycastle L.L., RA Boomsma D.I., Boekholdt S.M., Bergman R.N., Barroso I., Bandinelli S., RA Ballantyne C.M., Assimes T.L., Quertermous T., Altshuler D., Seielstad M., RA Wong T.Y., Tai E.S., Feranil A.B., Kuzawa C.W., Adair L.S., RA Taylor H.A. Jr., Borecki I.B., Gabriel S.B., Wilson J.G., Holm H., RA Thorsteinsdottir U., Gudnason V., Krauss R.M., Mohlke K.L., Ordovas J.M., RA Munroe P.B., Kooner J.S., Tall A.R., Hegele R.A., Kastelein J.J., RA Schadt E.E., Rotter J.I., Boerwinkle E., Strachan D.P., Mooser V., RA Stefansson K., Reilly M.P., Samani N.J., Schunkert H., Cupples L.A., RA Sandhu M.S., Ridker P.M., Rader D.J., van Duijn C.M., Peltonen L., RA Abecasis G.R., Boehnke M., Kathiresan S.; RT "Biological, clinical and population relevance of 95 loci for blood RT lipids."; RL Nature 466:707-713(2010). RN [26] RP VARIANTS LGMDR28 GLN-443; TRP-443; MET-467; SER-508 DEL; THR-515; SER-546; RP ASN-623 AND CYS-792, CHARACTERIZATION OF VARIANTS LGMDR28 GLN-443; ASN-623 RP AND CYS-792, AND INVOLVEMENT IN LGMDR28. RX PubMed=37167966; DOI=10.1016/j.ajhg.2023.04.006; RA Morales-Rosado J.A., Schwab T.L., Macklin-Mantia S.K., Foley A.R., RA Pinto Vairo F., Pehlivan D., Donkervoort S., Rosenfeld J.A., Boyum G.E., RA Hu Y., Cong A.T.Q., Lotze T.E., Mohila C.A., Saade D., Bharucha-Goebel D., RA Chao K.R., Grunseich C., Bruels C.C., Littel H.R., Estrella E.A., Pais L., RA Kang P.B., Zimmermann M.T., Lupski J.R., Lee B., Schellenberg M.J., RA Clark K.J., Wierenga K.J., Boennemann C.G., Klee E.W.; RT "Bi-allelic variants in HMGCR cause an autosomal-recessive progressive RT limb-girdle muscular dystrophy."; RL Am. J. Hum. Genet. 110:989-997(2023). RN [27] RP VARIANT LGMDR28 ASP-822, CHARACTERIZATION OF VARIANT LGMDR28 ASP-822, RP INVOLVEMENT IN LGMDR28, FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL RP PROPERTIES, AND ACTIVITY REGULATION. RX PubMed=36745799; DOI=10.1073/pnas.2217831120; RA Yogev Y., Shorer Z., Koifman A., Wormser O., Drabkin M., Halperin D., RA Dolgin V., Proskorovski-Ohayon R., Hadar N., Davidov G., Nudelman H., RA Zarivach R., Shelef I., Perez Y., Birk O.S.; RT "Limb girdle muscular disease caused by HMGCR mutation and statin myopathy RT treatable with mevalonolactone."; RL Proc. Natl. Acad. Sci. U.S.A. 120:e2217831120-e2217831120(2023). CC -!- FUNCTION: Catalyzes the conversion of (3S)-hydroxy-3-methylglutaryl-CoA CC (HMG-CoA) to mevalonic acid, the rate-limiting step in the synthesis of CC cholesterol and other isoprenoids, thus plays a critical role in CC cellular cholesterol homeostasis (PubMed:2991281, PubMed:21357570, CC PubMed:6995544, PubMed:36745799). HMGCR is the main target of statins, CC a class of cholesterol-lowering drugs (PubMed:11349148, CC PubMed:18540668, PubMed:36745799). {ECO:0000269|PubMed:11349148, CC ECO:0000269|PubMed:18540668, ECO:0000269|PubMed:21357570, CC ECO:0000269|PubMed:2991281, ECO:0000269|PubMed:36745799, CC ECO:0000269|PubMed:6995544}. CC -!- CATALYTIC ACTIVITY: CC Reaction=(R)-mevalonate + CoA + 2 NADP(+) = (3S)-hydroxy-3- CC methylglutaryl-CoA + 2 H(+) + 2 NADPH; Xref=Rhea:RHEA:15989, CC ChEBI:CHEBI:15378, ChEBI:CHEBI:36464, ChEBI:CHEBI:43074, CC ChEBI:CHEBI:57287, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349; EC=1.1.1.34; CC Evidence={ECO:0000269|PubMed:21357570, ECO:0000269|PubMed:2991281, CC ECO:0000269|PubMed:36745799, ECO:0000269|PubMed:6995544}; CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:15991; CC Evidence={ECO:0000269|PubMed:36745799}; CC -!