HMDH_PIG
ID HMDH_PIG Reviewed; 885 AA.
AC Q1W675;
DT 31-OCT-2006, integrated into UniProtKB/Swiss-Prot.
DT 02-MAY-2006, sequence version 1.
DT 03-AUG-2022, entry version 105.
DE RecName: Full=3-hydroxy-3-methylglutaryl-coenzyme A reductase;
DE Short=HMG-CoA reductase;
DE EC=1.1.1.34 {ECO:0000250|UniProtKB:P04035};
GN Name=HMGCR; Synonyms=HMGR;
OS Sus scrofa (Pig).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Suina; Suidae; Sus.
OX NCBI_TaxID=9823;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY.
RC TISSUE=Liver;
RX PubMed=22240315; DOI=10.1016/j.gene.2011.12.051;
RA Chen X., Wang X., Li Z., Kong L., Liu G., Fu J., Wang A.;
RT "Molecular cloning, tissue expression and protein structure prediction of
RT the porcine 3-hydroxy-3-methylglutaryl-Coenzyme A reductase (HMGR) gene.";
RL Gene 495:170-177(2012).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
RC TISSUE=Liver;
RA Wang X.F., Wang A.G., Fu J.L., Li Z.J., Kong L.J., Liu G.F., Fang W.N.,
RA Lu J.H.;
RT "Molecular cloning, expression analysis and chromosomal location of the
RT porcine 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR) gene.";
RL Submitted (MAY-2006) to the EMBL/GenBank/DDBJ databases.
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:0000250|UniProtKB:P04035}.
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:0000250|UniProtKB:P04035};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:15991;
CC Evidence={ECO:0000250|UniProtKB:P04035};
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-869 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. Homodimer. Interacts (via its SSD) with INSIG1;
CC the interaction, accelerated by sterols, leads to the recruitment of
CC HMGCR to AMFR/gp78 for its ubiquitination by the sterol-mediated ERAD
CC pathway. Interacts with UBIAD1. {ECO:0000250|UniProtKB:P04035}.
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 -!- TISSUE SPECIFICITY: High expression found in liver, heart, kidney,
CC bladder and subcutaneous fat. Lower levels in lung, uterus and large
CC intestine. Lowest levels in cerebrum, spleen, spinal cord, stomach,
CC ovary, longissimus muscle, and small intestine.
CC {ECO:0000269|PubMed:22240315}.
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-869 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; DQ531631; ABF83891.1; -; Genomic_DNA.
DR EMBL; DQ432054; ABD96089.1; -; mRNA.
DR RefSeq; NP_001116460.1; NM_001122988.1.
DR AlphaFoldDB; Q1W675; -.
DR SMR; Q1W675; -.
DR STRING; 9823.ENSSSCP00000014973; -.
DR BindingDB; Q1W675; -.
DR ChEMBL; CHEMBL3593154; -.
DR DrugCentral; Q1W675; -.
DR iPTMnet; Q1W675; -.
DR PaxDb; Q1W675; -.
DR PRIDE; Q1W675; -.
DR GeneID; 100144446; -.
DR KEGG; ssc:100144446; -.
DR CTD; 3156; -.
DR eggNOG; KOG2480; Eukaryota.
DR InParanoid; Q1W675; -.
DR OrthoDB; 907394at2759; -.
DR BRENDA; 1.1.1.34; 6170.
DR UniPathway; UPA00058; UER00103.
DR Proteomes; UP000008227; Unplaced.
DR Proteomes; UP000314985; Unplaced.
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:0005778; C:peroxisomal membrane; ISS:UniProtKB.
DR GO; GO:0004420; F:hydroxymethylglutaryl-CoA reductase (NADPH) activity; IBA:GO_Central.
DR GO; GO:0050661; F:NADP binding; IEA:InterPro.
DR GO; GO:0006695; P:cholesterol biosynthetic process; IEA:UniProtKB-KW.
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:0016126; P:sterol biosynthetic process; IBA:GO_Central.
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 2: Evidence at transcript level;
KW Cholesterol biosynthesis; Cholesterol metabolism; Endoplasmic reticulum;
KW Glycoprotein; Isopeptide bond; Lipid biosynthesis; Lipid metabolism;
KW Membrane; NADP; Oxidoreductase; Peroxisome; Phosphoprotein;
KW Reference proteome; Steroid biosynthesis; Steroid metabolism;
KW Sterol biosynthesis; Sterol metabolism; Transmembrane; Transmembrane helix;
KW Ubl conjugation.
FT CHAIN 1..885
FT /note="3-hydroxy-3-methylglutaryl-coenzyme A reductase"
FT /id="PRO_0000258020"
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..885
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 688
FT /note="Charge relay system"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT ACT_SITE 764
FT /note="Charge relay system"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT ACT_SITE 863
FT /note="Proton donor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10003"
FT MOD_RES 869
FT /note="Phosphoserine; by AMPK"
FT /evidence="ECO:0000250|UniProtKB:P51639"
FT CARBOHYD 281
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 296
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"
SQ SEQUENCE 885 AA; 97151 MW; 046E93BF1155FAD2 CRC64;
MLSRLFRMHG LFVASHPWEV IVGTVTLTIC MMSMNMFTGN DKICGWNYEC PKFEEDVLSS
DIIILTITRC IAILYIYFQF QNLRQLGSKY ILGIAGLFTI FSSFVFSTVV IHFLDKELTG
LNEALPFFLL LIDLSRASAL AKFALSSNSQ DEVRENIARG MAILGPTFTL DALVECLVIG
VGTMSGVRQL EIMCCFGCMS VLATYFVFMT FFPACVSLVL ELSRESREGR PIWQLSHFAR
VLEGEENKPN PVTQRVKIIM SLGLVLVHAH SRWIADPSPQ NSTADNSKVS LGLDENVSKR
IEPSVSLWQF YLSKMISMDI EQVITLTLAL LLAVKYIFFE QAETESTLSL KNPITSPVVT
QKKVTDDCCR REPTLVRNDQ KFHTVEEEAR INRERKVEVI KPLVAETDTS SRPTFVVGNS
TLDSSLELEM QEPEIQIPSE PRPNEECLQI LGNAEKGAKF LSDAEIIQLV NAKHIPAYKL
ETLMETHERG VSIRRQLLSK KLPEPSSLQY LPYRDYNYSL VMGACCENVI GYMPIPVGVA
GPLCLDGKEF QVPMATTEGC LVASTNRGCR AIGLGGGASS RILADGMTPV VRFPRACDSA
EVKAWLETPE GFAVIKEAFD STSRFARLQK LQMSVAGRNL YIRFQSRSGD AMGMNMISKG
TEKALSKLHE YFPEMQILAV SGNYCTDKKP AAVNWIEGRG KSVVCEAVIP AKVVREVLKT
TTEAMVEVNI NKNLVGSAMA GSIGGYNAHA ANIVTAIYIA CGQDAAQNVG SSNCITLMEA
SGPTNEDLYI SCTMPSIEIG TVGGGTSLLP QQACLQMLGV QGACKDNPGE NARQLARIVC
GTVMAGELSL MAALAAGHLV RSHMIHNRSK INLQDLQGTC TKKAA
