HMGCR 3-hydroxy-3-methylglutaryl-CoA reductase [Homo sapiens (human)] - Gene

Summary

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Official Symbol: HMGCRprovided by HGNC
Official Full Name: 3-hydroxy-3-methylglutaryl-CoA reductaseprovided by HGNC
Primary source: HGNC:5006
See related: Ensembl:ENSG00000113161; HPRD:00836; MIM:142910; Vega:OTTHUMG00000102069
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: LDLCQ3
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]

Genomic context

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Location :: 5q13.3-q14

Sequence :: Chromosome: 5; NC_000005.9 (74632993..74657926)

See HMGCR in Epigenomics, MapViewer

Chromosome 5 - NC_000005.9 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Genomic Sequence

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Bibliography

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GeneRIFs: Gene References Into Functions What's a GeneRIF?

Statins up-regulate the expression of HMGCR, the major target of autoantibodies in statin-associated immune-mediated necrotizing myopathy.
Title: Autoantibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase in patients with statin-associated autoimmune myopathy.
The association of HMGCR promoter region polymorphisms with cholesterol levels and coronary artery disease in patients from Western India are reported.
Title: Evaluation of the promoter polymorphism -911C>A in the 3-hydroxy-3-methylglutaryl-Coenzyme A reductase gene with coronary artery disease risk and cholesterol levels in a population from Western India.
This study was designed to understand the mode of interactions of HMGCR isoform 2 with statins Atorvastatin, Lovastatin, Fluvastatin, Simvastatin, Pravastatin, Rosuvastatin and Cerivastatin.
Title: Explication of interactions between HMGCR isoform 2 and various statins through In silico modeling and docking.
The HMGCR rs3846662 GG genotype was quantitatively documented to be a significant determinant for higher LDL-C level in basal state and possibly in response to atorvastatin.
Title: Effect of HMGCR variant alleles on low-density lipoprotein cholesterol-lowering response to atorvastatin in healthy Korean subjects.
Reductions in plasma insulin may have affected the expression of a key regulatory gene of cholesterol synthesis, HMG-CoA reductase and low-density lipoprotein receptor.
Title: A Mediterranean-style, low-glycemic-load diet reduces the expression of 3-hydroxy-3-methylglutaryl-coenzyme A reductase in mononuclear cells and plasma insulin in women with metabolic syndrome.
HMG-CoA reductase activation and urinary pellet cholesterol elevations in acute kidney injury.
Title: HMG-CoA reductase activation and urinary pellet cholesterol elevations in acute kidney injury.
HMG-CoA reductase regulation takes place at the levels of transcription, translation, post-translational modification and degradation. (Review)
Title: Regulation of HMG-CoA reductase in mammals and yeast.
Linalool reduces the expression of 3-hydroxy-3-methylglutaryl CoA reductase via sterol regulatory element binding protein-2- and ubiquitin-dependent mechanisms.
Title: Linalool reduces the expression of 3-hydroxy-3-methylglutaryl CoA reductase via sterol regulatory element binding protein-2- and ubiquitin-dependent mechanisms.
inhibition of protein geranylgeranylation markedly attenuated ubiquitylation and dislocation, implicating for the first time a geranylgeranylated protein(s) in the metabolically regulated ERAD of HMGR.
Title: Metabolically regulated endoplasmic reticulum-associated degradation of 3-hydroxy-3-methylglutaryl-CoA reductase: evidence for requirement of a geranylgeranylated protein.
Data show that the antioxidant property of 4-methylesculetin led to the reduction of 3-hydroxy-3-methylglutaryl coenzyme A reductase activation state through the increase of the enzyme phosphorylation.
Title: Short- and long-term regulation of 3-hydroxy 3-methylglutaryl coenzyme A reductase by a 4-methylcoumarin.

Submit: New GeneRIF Correction See all (58)

Phenotypes

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Review eQTL and phenotype association data in this region using PheGenI

NHGRI GWAS Catalog

Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index.

Biological, clinical and population relevance of 95 loci for blood lipids.

Common SNPs in HMGCR in micronesians and whites associated with LDL-cholesterol levels affect alternative splicing of exon13.

Common variants at 30 loci contribute to polygenic dyslipidemia.