- ACTIVITY REGULATION: Regulated by a negative feedback mechanism through CC sterols and non-sterol metabolites derived from mevalonate CC (PubMed:6995544). Phosphorylation at Ser-872 down-regulates the CC catalytic activity (By similarity). Inhibited by statins, a class of CC hypolipidemic agents used as pharmaceuticals to lower cholesterol CC levels in individuals at risk from cardiovascular disease due to CC hypercholesterolemia (PubMed:11349148, PubMed:18540668). Inhibition of CC HMGCR in the liver stimulates the LDL-receptors, which results in an CC increased clearance of LDL from the bloodstream and a decrease in blood CC cholesterol levels (PubMed:11349148, PubMed:18540668). The first CC results can be seen after one week of statin use and the effect is CC maximal after four to six weeks (PubMed:11349148, PubMed:18540668). CC Inhibited by pravastatin (PubMed:36745799). CC {ECO:0000250|UniProtKB:P00347, ECO:0000269|PubMed:11349148, CC ECO:0000269|PubMed:18540668, ECO:0000269|PubMed:36745799, CC ECO:0000303|PubMed:6995544}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=13.73 uM for (3S)-hydroxy-3-methylglutaryl-CoA CC {ECO:0000269|PubMed:36745799}; CC -!- PATHWAY: Metabolic intermediate biosynthesis; (R)-mevalonate CC biosynthesis; (R)-mevalonate from acetyl-CoA: step 3/3. CC -!- SUBUNIT: Homotetramer (PubMed:10698924). Homodimer (PubMed:10698924). CC Interacts (via its SSD) with INSIG1; the interaction, accelerated by CC sterols, leads to the recruitment of HMGCR to AMFR/gp78 for its CC ubiquitination by the sterol-mediated ERAD pathway (PubMed:12535518, CC PubMed:19458199). Interacts with UBIAD1 (PubMed:23169578). CC {ECO:0000269|PubMed:10698924, ECO:0000269|PubMed:11349148, CC ECO:0000269|PubMed:12535518, ECO:0000269|PubMed:19458199, CC ECO:0000269|PubMed:23169578}. CC -!- INTERACTION: CC P04035; Q9Y5Z9: UBIAD1; NbExp=3; IntAct=EBI-465513, EBI-2819725; CC P04035; Q9Y5Z9-1: UBIAD1; NbExp=5; IntAct=EBI-465513, EBI-6621921; CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane CC {ECO:0000269|PubMed:17180682, ECO:0000305|PubMed:2991281}; Multi-pass CC membrane protein {ECO:0000250|UniProtKB:P00347}. Peroxisome membrane CC {ECO:0000269|PubMed:17180682}; Multi-pass membrane protein CC {ECO:0000250|UniProtKB:P00347}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; Synonyms=HMGCR-1a {ECO:0000303|PubMed:22989091}; CC IsoId=P04035-1; Sequence=Displayed; CC Name=2; Synonyms=HMGCR-1c {ECO:0000303|PubMed:22989091}; CC IsoId=P04035-2; Sequence=VSP_002207; CC Name=3; Synonyms=HMGCR-1b {ECO:0000303|PubMed:22989091}; CC IsoId=P04035-3; Sequence=VSP_046492; CC -!- TISSUE SPECIFICITY: [Isoform 1]: Ubiquitously expressed with the CC highest levels in the cerebellum, fetal brain, testis, skin and adrenal CC gland. {ECO:0000269|PubMed:22989091}. CC -!- TISSUE SPECIFICITY: [Isoform 2]: Detected in the cerebellum, fetal CC brain, testis and adrenal gland. {ECO:0000269|PubMed:22989091}. CC -!- TISSUE SPECIFICITY: [Isoform 3]: Low abundance except in skin, CC esophagus, and uterine cervix. {ECO:0000269|PubMed:22989091}. CC -!- PTM: N-glycosylated. Deglycosylated by NGLY1 on release from the CC endoplasmic reticulum (ER) in a sterol-mediated manner. CC {ECO:0000269|PubMed:19458199}. CC -!