HMDH_RAT
ID HMDH_RAT Reviewed; 887 AA.
AC P51639; Q64601; Q6P2A6;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 31-OCT-2006, sequence version 2.
DT 03-AUG-2022, entry version 184.
DE RecName: Full=3-hydroxy-3-methylglutaryl-coenzyme A reductase;
DE Short=HMG-CoA reductase;
DE EC=1.1.1.34 {ECO:0000269|PubMed:4019513};
GN Name=Hmgcr;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Hangjiong C., Williams D., Shapiro D.;
RT "Cloning and sequencing of rat 3-hydroxy-3-methylglutaryl coenzyme A
RT reductase.";
RL Submitted (AUG-1994) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Prostate;
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 [3]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 644-887.
RC STRAIN=Sprague-Dawley; TISSUE=Liver;
RA Khan S., Kabat S., Stambrook P.;
RT "Rat HMG-CoA reductase cDNA sequence contains an unusual 36 bp insert
RT bounded by inverted repeats.";
RL Submitted (OCT-1990) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP PROTEIN SEQUENCE OF 423-443 AND 867-878, AND PHOSPHORYLATION AT SER-871.
RC TISSUE=Liver;
RX PubMed=2369897; DOI=10.1002/j.1460-2075.1990.tb07420.x;
RA Clarke P.R., Hardie D.G.;
RT "Regulation of HMG-CoA reductase: identification of the site phosphorylated
RT by the AMP-activated protein kinase in vitro and in intact rat liver.";
RL EMBO J. 9:2439-2446(1990).
RN [5]
RP CATALYTIC ACTIVITY, FUNCTION, AND SUBUNIT.
RC TISSUE=Liver;
RX PubMed=4019513; DOI=10.1016/s0021-9258(17)39243-8;
RA Edwards P.A., Kempner E.S., Lan S.-F., Erickson S.K.;
RT "Functional size of rat hepatic 3-hydroxy-3-methylglutaryl coenzyme A
RT reductase as determined by radiation inactivation.";
RL J. Biol. Chem. 260:10278-10282(1985).
RN [6]
RP PHOSPHORYLATION AT SER-871.
RC TISSUE=Liver;
RX PubMed=1628744; DOI=10.1016/0014-5793(92)80837-7;
RA Gillespie J.G., Hardie D.G.;
RT "Phosphorylation and inactivation of HMG-CoA reductase at the AMP-activated
RT protein kinase site in response to fructose treatment of isolated rat
RT hepatocytes.";
RL FEBS Lett. 306:59-62(1992).
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. {ECO:0000269|PubMed:4019513}.
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:4019513};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:15991;
CC Evidence={ECO:0000305|PubMed:4019513};
CC -!- ACTIVITY REGULATION: Regulated by a negative feedback mechanism through
CC sterols and non-sterol metabolites derived from mevalonate (By
CC similarity). Phosphorylation at Ser-871 down-regulates the catalytic
CC activity (By similarity). {ECO:0000250|UniProtKB:P00347,
CC ECO:0000250|UniProtKB:P04035}.
CC -!- PATHWAY: Metabolic intermediate biosynthesis; (R)-mevalonate
CC biosynthesis; (R)-mevalonate from acetyl-CoA: step 3/3.
CC -!- SUBUNIT: Homotetramer (By similarity). Homodimer (PubMed:4019513).
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. Interacts with
CC UBIAD1 (By similarity). {ECO:0000250|UniProtKB:P04035,
CC ECO:0000269|PubMed:4019513}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000250|UniProtKB:P04035}; Multi-pass membrane protein
CC {ECO:0000250|UniProtKB:P00347}. Peroxisome membrane
CC {ECO:0000250|UniProtKB:P04035}; Multi-pass membrane protein
CC {ECO:0000250|UniProtKB:P00347}.
CC -!- PTM: Undergoes sterol-mediated ubiquitination and ER-associated
CC degradation (ERAD). Accumulation of sterols in the endoplasmic
CC reticulum (ER) membrane, triggers binding of the reductase to the ER
CC membrane protein INSIG1 or INSIG2. The INSIG1 binding leads to the
CC recruitment of the ubiquitin ligase, AMFR/gp78, RNF139 or RNF145,
CC initiating ubiquitination of the reductase. The ubiquitinated reductase
CC is then extracted from the ER membrane and delivered to cytosolic 26S
CC proteosomes by a mechanism probably mediated by the ATPase Valosin-
CC containing protein VCP/p97. The INSIG2-binding leads to the recruitment
CC of the ubiquitin ligase RNF139, initiating ubiquitination of the
CC reductase. Lys-248 is the main site of ubiquitination. Ubiquitination
CC is enhanced by the presence of a geranylgeranylated protein.
CC {ECO:0000250|UniProtKB:P04035}.
CC -!- PTM: N-glycosylated. Deglycosylated by NGLY1 on release from the
CC endoplasmic reticulum (ER) in a sterol-mediated manner.
CC {ECO:0000250|UniProtKB:P04035}.
CC -!- PTM: Phosphorylated. Phosphorylation at Ser-871 reduces the catalytic
CC activity. {ECO:0000250|UniProtKB:P00347}.
