Gene/Proteome Database (LMPD)

LMPD ID
LMP000206
Gene ID
3156
Species
Homo sapiens (Human)
Gene Name
3-hydroxy-3-methylglutaryl-CoA reductase
Gene Symbol
HMGCR
Synonyms
LDLCQ3
Alternate Names
3-hydroxy-3-methylglutaryl-Coenzyme A reductase; HMG-CoA reductase; hydroxymethylglutaryl-CoA reductase; 3-hydroxy-3-methylglutaryl CoA reductase (NADPH)
Chromosome
5
Map Location
5q13.3-q14
EC Number
1.1.1.34
Summary
HMG-CoA reductase is the rate-limiting enzyme for cholesterol synthesis and is regulated via a negative feedback mechanism mediated by sterols and non-sterol metabolites derived from mevalonate, the product of the reaction catalyzed by reductase. Normally in mammalian cells this enzyme is suppressed by cholesterol derived from the internalization and degradation of low density lipoprotein (LDL) via the LDL receptor. Competitive inhibitors of the reductase induce the expression of LDL receptors in the liver, which in turn increases the catabolism of plasma LDL and lowers the plasma concentration of cholesterol, an important determinant of atherosclerosis. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]
Orthologs
View orthologs and multiple alignments for HMGCR

Proteins

3-hydroxy-3-methylglutaryl-Coenzyme A reductase isoform 1
Refseq ID NP_000850
Protein GI 4557643
UniProt ID P04035
mRNA ID NM_000859
Length 888
RefSeq Status REVIEWED
MLSRLFRMHGLFVASHPWEVIVGTVTLTICMMSMNMFTGNNKICGWNYECPKFEEDVLSSDIIILTITRCIAILYIYFQFQNLRQLGSKYILGIAGLFTIFSSFVFSTVVIHFLDKELTGLNEALPFFLLLIDLSRASTLAKFALSSNSQDEVRENIARGMAILGPTFTLDALVECLVIGVGTMSGVRQLEIMCCFGCMSVLANYFVFMTFFPACVSLVLELSRESREGRPIWQLSHFARVLEEEENKPNPVTQRVKMIMSLGLVLVHAHSRWIADPSPQNSTADTSKVSLGLDENVSKRIEPSVSLWQFYLSKMISMDIEQVITLSLALLLAVKYIFFEQTETESTLSLKNPITSPVVTQKKVPDNCCRREPMLVRNNQKCDSVEEETGINRERKVEVIKPLVAETDTPNRATFVVGNSSLLDTSSVLVTQEPEIELPREPRPNEECLQILGNAEKGAKFLSDAEIIQLVNAKHIPAYKLETLMETHERGVSIRRQLLSKKLSEPSSLQYLPYRDYNYSLVMGACCENVIGYMPIPVGVAGPLCLDEKEFQVPMATTEGCLVASTNRGCRAIGLGGGASSRVLADGMTRGPVVRLPRACDSAEVKAWLETSEGFAVIKEAFDSTSRFARLQKLHTSIAGRNLYIRFQSRSGDAMGMNMISKGTEKALSKLHEYFPEMQILAVSGNYCTDKKPAAINWIEGRGKSVVCEAVIPAKVVREVLKTTTEAMIEVNINKNLVGSAMAGSIGGYNAHAANIVTAIYIACGQDAAQNVGSSNCITLMEASGPTNEDLYISCTMPSIEIGTVGGGTNLLPQQACLQMLGVQGACKDNPGENARQLARIVCGTVMAGELSLMAALAAGHLVKSHMIHNRSKINLQDLQGACTKKTA
3-hydroxy-3-methylglutaryl-Coenzyme A reductase isoform 2
Refseq ID NP_001124468
Protein GI 196049380
UniProt ID P04035
mRNA ID NM_001130996
Length 835
RefSeq Status REVIEWED
MLSRLFRMHGLFVASHPWEVIVGTVTLTICMMSMNMFTGNNKICGWNYECPKFEEDVLSSDIIILTITRCIAILYIYFQFQNLRQLGSKYILGIAGLFTIFSSFVFSTVVIHFLDKELTGLNEALPFFLLLIDLSRASTLAKFALSSNSQDEVRENIARGMAILGPTFTLDALVECLVIGVGTMSGVRQLEIMCCFGCMSVLANYFVFMTFFPACVSLVLELSRESREGRPIWQLSHFARVLEEEENKPNPVTQRVKMIMSLGLVLVHAHSRWIADPSPQNSTADTSKVSLGLDENVSKRIEPSVSLWQFYLSKMISMDIEQVITLSLALLLAVKYIFFEQTETESTLSLKNPITSPVVTQKKVPDNCCRREPMLVRNNQKCDSVEEETGINRERKVEVIKPLVAETDTPNRATFVVGNSSLLDTSSVLVTQEPEIELPREPRPNEECLQILGNAEKGAKFLSDAEIIQLVNAKHIPAYKLETLMETHERGVSIRRQLLSKKLSEPSSLQYLPYRDYNYSLLGGGASSRVLADGMTRGPVVRLPRACDSAEVKAWLETSEGFAVIKEAFDSTSRFARLQKLHTSIAGRNLYIRFQSRSGDAMGMNMISKGTEKALSKLHEYFPEMQILAVSGNYCTDKKPAAINWIEGRGKSVVCEAVIPAKVVREVLKTTTEAMIEVNINKNLVGSAMAGSIGGYNAHAANIVTAIYIACGQDAAQNVGSSNCITLMEASGPTNEDLYISCTMPSIEIGTVGGGTNLLPQQACLQMLGVQGACKDNPGENARQLARIVCGTVMAGELSLMAALAAGHLVKSHMIHNRSKINLQDLQGACTKKTA