- PTM: Undergoes sterol-mediated ubiquitination and ER-associated CC degradation (ERAD) (PubMed:12535518, PubMed:19458199, PubMed:21778231). CC Accumulation of sterols in the endoplasmic reticulum (ER) membrane, CC triggers binding of the reductase to the ER membrane protein INSIG1 or CC INSIG2 (PubMed:12535518, PubMed:19458199, PubMed:21778231, CC PubMed:22143767). The INSIG1 binding leads to the recruitment of the CC ubiquitin ligase, AMFR/gp78, RNF139 or RNF145, initiating CC ubiquitination of the reductase (PubMed:12535518, PubMed:19458199, CC PubMed:21778231). The ubiquitinated reductase is then extracted from CC the ER membrane and delivered to cytosolic 26S proteosomes by a CC mechanism probably mediated by the ATPase Valosin-containing protein CC VCP/p97 (PubMed:12535518, PubMed:19458199, PubMed:21778231). The CC INSIG2-binding leads to the recruitment of the ubiquitin ligase RNF139, CC initiating ubiquitination of the reductase (PubMed:22143767). Lys-248 CC is the main site of ubiquitination (PubMed:19458199). Ubiquitination is CC enhanced by the presence of a geranylgeranylated protein CC (PubMed:21778231). {ECO:0000269|PubMed:12535518, CC ECO:0000269|PubMed:19458199, ECO:0000269|PubMed:21778231, CC ECO:0000269|PubMed:22143767}. CC -!- PTM: Phosphorylated. Phosphorylation at Ser-872 reduces the catalytic CC activity. {ECO:0000250|UniProtKB:P00347}. CC -!- POLYMORPHISM: Genetic variation in HMGCR is associated with modulation CC of LDL or HDL cholesterol levels and defines the low density CC lipoprotein cholesterol level quantitative trait locus 3 (LDLCQ3) CC [MIM:620410]. {ECO:0000269|PubMed:18193044, CC ECO:0000269|PubMed:18354102, ECO:0000269|PubMed:20686565}. CC -!- DISEASE: Muscular dystrophy, limb-girdle, autosomal recessive 28 CC (LGMDR28) [MIM:620375]: An autosomal recessive form of limb girdle CC muscular dystrophy, a group of genetically heterogeneous muscular CC disorders that share proximal muscle weakness as the major attribute. CC Most limb girdle muscular dystrophies present with elevated creatinine CC kinase and myopathic electromyographic features. Disease is usually CC progressive to a variable degree, ranging from minor disability to CC complete inability to ambulate, and can involve the large proximal CC muscles, as well as axial and facial muscles. Different disease forms CC may exhibit skeletal muscle hypertrophy, kyphoscoliosis, and CC contractures or involve other muscle groups and manifest with distal CC weakness, cardiomyopathy, dysphagia, and respiratory difficulties. CC LGMDR28 is characterized by progressive muscle weakness affecting the CC proximal and axial muscles of the upper and lower limbs, and highly CC variable age at onset. Most patients have limited ambulation or become CC wheelchair-bound within a few decades, and respiratory insufficiency CC commonly occurs. {ECO:0000269|PubMed:36745799, CC ECO:0000269|PubMed:37167966}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the HMG-CoA reductase family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=BAH12375.1; Type=Frameshift; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; M11058; AAA52679.1; -; mRNA. DR EMBL; AF273765; AAG21343.1; -; Genomic_DNA. DR EMBL; AF273754; AAG21343.1; JOINED; Genomic_DNA. DR EMBL; AF273755; AAG21343.1; JOINED; Genomic_DNA. DR EMBL; AF273756; AAG21343.1; JOINED; Genomic_DNA. DR EMBL; AF273757; AAG21343.1; JOINED; Genomic_DNA. DR EMBL; AF273758; AAG21343.1; JOINED; Genomic_DNA. DR EMBL; AF273759; AAG21343.1; JOINED; Genomic_DNA. DR EMBL; AF273760; AAG21343.1; JOINED; Genomic_DNA. DR EMBL; AF273761; AAG21343.1; JOINED; Genomic_DNA. DR EMBL; AF273762; AAG21343.1; JOINED; Genomic_DNA. DR EMBL; AF273763; AAG21343.1; JOINED; Genomic_DNA. DR EMBL; AF273764; AAG21343.1; JOINED; Genomic_DNA. DR EMBL; AY321356; AAP72015.1; -; Genomic_DNA. DR EMBL; AK296499; BAH12375.1; ALT_FRAME; mRNA. DR EMBL; AC008897; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC033692; AAH33692.1; -; mRNA. DR CCDS; CCDS4027.1; -. [P04035-1] DR CCDS; CCDS47234.1; -. [P04035-2] DR PIR; A00356; RDHUE. DR RefSeq; NP_000850.1; NM_000859.2. [P04035-1] DR