Genetic variants influencing circulating lipid levels and risk of coronary artery disease.

HIV-1 protein interactions

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Protein	Gene	Interaction	Pubs
Nef, p27	nef	HIV-1 Nef modulates expression of 3-hydroxy-3-methylglutaryl-Coenzyme A reductase (HMGCR) in Jurkat cells	PubMed

Go to the HIV-1, Human Protein Interaction Database

Interactions

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Products	Interactant	Other Gene	Source	Pubs	Description
NP_000850.1	NP_821074.1	STARD13	BIND	PubMed	STARD13 (RhoGAP) interacts with HMGCR (HMG CoA reductase).
P04035	Q07960	ARHGAP1	HPRD	PubMed
P04035	P04035	HMGCR	HPRD	PubMed
P04035	O15503	INSIG1	HPRD	PubMed
P04035	P17612	PRKACA	HPRD	PubMed
P04035	Q9Y3M8	STARD13	HPRD	PubMed
BioGRID:109399	BioGRID:106764	AMFR	BioGRID	PubMed	Affinity Capture-Western
BioGRID:109399	BioGRID:107031	AUP1	BioGRID	PubMed	Affinity Capture-Western
BioGRID:109399	BioGRID:119920	DCUN1D1	BioGRID	PubMed	Affinity Capture-MS
BioGRID:109399	BioGRID:116331	ERLIN2	BioGRID	PubMed	Affinity Capture-Western
BioGRID:109399	BioGRID:109850	INSIG1	BioGRID	PubMed	Affinity Capture-Western
BioGRID:109399	BioGRID:116401	RNF139	BioGRID	PubMed	Affinity Capture-Western
BioGRID:109399	BioGRID:124744	STARD13	BioGRID	PubMed	Two-hybrid
BioGRID:109399	BioGRID:113164	UBC	BioGRID	PubMed	Affinity Capture-MS; Affinity Capture-Western
BioGRID:109399	BioGRID:113258	VCP	BioGRID	PubMed	Affinity Capture-Western