Gene Information

Entrez Gene ID
3156
Gene Name
3-hydroxy-3-methylglutaryl-CoA reductase
Gene Symbol
HMGCR
Species
Homo sapiens

Gene Ontology (GO Annotations)

GO ID Source Type Description
GO:0005783 IDA:UniProtKB C endoplasmic reticulum
GO:0005789 TAS:UniProtKB C endoplasmic reticulum membrane
GO:0016021 IEA:UniProtKB-KW C integral component of membrane
GO:0005778 IDA:UniProtKB C peroxisomal membrane
GO:0070402 IDA:UniProtKB F NADPH binding
GO:0050662 IDA:UniProtKB F coenzyme binding
GO:0004420 IEA:UniProtKB-EC F hydroxymethylglutaryl-CoA reductase (NADPH) activity
GO:0042282 IDA:UniProtKB F hydroxymethylglutaryl-CoA reductase activity
GO:0007568 IEA:Ensembl P aging
GO:0044255 TAS:Reactome P cellular lipid metabolic process
GO:0006695 TAS:Reactome P cholesterol biosynthetic process
GO:0015936 IEA:InterPro P coenzyme A metabolic process
GO:0008299 IEA:Ensembl P isoprenoid biosynthetic process
GO:0045445 IEA:Ensembl P myoblast differentiation
GO:0043407 IEA:Ensembl P negative regulation of MAP kinase activity
GO:0061179 IEA:Ensembl P negative regulation of insulin secretion involved in cellular response to glucose stimulus
GO:0010664 IEA:Ensembl P negative regulation of striated muscle cell apoptotic process
GO:0045908 IEA:Ensembl P negative regulation of vasodilation
GO:0061045 IEA:Ensembl P negative regulation of wound healing
GO:0070374 IEA:Ensembl P positive regulation of ERK1 and ERK2 cascade
GO:0010666 IEA:Ensembl P positive regulation of cardiac muscle cell apoptotic process
GO:0048643 IEA:Ensembl P positive regulation of skeletal muscle tissue development
GO:0048661 IEA:Ensembl P positive regulation of smooth muscle cell proliferation
GO:0032874 IEA:Ensembl P positive regulation of stress-activated MAPK cascade
GO:0051262 IDA:UniProtKB P protein tetramerization
GO:0045471 IEA:Ensembl P response to ethanol
GO:0007584 IEA:Ensembl P response to nutrient
GO:0044281 TAS:Reactome P small molecule metabolic process
GO:0006743 IEA:Ensembl P ubiquinone metabolic process
GO:0008542 IEA:Ensembl P visual learning