RefSeq; NP_001124468.1; NM_001130996.1. [P04035-2] DR RefSeq; XP_011541659.1; XM_011543357.1. [P04035-3] DR RefSeq; XP_011541660.1; XM_011543358.1. [P04035-1] DR PDB; 1DQ8; X-ray; 2.10 A; A/B/C/D=426-888. DR PDB; 1DQ9; X-ray; 2.80 A; A/B/C/D=426-888. DR PDB; 1DQA; X-ray; 2.00 A; A/B/C/D=426-888. DR PDB; 1HW8; X-ray; 2.10 A; A/B/C/D=426-888. DR PDB; 1HW9; X-ray; 2.33 A; A/B/C/D=426-888. DR PDB; 1HWI; X-ray; 2.30 A; A/B/C/D=426-888. DR PDB; 1HWJ; X-ray; 2.26 A; A/B/C/D=426-888. DR PDB; 1HWK; X-ray; 2.22 A; A/B/C/D=426-888. DR PDB; 1HWL; X-ray; 2.10 A; A/B/C/D=426-888. DR PDB; 2Q1L; X-ray; 2.05 A; A/B/C/D=441-875. DR PDB; 2Q6B; X-ray; 2.00 A; A/B/C/D=441-875. DR PDB; 2Q6C; X-ray; 2.00 A; A/B/C/D=441-875. DR PDB; 2R4F; X-ray; 1.70 A; A/B/C/D=441-875. DR PDB; 3BGL; X-ray; 2.23 A; A/B/C/D=441-875. DR PDB; 3CCT; X-ray; 2.12 A; A/B/C/D=441-875. DR PDB; 3CCW; X-ray; 2.10 A; A/B/C/D=441-875. DR PDB; 3CCZ; X-ray; 1.70 A; A/B/C/D=441-875. DR PDB; 3CD0; X-ray; 2.40 A; A/B/C/D=441-875. DR PDB; 3CD5; X-ray; 2.39 A; A/B/C/D=441-875. DR PDB; 3CD7; X-ray; 2.05 A; A/B/C/D=441-875. DR PDB; 3CDA; X-ray; 2.07 A; A/B/C/D=441-875. DR PDB; 3CDB; X-ray; 2.30 A; A/B/C/D=441-875. DR PDBsum; 1DQ8; -. DR PDBsum; 1DQ9; -. DR PDBsum; 1DQA; -. DR PDBsum; 1HW8; -. DR PDBsum; 1HW9; -. DR PDBsum; 1HWI; -. DR PDBsum; 1HWJ; -. DR PDBsum; 1HWK; -. DR PDBsum; 1HWL; -. DR PDBsum; 2Q1L; -. DR PDBsum; 2Q6B; -. DR PDBsum; 2Q6C; -. DR PDBsum; 2R4F; -. DR PDBsum; 3BGL; -. DR PDBsum; 3CCT; -. DR PDBsum; 3CCW; -. DR PDBsum; 3CCZ; -. DR PDBsum; 3CD0; -. DR PDBsum; 3CD5; -. DR PDBsum; 3CD7; -. DR PDBsum; 3CDA; -. DR PDBsum; 3CDB; -. DR AlphaFoldDB; P04035; -. DR SMR; P04035; -. DR BioGRID; 109399; 144. DR ELM; P04035; -. DR IntAct; P04035; 19. DR STRING; 9606.ENSP00000287936; -. DR BindingDB; P04035; -. DR ChEMBL; CHEMBL402; -. DR DrugBank; DB03169; (S)-Hmg-Coa. DR DrugBank; DB04447; 1,4-Dithiothreitol. DR DrugBank; DB01076; Atorvastatin. DR DrugBank; DB09061; Cannabidiol. DR DrugBank; DB00439; Cerivastatin. DR DrugBank; DB01992; Coenzyme A. DR DrugBank; DB01095; Fluvastatin. DR DrugBank; DB00227; Lovastatin. DR DrugBank; DB14009; Medical Cannabis. DR DrugBank; DB04377; Meglutol. DR DrugBank; DB06693; Mevastatin. DR DrugBank; DB14011; Nabiximols. DR DrugBank; DB00157; NADH. DR DrugBank; DB03461; Nicotinamide adenine dinucleotide phosphate. DR DrugBank; DB08860; Pitavastatin. DR DrugBank; DB00175; Pravastatin. DR DrugBank; DB01098; Rosuvastatin. DR DrugBank; DB00641; Simvastatin. DR DrugBank; DB05317; TAK-475. DR DrugBank; DB09270; Ubidecarenone. DR DrugCentral; P04035; -. DR GuidetoPHARMACOLOGY; 639; -. DR SwissLipids; SLP:000001246; -. DR TCDB; 2.A.6.6.5; the resistance-nodulation-cell division (rnd) superfamily. DR GlyConnect; 983; 3 N-Linked glycans (1 site). DR GlyCosmos; P04035; 2 sites, 3 glycans. DR GlyGen; P04035; 3 sites, 3 N-linked glycans (1 site), 1 O-linked glycan (1 site). DR iPTMnet; P04035; -. DR MetOSite; P04035; -. DR PhosphoSitePlus; P04035; -. DR SwissPalm; P04035; -. DR BioMuta; HMGCR; -. DR DMDM; 123343; -. DR EPD; P04035; -. DR jPOST; P04035; -. DR MassIVE; P04035; -. DR MaxQB; P04035; -. DR PaxDb; 9606-ENSP00000287936; -. DR PeptideAtlas; P04035; -. DR ProteomicsDB; 51634; -. [P04035-1] DR ProteomicsDB; 51635; -. [P04035-2] DR Pumba; P04035; -. DR Antibodypedia; 24380; 469 antibodies from 35 providers. DR DNASU; 3156; -. DR Ensembl; ENST00000287936.9; ENSP00000287936.4; ENSG00000113161.17. [P04035-1] DR Ensembl; ENST00000343975.9; ENSP00000340816.5; ENSG00000113161.17. [P04035-2] DR Ensembl; ENST00000511206.5; ENSP00000426745.1; ENSG00000113161.17. [P04035-1] DR