CC -!- SIMILARITY: Belongs to the HMG-CoA reductase family. {ECO:0000305}.
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DR EMBL; M29249; AAA40608.1; -; Genomic_DNA.
DR EMBL; BC064654; AAH64654.1; -; mRNA.
DR EMBL; X55286; CAA39001.1; -; mRNA.
DR PIR; S33175; S33175.
DR RefSeq; NP_037266.2; NM_013134.2.
DR AlphaFoldDB; P51639; -.
DR SMR; P51639; -.
DR BioGRID; 247704; 1.
DR MINT; P51639; -.
DR STRING; 10116.ENSRNOP00000022055; -.
DR BindingDB; P51639; -.
DR ChEMBL; CHEMBL3247; -.
DR DrugCentral; P51639; -.
DR GuidetoPHARMACOLOGY; 639; -.
DR GlyGen; P51639; 1 site.
DR iPTMnet; P51639; -.
DR PhosphoSitePlus; P51639; -.
DR jPOST; P51639; -.
DR PaxDb; P51639; -.
DR PRIDE; P51639; -.
DR GeneID; 25675; -.
DR KEGG; rno:25675; -.
DR CTD; 3156; -.
DR RGD; 2803; Hmgcr.
DR VEuPathDB; HostDB:ENSRNOG00000016122; -.
DR eggNOG; KOG2480; Eukaryota.
DR HOGENOM; CLU_001734_0_1_1; -.
DR InParanoid; P51639; -.
DR OMA; CHGWSQS; -.
DR OrthoDB; 907394at2759; -.
DR PhylomeDB; P51639; -.
DR TreeFam; TF105362; -.
DR BRENDA; 1.1.1.34; 5301.
DR Reactome; R-RNO-191273; Cholesterol biosynthesis.
DR UniPathway; UPA00058; UER00103.
DR PRO; PR:P51639; -.
DR Proteomes; UP000002494; Chromosome 2.
DR Bgee; ENSRNOG00000016122; Expressed in duodenum and 20 other tissues.
DR Genevisible; P51639; RN.
DR GO; GO:0005783; C:endoplasmic reticulum; ISS:UniProtKB.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IBA:GO_Central.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:RGD.
DR GO; GO:0005778; C:peroxisomal membrane; ISS:UniProtKB.
DR GO; GO:0120225; F:coenzyme A binding; ISO:RGD.
DR GO; GO:0004420; F:hydroxymethylglutaryl-CoA reductase (NADPH) activity; ISO:RGD.
DR GO; GO:0042802; F:identical protein binding; IPI:RGD.
DR GO; GO:0070402; F:NADPH binding; ISO:RGD.
DR GO; GO:0051721; F:protein phosphatase 2A binding; IPI:RGD.
DR GO; GO:0007568; P:aging; IEP:RGD.
DR GO; GO:0038183; P:bile acid signaling pathway; IEP:RGD.
DR GO; GO:0006695; P:cholesterol biosynthetic process; ISO:RGD.
DR GO; GO:0042632; P:cholesterol homeostasis; IEP:RGD.
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:0045445; P:myoblast differentiation; IEP:RGD.
DR GO; GO:1900222; P:negative regulation of amyloid-beta clearance; ISO:RGD.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IMP:RGD.
DR GO; GO:0061179; P:negative regulation of insulin secretion involved in cellular response to glucose stimulus; IMP:RGD.
DR GO; GO:0043407; P:negative regulation of MAP kinase activity; ISO:RGD.
DR GO; GO:0042177; P:negative regulation of protein catabolic process; ISO:RGD.
DR GO; GO:0050709; P:negative regulation of protein secretion; ISO:RGD.
DR GO; GO:0010664; P:negative regulation of striated muscle cell apoptotic process; IMP:RGD.
DR GO; GO:0061045; P:negative regulation of wound healing; IMP:RGD.
DR GO; GO:0010666; P:positive regulation of cardiac muscle cell apoptotic process; IMP:RGD.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; IMP:RGD.
DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IMP:RGD.
DR GO; GO:0048643; P:positive regulation of skeletal muscle tissue development; IMP:RGD.
DR GO; GO:0048661; P:positive regulation of smooth muscle cell proliferation; IMP:RGD.
DR GO; GO:0032874; P:positive regulation of stress-activated MAPK cascade; IMP:RGD.
DR GO; GO:0045907; P:positive regulation of vasoconstriction; IMP:RGD.
DR GO; GO:0070723; P:response to cholesterol; IEP:RGD.
DR GO; GO:0045471; P:response to ethanol; IEP:RGD.
DR GO; GO:0007584; P:response to nutrient; IEP:RGD.
DR GO; GO:0031667; P:response to nutrient levels; IEP:RGD.
DR GO; GO:0016126; P:sterol biosynthetic process; IBA:GO_Central.
DR GO; GO:0070328; P:triglyceride homeostasis; IEP:RGD.
DR GO; GO:0006743; P:ubiquinone metabolic process; IMP:RGD.
DR GO; GO:0008542; P:visual learning; ISO:RGD.