KEGG Pathway Links

KEGG Pathway ID Description
hsa04152 AMPK signaling pathway

Domain Information

InterPro Annotations

Accession Description
IPR023282 Hydroxymethylglutaryl-CoA reductase, N-terminal
IPR002202 Hydroxymethylglutaryl-CoA reductase, class I/II
IPR009023 Hydroxymethylglutaryl-CoA reductase, class I/II, NAD/NADP-binding domain
IPR023074 Hydroxymethylglutaryl-CoA reductase, class I/II, catalytic domain
IPR023076 Hydroxymethylglutaryl-CoA reductase, class I/II, conserved site
IPR009029 Hydroxymethylglutaryl-CoA reductase, class I/II, substrate-binding domain
IPR004554 Hydroxymethylglutaryl-CoA reductase, eukaryotic/arcaheal type
IPR004816 Hydroxymethylglutaryl-CoA reductase, metazoan
IPR000731 Sterol-sensing domain

UniProt Annotations

Entry Information

Gene Name
3-hydroxy-3-methylglutaryl-CoA reductase
Protein Entry
HMDH_HUMAN
UniProt ID
P04035
Species
Human

Comments

Comment Type Description
Alternative Products Event=Alternative splicing; Named isoforms=3; Name=1; IsoId=P04035-1; Sequence=Displayed; Name=2; IsoId=P04035-2; Sequence=VSP_002207; Note=No experimental confirmation available.; Name=3; Synonyms=HMGCR-1b; IsoId=P04035-3; Sequence=VSP_046492; Note=Most highly expressed transcript in skin, esophagus, and uterine cervix.;
Catalytic Activity (R)-mevalonate + CoA + 2 NADP(+) = (S)-3- hydroxy-3-methylglutaryl-CoA + 2 NADPH. {ECO
Enzyme Regulation Regulated by a negative feedback mechanism through sterols and non-sterol metabolites derived from mevalonate. Inhibited by statins, a class of hypolipidemic agents used as pharmaceuticals to lower cholesterol levels in individuals at risk from cardiovascular disease due to hypercholesterolemia. Inhibition of HMGCR in the liver stimulates the LDL-receptors, which results in an increased clearance of LDL from the bloodstream and a decrease in blood cholesterol levels. The first results can be seen after one week of statin use and the effect is maximal after four to six weeks.
Function Transmembrane glycoprotein that is the rate-limiting enzyme in cholesterol biosynthesis as well as in the biosynthesis of nonsterol isoprenoids that are essential for normal cell function including ubiquinone and geranylgeranyl proteins.
Interaction Q9Y5Z9:UBIAD1; NbExp=3; IntAct=EBI-465513, EBI-2819725; Q9Y5Z9-1:UBIAD1; NbExp=5; IntAct=EBI-465513, EBI-6621921;
Pathway Metabolic intermediate biosynthesis; (R)-mevalonate biosynthesis; (R)-mevalonate from acetyl-CoA
Ptm N-glycosylated. Deglycosylated by NGLY1 on release from the endoplasmic reticulum (ER) in a sterol-mediated manner.
Ptm Undergoes sterol-mediated ubiquitination and ER-association degradation (ERAD). Accumulation of sterols in the endoplasmic reticulum (ER) membrane, triggers binding of the reductase to the ER membrane protein INSIG1. This INSIG1 binding leads to the recruitment of the ubiquitin ligase, AMFR/gp78, initiating ubiquitination of the reductase. The ubiquitinated reductase is then extracted from the ER membrane and delivered to cytosolic 26S proteosomes by a mechanism probably mediated by the ATPase Valosin-containing protein VCP/p97. Lys-248 is the main site of ubiquitination. Ubiquitination is enhanced by the presence of a geranylgeranylated protein. {ECO
Sequence Caution Sequence=BAH12375.1; Type=Frameshift; Positions=122; Evidence= ;
Similarity Belongs to the HMG-CoA reductase family.
Similarity Contains 1 SSD (sterol-sensing) domain.
Subcellular Location Endoplasmic reticulum membrane; Multi-pass membrane protein.
Subunit Homodimer. Interacts (via its SSD) with INSIG1; the interaction, accelerated by sterols, leads to the recruitment of HMGCR to AMFR/gp78 for its ubiquitination by the sterol-mediated ERAD pathway. Interacts with UBIAD1. {ECO