Ensembl; ENST00000680940.1; ENSP00000505561.1; ENSG00000113161.17. [P04035-1] DR Ensembl; ENST00000681271.1; ENSP00000505805.1; ENSG00000113161.17. [P04035-1] DR Ensembl; ENST00000681410.1; ENSP00000506232.1; ENSG00000113161.17. [P04035-1] DR GeneID; 3156; -. DR KEGG; hsa:3156; -. DR MANE-Select; ENST00000287936.9; ENSP00000287936.4; NM_000859.3; NP_000850.1. DR UCSC; uc003kdp.4; human. [P04035-1] DR AGR; HGNC:5006; -. DR CTD; 3156; -. DR DisGeNET; 3156; -. DR GeneCards; HMGCR; -. DR HGNC; HGNC:5006; HMGCR. DR HPA; ENSG00000113161; Tissue enhanced (liver). DR MalaCards; HMGCR; -. DR MIM; 142910; gene. DR MIM; 620375; phenotype. DR MIM; 620410; phenotype. DR neXtProt; NX_P04035; -. DR OpenTargets; ENSG00000113161; -. DR Orphanet; 653725; Autosomal recessive limb-girdle muscular dystrophy, type 28. DR PharmGKB; PA189; -. DR VEuPathDB; HostDB:ENSG00000113161; -. DR eggNOG; KOG2480; Eukaryota. DR GeneTree; ENSGT00940000155305; -. DR HOGENOM; CLU_001734_0_1_1; -. DR InParanoid; P04035; -. DR OMA; DCHIAMD; -. DR OrthoDB; 816560at2759; -. DR PhylomeDB; P04035; -. DR TreeFam; TF105362; -. DR BioCyc; MetaCyc:HS03652-MONOMER; -. DR BRENDA; 1.1.1.34; 2681. DR PathwayCommons; P04035; -. DR Reactome; R-HSA-191273; Cholesterol biosynthesis. DR Reactome; R-HSA-1989781; PPARA activates gene expression. [P04035-1] DR Reactome; R-HSA-2426168; Activation of gene expression by SREBF (SREBP). [P04035-1] DR Reactome; R-HSA-9619665; EGR2 and SOX10-mediated initiation of Schwann cell myelination. DR SABIO-RK; P04035; -. DR SignaLink; P04035; -. DR SIGNOR; P04035; -. DR UniPathway; UPA00058; UER00103. DR BioGRID-ORCS; 3156; 655 hits in 1170 CRISPR screens. DR ChiTaRS; HMGCR; human. DR EvolutionaryTrace; P04035; -. DR GeneWiki; HMG-CoA_reductase; -. DR GenomeRNAi; 3156; -. DR Pharos; P04035; Tclin. DR PRO; PR:P04035; -. DR Proteomes; UP000005640; Chromosome 5. DR RNAct; P04035; Protein. DR Bgee; ENSG00000113161; Expressed in adrenal tissue and 199 other cell types or tissues. DR ExpressionAtlas; P04035; baseline and differential. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IBA:GO_Central. DR GO; GO:0005778; C:peroxisomal membrane; IDA:UniProtKB. DR GO; GO:0120225; F:coenzyme A binding; IDA:UniProtKB. DR GO; GO:0030695; F:GTPase regulator activity; IEA:Ensembl. DR GO; GO:0004420; F:hydroxymethylglutaryl-CoA reductase (NADPH) activity; IDA:UniProtKB. DR GO; GO:0070402; F:NADPH binding; IDA:UniProtKB. DR GO; GO:0006695; P:cholesterol biosynthetic process; IDA:CACAO. DR GO; GO:0015936; P:coenzyme A metabolic process; IEA:InterPro. DR GO; GO:0008299; P:isoprenoid biosynthetic process; IBA:GO_Central. DR GO; GO:0060291; P:long-term synaptic potentiation; IEA:Ensembl. DR GO; GO:1900222; P:negative regulation of amyloid-beta clearance; ISS:ARUK-UCL. DR GO; GO:0042177; P:negative regulation of protein catabolic process; ISS:ARUK-UCL. DR GO; GO:0050709; P:negative regulation of protein secretion; ISS:ARUK-UCL. DR GO; GO:0070372; P:regulation of ERK1 and ERK2 cascade; IEA:Ensembl. DR GO; GO:0016126; P:sterol biosynthetic process; IBA:GO_Central. DR GO; GO:0008542; P:visual learning; IEA:Ensembl. DR CDD; cd00643; HMG-CoA_reductase_classI; 1. DR DisProt; DP02709; -. DR Gene3D; 1.10.3270.10; HMGR, N-terminal domain; 1. DR Gene3D; 3.30.70.420; Hydroxymethylglutaryl-CoA reductase, class I/II, NAD/NADP-binding domain; 1. DR InterPro; IPR002202; HMG_CoA_Rdtase. DR InterPro; IPR023074; HMG_CoA_Rdtase_cat_sf. DR InterPro; IPR023076; HMG_CoA_Rdtase_CS. DR InterPro; IPR004554; HMG_CoA_Rdtase_eu_arc. DR InterPro; IPR004816; HMG_CoA_Rdtase_metazoan. DR InterPro; IPR023282; HMG_CoA_Rdtase_N. DR InterPro; IPR009023; HMG_CoA_Rdtase_NAD(P)-bd_sf. DR