DR CDD; cd00643; HMG-CoA_reductase_classI; 1.
DR Gene3D; 1.10.3270.10; -; 1.
DR Gene3D; 3.30.70.420; -; 1.
DR Gene3D; 3.90.770.10; -; 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 PANTHER; PTHR10572; PTHR10572; 1.
DR Pfam; PF00368; HMG-CoA_red; 1.
DR Pfam; PF12349; Sterol-sensing; 1.
DR PRINTS; PR00071; HMGCOARDTASE.
DR SUPFAM; SSF55035; SSF55035; 1.
DR SUPFAM; SSF56542; SSF56542; 1.
DR TIGRFAMs; TIGR00920; 2A060605; 1.
DR TIGRFAMs; TIGR00533; HMG_CoA_R_NADP; 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.
PE 1: Evidence at protein level;
KW Cholesterol biosynthesis; Cholesterol metabolism;
KW Direct protein sequencing; Endoplasmic reticulum; Glycoprotein;
KW Isopeptide bond; Lipid biosynthesis; Lipid metabolism; Membrane; NADP;
KW Oxidoreductase; Peroxisome; Phosphoprotein; Reference proteome;
KW Steroid biosynthesis; Steroid metabolism; Sterol biosynthesis;
KW Sterol metabolism; Transmembrane; Transmembrane helix; Ubl conjugation.
FT CHAIN 1..887
FT /note="3-hydroxy-3-methylglutaryl-coenzyme A reductase"
FT /id="PRO_0000114424"
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..887
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:0000250|UniProtKB:P04035"
FT ACT_SITE 558
FT /note="Charge relay system"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT ACT_SITE 690
FT /note="Charge relay system"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT ACT_SITE 766
FT /note="Charge relay system"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT ACT_SITE 865
FT /note="Proton donor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10003"
FT MOD_RES 871
FT /note="Phosphoserine; by AMPK"
FT /evidence="ECO:0000269|PubMed:2369897"
FT CARBOHYD 281
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CROSSLNK 89
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:P00347"
FT CROSSLNK 248
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:P00347"
FT CONFLICT 423
FT /note="S -> T (in Ref. 4; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 428
FT /note="L -> V (in Ref. 4; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 443
FT /note="P -> N (in Ref. 4; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 644..653
FT /note="IRLQSKTGDA -> PIRSPKRGTS (in Ref. 3; CAA39001)"
FT /evidence="ECO:0000305"
FT CONFLICT 673..674
FT /note="FF -> GV (in Ref. 1; AAA40608)"
FT /evidence="ECO:0000305"
FT CONFLICT 722
FT /note="T -> S (in Ref. 3; CAA39001)"
FT /evidence="ECO:0000305"
FT CONFLICT 750
FT /note="A -> L (in Ref. 1; AAA40608)"
FT /evidence="ECO:0000305"
FT CONFLICT 764
FT /note="G -> A (in Ref. 3; CAA39001)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 887 AA; 96688 MW; 856D99A9D5FA965C CRC64;
MLSRLFRMHG LFVASHPWEV IVGTVTLTIC MMSMNMFTGN NKICGWNYEC PKFEEDVLSS
DIIILTITRC IAILYIYFQF QNLRQLGSKY ILGIAGLFTI FSSFVFSTVV IHFLDKELTG
LNEALPFFLL LIDLSRASAL AKFALSSNSQ DEVRENIARG MAILGPTFTL DALVECLVIG
VGTMSGVRQL EIMCCFGCMS VLANYFVFMT FFPACVSLVL ELSRESREGR PIWQLSHFAR
VLEEEENKPN PVTQRVKMIM SLGLVLVHAH SRWIADPSPQ NSTAEQSKVS LGLAEDVSKR
IEPSVSLWQF YLSKMISMDI EQVITLSLAL LLAVKYIFFE QAETESTLSL KNPITSPVVT
PKKAQDNCCR REPLLVRRNQ KLSSVEEDPG VNQDRKVEVI KPLVAEAETS GRATFVLGAS
AASPPLALGA QEPGIELPSE PRPNEECLQI LESAEKGAKF LSDAEIIQLV NAKHIPAYKL
ETLMETHERG VSIRRQLLSA KLAEPSSLQY LPYRDYNYSL VMGACCENVI GYMPIPVGVA
GPLCLDGKEY QVPMATTEGC LVASTNRGCR AISLGGGASS RVLADGMSRG PVVRLPRACD
SAEVKSWLET PEGFAVVKEA FDSTSRFARL QKLHVTLAGR NLYIRLQSKT GDAMGMNMIS
KGTEKALLKL QEFFPELQIL AVSGNYCTDK KPAAINWIEG RGKTVVCEAV IPAKVVREVL
KTTTEAMVDV NINKNLVGSA MAGSIGGYNA HAANIVTAIY IACGQDAAQN VGSSNCITLM
EASGPTNEDL YISCTMPSIE IGTVGGGTNL LPQQACLQML GVQGACKDNP GENARQLARI
VCGTVMAGEL SLMAALAAGH LVRSHMVHNR SKINLQDLQG TCTKKAA