Identical and Related Proteins

Unique RefSeq proteins for LMP000206 (as displayed in Record Overview)

Protein GI Database Accession Length Protein Name
4557643 RefSeq NP_000850 888 3-hydroxy-3-methylglutaryl-Coenzyme A reductase isoform 1
196049380 RefSeq NP_001124468 835 3-hydroxy-3-methylglutaryl-Coenzyme A reductase isoform 2

Identical Sequences to LMP000206 proteins

Reference Database Accession Length Protein Name
GI:4557643 DBBJ BAI45577.1 888 3-hydroxy-3-methylglutaryl-Coenzyme A reductase, partial [synthetic construct]
GI:4557643 EMBL CAZ64465.1 888 unnamed protein product [Homo sapiens]
GI:196049380 GenBank AAH33692.1 835 HMGCR protein [Homo sapiens]
GI:4557643 GenBank EAW95755.1 888 3-hydroxy-3-methylglutaryl-Coenzyme A reductase, isoform CRA_a [Homo sapiens]
GI:196049380 GenBank EAW95756.1 835 3-hydroxy-3-methylglutaryl-Coenzyme A reductase, isoform CRA_b [Homo sapiens]
GI:196049380 GenBank ABM81781.1 835 3-hydroxy-3-methylglutaryl-Coenzyme A reductase [synthetic construct]
GI:196049380 GenBank ABM84935.1 835 3-hydroxy-3-methylglutaryl-Coenzyme A reductase, partial [synthetic construct]
GI:4557643 GenBank ADC20508.1 888 Sequence 992 from patent US 7638288
GI:4557643 GenBank AFO15036.1 888 Sequence 520 from patent US 8211634
GI:4557643 GenBank AGD01469.1 888 Sequence 992 from patent US 8338124
GI:196049380 GenBank AIC48948.1 835 HMGCR, partial [synthetic construct]

Related Sequences to LMP000206 proteins

Reference Database Accession Length Protein Name
GI:4557643 DBBJ BAF85581.1 888 unnamed protein product [Homo sapiens]
GI:196049380 GenBank AAG21343.1 888 3-hydroxy-3-methylglutaryl-coenzyme A reductase [Homo sapiens]
GI:4557643 GenBank ACM83223.1 896 Sequence 8721 from patent US 6812339
GI:4557643 GenBank JAA08150.1 888 3-hydroxy-3-methylglutaryl-CoA reductase [Pan troglodytes]
GI:196049380 GenBank JAA17804.1 835 3-hydroxy-3-methylglutaryl-CoA reductase [Pan troglodytes]
GI:196049380 RefSeq XP_001104536.1 835 PREDICTED: 3-hydroxy-3-methylglutaryl-coenzyme A reductase isoform 4 [Macaca mulatta]
GI:196049380 RefSeq XP_003266122.1 835 PREDICTED: 3-hydroxy-3-methylglutaryl-coenzyme A reductase isoform 2 [Nomascus leucogenys]
GI:4557643 RefSeq XP_003810506.1 888 PREDICTED: 3-hydroxy-3-methylglutaryl-Coenzyme A reductase [Pan paniscus]
GI:4557643 RefSeq XP_004058753.1 888 PREDICTED: 3-hydroxy-3-methylglutaryl-coenzyme A reductase isoform 1 [Gorilla gorilla gorilla]
GI:196049380 RefSeq XP_004058754.1 835 PREDICTED: 3-hydroxy-3-methylglutaryl-coenzyme A reductase isoform 2 [Gorilla gorilla gorilla]
GI:196049380 RefSeq XP_005557236.1 835 PREDICTED: 3-hydroxy-3-methylglutaryl-coenzyme A reductase isoform X4 [Macaca fascicularis]
GI:4557643 RefSeq XP_009447288.1 888 PREDICTED: 3-hydroxy-3-methylglutaryl-Coenzyme A reductase [Pan troglodytes]