InterPro; IPR009029; HMG_CoA_Rdtase_sub-bd_dom_sf. DR InterPro; IPR000731; SSD. DR NCBIfam; TIGR00920; 2A060605; 1. DR NCBIfam; TIGR00533; HMG_CoA_R_NADP; 1. DR PANTHER; PTHR10572; 3-HYDROXY-3-METHYLGLUTARYL-COENZYME A REDUCTASE; 1. DR PANTHER; PTHR10572:SF24; 3-HYDROXY-3-METHYLGLUTARYL-COENZYME A REDUCTASE; 1. DR Pfam; PF00368; HMG-CoA_red; 1. DR Pfam; PF12349; Sterol-sensing; 1. DR PRINTS; PR00071; HMGCOARDTASE. DR SUPFAM; SSF82866; Multidrug efflux transporter AcrB transmembrane domain; 1. DR SUPFAM; SSF55035; NAD-binding domain of HMG-CoA reductase; 1. DR SUPFAM; SSF56542; Substrate-binding domain of HMG-CoA reductase; 1. DR PROSITE; PS00066; HMG_COA_REDUCTASE_1; 1. DR PROSITE; PS00318; HMG_COA_REDUCTASE_2; 1. DR PROSITE; PS01192; HMG_COA_REDUCTASE_3; 1. DR PROSITE; PS50065; HMG_COA_REDUCTASE_4; 1. DR PROSITE; PS50156; SSD; 1. DR Genevisible; P04035; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cholesterol biosynthesis; KW Cholesterol metabolism; Disease variant; Endoplasmic reticulum; KW Glycoprotein; Isopeptide bond; Limb-girdle muscular dystrophy; KW Lipid biosynthesis; Lipid metabolism; Membrane; NADP; Oxidoreductase; KW Peroxisome; Phosphoprotein; Reference proteome; Steroid biosynthesis; KW Steroid metabolism; Sterol biosynthesis; Sterol metabolism; Transmembrane; KW Transmembrane helix; Ubl conjugation. FT CHAIN 1..888 FT /note="3-hydroxy-3-methylglutaryl-coenzyme A reductase" FT /id="PRO_0000114419" FT TOPO_DOM 1..9 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:P00347" FT TRANSMEM 10..39 FT /note="Helical" FT /evidence="ECO:0000250|UniProtKB:P00347" FT TOPO_DOM 40..56 FT /note="Lumenal" FT /evidence="ECO:0000250|UniProtKB:P00347" FT TRANSMEM 57..78 FT /note="Helical" FT /evidence="ECO:0000250|UniProtKB:P00347" FT TOPO_DOM 79..89 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:P00347" FT TRANSMEM 90..114 FT /note="Helical" FT /evidence="ECO:0000250|UniProtKB:P00347" FT TOPO_DOM 115..123 FT /note="Lumenal" FT /evidence="ECO:0000250|UniProtKB:P00347" FT TRANSMEM 124..149 FT /note="Helical" FT /evidence="ECO:0000250|UniProtKB:P00347" FT TOPO_DOM 150..159 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:P00347" FT TRANSMEM 160..187 FT /note="Helical" FT /evidence="ECO:0000250|UniProtKB:P00347" FT TOPO_DOM 188..191 FT /note="Lumenal" FT /evidence="ECO:0000250|UniProtKB:P00347" FT TRANSMEM 192..220 FT /note="Helical" FT /evidence="ECO:0000250|UniProtKB:P00347" FT TOPO_DOM 221..248 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:P00347" FT TRANSMEM 249..275 FT /note="Helical" FT /evidence="ECO:0000250|UniProtKB:P00347" FT TOPO_DOM 276..314 FT /note="Lumenal" FT /evidence="ECO:0000250|UniProtKB:P00347" FT TRANSMEM 315..339 FT /note="Helical" FT /evidence="ECO:0000250|UniProtKB:P00347" FT TOPO_DOM 340..888 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:P00347" FT DOMAIN 61..218 FT /note="SSD" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00199" FT MOTIF 75..78 FT /note="INSIG-binding motif" FT /evidence="ECO:0000269|PubMed:19458199" FT ACT_SITE 559 FT /note="Charge relay system" FT /evidence="ECO:0000303|PubMed:10698924, FT ECO:0000303|PubMed:11349148" FT ACT_SITE 691 FT /note="Charge relay system" FT /evidence="ECO:0000303|PubMed:10698924, FT ECO:0000303|PubMed:11349148" FT ACT_SITE 767 FT /note="Charge relay system" FT /evidence="ECO:0000303|PubMed:10698924, FT ECO:0000303|PubMed:11349148" FT ACT_SITE 866 FT /note="Proton donor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10003" FT BINDING 565..571 FT /ligand="CoA" FT /ligand_id="ChEBI:CHEBI:57287" FT /evidence="ECO:0000269|PubMed:11349148, FT ECO:0007744|PDB:1DQA" FT BINDING 626..628 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT /evidence="ECO:0000269|PubMed:11349148, FT ECO:0007744|PDB:1DQA" FT BINDING 653..661 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT /evidence="ECO:0000269|PubMed:11349148, FT ECO:0007744|PDB:1DQA" FT BINDING 720..722 FT /ligand="CoA" FT /ligand_id="ChEBI:CHEBI:57287" FT /evidence="ECO:0000269|PubMed:11349148, FT ECO:0007744|PDB:1DQA" FT BINDING 865..866 FT /ligand="CoA" FT /ligand_id="ChEBI:CHEBI:57287" FT /evidence="ECO:0000269|PubMed:11349148, FT ECO:0007744|PDB:1DQA" FT BINDING 870..871 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT /evidence="ECO:0000269|PubMed:11349148, FT ECO:0007744|PDB:1DQA" FT MOD_RES 504 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 872 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P00347, FT ECO:0007744|PubMed:24275569" FT CARBOHYD 281 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498" FT CARBOHYD 296 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498" FT CROSSLNK 89 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:19458199" FT CROSSLNK 248 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:19458199" FT VAR_SEQ 1 FT /note="M -> MQWMSHTRERDAGSKDSVATM (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_046492" FT VAR_SEQ 522..574 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_002207" FT VARIANT 443 FT /note="R -> Q (in LGMDR28; likely pathogenic; decreased FT hydroxymethylglutaryl-CoA reductase (NADPH) activity to 1% FT of wild-type activity; decreased thermal stability)" FT /evidence="ECO:0000269|PubMed:37167966" FT /id="VAR_088585" FT VARIANT 443 FT /note="R -> W (in LGMDR28; likely pathogenic)" FT /evidence="ECO:0000269|PubMed:37167966" FT /id="VAR_088586" FT VARIANT 467 FT /note="I -> M (in LGMDR28; uncertain significance)" FT /evidence="ECO:0000269|PubMed:37167966" FT /id="VAR_088587" FT VARIANT 508 FT /note="Missing (in LGMDR28; uncertain significance)" FT /evidence="ECO:0000269|PubMed:37167966" FT /id="VAR_088588" FT VARIANT 515 FT /note="R -> T (in LGMDR28; uncertain significance)" FT /evidence="ECO:0000269|PubMed:37167966" FT /id="VAR_088589" FT VARIANT 546 FT /note="L -> S (in LGMDR28; uncertain significance)" FT /evidence="ECO:0000269|PubMed:37167966" FT /id="VAR_088590" FT VARIANT 623 FT /note="D -> N (in LGMDR28; likely pathogenic; decreased FT hydroxymethylglutaryl-CoA reductase (NADPH) activity to 50% FT of wild-type activity)" FT /evidence="ECO:0000269|PubMed:37167966" FT /id="VAR_088591" FT VARIANT 638 FT /note="I -> V (in dbSNP:rs5908)" FT /evidence="ECO:0000269|PubMed:10391209" FT /id="VAR_011954" FT VARIANT 792 FT /note="Y -> C (in LGMDR28; likely pathogenic; decreased FT hydroxymethylglutaryl-CoA reductase (NADPH) activity to 25% FT of wild-type activity)" FT /evidence="ECO:0000269|PubMed:37167966" FT /id="VAR_088592" FT VARIANT 822 FT /note="G -> D (in LGMDR28; likely pathogenic; decreased FT hydroxymethylglutaryl-CoA reductase (NADPH) activity; FT reduced Vmax for hydroxymethylglutaryl-CoA reductase FT (NADPH) activity; has very low affinity for pravastatin)" FT /evidence="ECO:0000269|PubMed:36745799" FT /id="VAR_088593" FT MUTAGEN 75..77 FT /note="YIY->AIA: Reduced sterol-mediated release from the FT ER. Not deglycosylated in response to sterols." FT /evidence="ECO:0000269|PubMed:19458199" FT MUTAGEN 89 FT /note="K->R: Abolishes sterol-mediated ubiquitination and FT degradation; when associated with R-248." FT /evidence="ECO:0000269|PubMed:19458199" FT MUTAGEN 248 FT /note="K->R: Abolishes sterol-mediated ubiquitination and FT degradation; when associated with R-89." FT /evidence="ECO:0000269|PubMed:19458199" FT MUTAGEN 807 FT /note="G->D: Does not affect hydroxymethylglutaryl-CoA FT reductase activity." FT /evidence="ECO:0000269|PubMed:21357570" FT HELIX 445..453 FT /evidence="ECO:0007829|PDB:2R4F" FT TURN 455..457 FT /evidence="ECO:0007829|PDB:2R4F" FT HELIX 458..460 FT /evidence="ECO:0007829|PDB:2R4F" FT HELIX 464..472 FT /evidence="ECO:0007829|PDB:2R4F" FT STRAND 474..476 FT /evidence="ECO:0007829|PDB:3CDA" FT HELIX 478..480 FT /evidence="ECO:0007829|PDB:2R4F" FT HELIX 481..484 FT /evidence="ECO:0007829|PDB:2R4F" FT STRAND 485..487 FT /evidence="ECO:0007829|PDB:2R4F" FT HELIX 488..502 FT /evidence="ECO:0007829|PDB:2R4F" FT STRAND 503..505 FT /evidence="ECO:0007829|PDB:2R4F" FT HELIX 508..511 FT /evidence="ECO:0007829|PDB:2R4F" FT STRAND 515..517 FT /evidence="ECO:0007829|PDB:1DQ9" FT HELIX 519..521 FT /evidence="ECO:0007829|PDB:2R4F" FT TURN 522..525 FT /evidence="ECO:0007829|PDB:2R4F" FT STRAND 528..546 FT /evidence="ECO:0007829|PDB:2R4F" FT STRAND 549..556 FT /evidence="ECO:0007829|PDB:2R4F" FT HELIX 562..575 FT /evidence="ECO:0007829|PDB:2R4F" FT STRAND 579..590 FT /evidence="ECO:0007829|PDB:2R4F" FT STRAND 593..595 FT /evidence="ECO:0007829|PDB:2R4F" FT HELIX 599..610 FT /evidence="ECO:0007829|PDB:2R4F" FT HELIX 612..623 FT /evidence="ECO:0007829|PDB:2R4F" FT STRAND 635..639 FT /evidence="ECO:0007829|PDB:2R4F" FT STRAND 642..650 FT /evidence="ECO:0007829|PDB:2R4F" FT HELIX 657..674 FT /evidence="ECO:0007829|PDB:2R4F" FT STRAND 679..683 FT /evidence="ECO:0007829|PDB:2R4F" FT STRAND 686..688 FT /evidence="ECO:0007829|PDB:1DQA" FT HELIX 695..700 FT /evidence="ECO:0007829|PDB:2R4F" FT STRAND 703..712 FT /evidence="ECO:0007829|PDB:2R4F" FT HELIX 714..719 FT /evidence="ECO:0007829|PDB:2R4F" FT STRAND 721..723 FT /evidence="ECO:0007829|PDB:2R4F" FT HELIX 725..736 FT /evidence="ECO:0007829|PDB:2R4F" FT HELIX 738..742 FT /evidence="ECO:0007829|PDB:2R4F" FT STRAND 746..752 FT /evidence="ECO:0007829|PDB:2R4F" FT HELIX 753..763 FT /evidence="ECO:0007829|PDB:2R4F" FT HELIX 768..770 FT /evidence="ECO:0007829|PDB:2R4F" FT HELIX 771..774 FT /evidence="ECO:0007829|PDB:2R4F" FT STRAND 777..785 FT /evidence="ECO:0007829|PDB:2R4F" FT STRAND 790..800 FT /evidence="ECO:0007829|PDB:2R4F" FT STRAND 804..806 FT /evidence="ECO:0007829|PDB:2R4F" FT HELIX 807..810 FT /evidence="ECO:0007829|PDB:2R4F" FT HELIX 812..820 FT /evidence="ECO:0007829|PDB:2R4F" FT STRAND 828..830 FT /evidence="ECO:0007829|PDB:2R4F" FT HELIX 833..859 FT /evidence="ECO:0007829|PDB:2R4F" FT HELIX 862..869 FT /evidence="ECO:0007829|PDB:1DQA" SQ SEQUENCE 888 AA; 97476 MW; 49B610DCCCFA26B6 CRC64; MLSRLFRMHG LFVASHPWEV IVGTVTLTIC MMSMNMFTGN NKICGWNYEC PKFEEDVLSS DIIILTITRC IAILYIYFQF QNLRQLGSKY ILGIAGLFTI FSSFVFSTVV IHFLDKELTG LNEALPFFLL LIDLSRASTL AKFALSSNSQ DEVRENIARG MAILGPTFTL DALVECLVIG VGTMSGVRQL EIMCCFGCMS VLANYFVFMT FFPACVSLVL ELSRESREGR PIWQLSHFAR VLEEEENKPN PVTQRVKMIM SLGLVLVHAH SRWIADPSPQ NSTADTSKVS LGLDENVSKR IEPSVSLWQF YLSKMISMDI EQVITLSLAL LLAVKYIFFE QTETESTLSL KNPITSPVVT QKKVPDNCCR REPMLVRNNQ KCDSVEEETG INRERKVEVI KPLVAETDTP NRATFVVGNS SLLDTSSVLV TQEPEIELPR EPRPNEECLQ ILGNAEKGAK FLSDAEIIQL VNAKHIPAYK LETLMETHER GVSIRRQLLS KKLSEPSSLQ YLPYRDYNYS LVMGACCENV IGYMPIPVGV AGPLCLDEKE FQVPMATTEG CLVASTNRGC RAIGLGGGAS SRVLADGMTR GPVVRLPRAC DSAEVKAWLE TSEGFAVIKE AFDSTSRFAR LQKLHTSIAG RNLYIRFQSR SGDAMGMNMI SKGTEKALSK LHEYFPEMQI LAVSGNYCTD KKPAAINWIE GRGKSVVCEA VIPAKVVREV LKTTTEAMIE VNINKNLVGS AMAGSIGGYN AHAANIVTAI YIACGQDAAQ NVGSSNCITL MEASGPTNED LYISCTMPSI EIGTVGGGTN LLPQQACLQM LGVQGACKDN PGENARQLAR IVCGTVMAGE LSLMAALAAG HLVKSHMIHN RSKINLQDLQ GACTKKTA //