Pathways from BioSystems

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AMPK signaling, organism-specific biosystem (from WikiPathways)
AMPK signaling, organism-specific biosystemAMPK signaling pathway, a fuel sensor and regulator, promotes ATP-producing and inhibits ATP-consuming pathways in various tissues. AMPK is a heterotrimer composed of alpha-catalytic and beta and gam...
Activation of Gene Expression by SREBP (SREBF), organism-specific biosystem (from REACTOME)
Activation of Gene Expression by SREBP (SREBF), organism-specific biosystemAfter transiting to the nucleus SREBPs (SREBP1A/1C/2, SREBFs) bind short sequences, sterol regulatory elements (SREs), in the promoters of target genes (reviewed in Eberle et al. 2004, Weber et al. 2...
Bile secretion, organism-specific biosystem (from KEGG)
Bile secretion, organism-specific biosystemBile is a vital secretion, essential for digestion and absorption of fats and fat-soluble vitamins in the small intestine. Moreover, bile is an important route of elimination for excess cholesterol a...
Bile secretion, conserved biosystem (from KEGG)
Bile secretion, conserved biosystemBile is a vital secretion, essential for digestion and absorption of fats and fat-soluble vitamins in the small intestine. Moreover, bile is an important route of elimination for excess cholesterol a...
C5 isoprenoid biosynthesis, mevalonate pathway, organism-specific biosystem (from KEGG)
C5 isoprenoid biosynthesis, mevalonate pathway, organism-specific biosystemPathway module; Carbohydrate and lipid metabolism; Terpenoid backbone biosynthesis
C5 isoprenoid biosynthesis, mevalonate pathway, conserved biosystem (from KEGG)
C5 isoprenoid biosynthesis, mevalonate pathway, conserved biosystemPathway module; Carbohydrate and lipid metabolism; Terpenoid backbone biosynthesis
Cholesterol biosynthesis, organism-specific biosystem (from WikiPathways)
Cholesterol biosynthesis, organism-specific biosystemCholesterol is a waxy steroid metabolite found in the cell membranes and transported in the blood plasma of all animals. It is an essential structural component of mammalian cell membranes, where it ...
Cholesterol biosynthesis, organism-specific biosystem (from REACTOME)
Cholesterol biosynthesis, organism-specific biosystemCholesterol is synthesized de novo from from acetyl CoA. The overall synthetic process is outlined in the figure below. Enzymes whose regulation plays a major role in determining the rate of choleste...
Fatty acid, triacylglycerol, and ketone body metabolism, organism-specific biosystem (from REACTOME)
Fatty acid, triacylglycerol, and ketone body metabolism, organism-specific biosystemThe reactions involved in the metabolism of fatty acids and of the triacylglycerols and ketone bodies derived from them form a closely interrelated, coordinately regulated module that plays a central...
Integrated Breast Cancer Pathway, organism-specific biosystem (from WikiPathways)
Integrated Breast Cancer Pathway, organism-specific biosystemThis pathway incorporates the most important proteins for Breast Cancer. The Rp score from the Connectivity-Maps (C-Maps) webserver was used to determine the rank of the most important proteins in Br...
Metabolism, organism-specific biosystem (from REACTOME)
Metabolism, organism-specific biosystemMetabolic processes in human cells generate energy through the oxidation of molecules consumed in the diet and mediate the synthesis of diverse essential molecules not taken in the diet as well as th...
Metabolism of lipids and lipoproteins, organism-specific biosystem (from REACTOME)
Metabolism of lipids and lipoproteins, organism-specific biosystemLipids are hydrophobic but otherwise chemically diverse molecules that play a wide variety of roles in human biology. They include ketone bodies, fatty acids, triacylglycerols, phospholipids and sphi...
PPARA Activates Gene Expression, organism-specific biosystem (from REACTOME)
PPARA Activates Gene Expression, organism-specific biosystemThe set of genes regulated by PPAR-alpha is not fully known in humans, however many examples have been found in mice. Genes directly activated by PPAR-alpha contain peroxisome proliferator receptor e...
Regulation of Cholesterol Biosynthesis by SREBP (SREBF), organism-specific biosystem (from REACTOME)
Regulation of Cholesterol Biosynthesis by SREBP (SREBF), organism-specific biosystemSterol regulatory element binding proteins (SREBPs, SREBFs) respond to low cholesterol concentrations by transiting to the nucleus and activating genes involved in cholesterol and lipid biosynthesis ...
Regulation of Lipid Metabolism by Peroxisome proliferator-activated receptor alpha (PPARalpha), organism-specific biosystem (from REACTOME)
Regulation of Lipid Metabolism by Peroxisome proliferator-activated receptor alpha (PPARalpha), organism-specific biosystemPeroxisome proliferator-activated receptor alpha (PPAR-alpha) is the major regulator of fatty acid oxidation in the liver. PPARalpha is also the target of fibrate drugs used to treat abnormal plasma ...
SREBF and miR33 in cholesterol and lipid homeostasis, organism-specific biosystem (from WikiPathways)
SREBF and miR33 in cholesterol and lipid homeostasis, organism-specific biosystemThis pathway describes transcription factor-microRNA circuits governing cholesterol and lipid homeostasis. It is based on a seminar by Dr. Anders N??r.
SREBP signalling, organism-specific biosystem (from WikiPathways)
SREBP signalling, organism-specific biosystemSterol regulatory element-binding proteins (SREBPs) are membrane-bound proteins that act as transcription factors. They regulate lipid, especially cholesterol, biosynthesis and uptake at a transcript...
Statin Pathway, organism-specific biosystem (from WikiPathways)
Statin Pathway, organism-specific biosystemStatins inhibit endogenous cholesterol production by competitive inhibition of HMG-CoA reductase (HMGCR), the enzyme that catalyzes conversion of HMG-CoA to mevalonate, an early rate-limiting step in...
Terpenoid backbone biosynthesis, organism-specific biosystem (from KEGG)
Terpenoid backbone biosynthesis, organism-specific biosystemTerpenoids, also known as isoprenoids, are a large class of natural products consisting of isoprene (C5) units. There are two biosynthetic pathways, the mevalonate pathway [MD:M00095] and the non-mev...
Terpenoid backbone biosynthesis, conserved biosystem (from KEGG)
Terpenoid backbone biosynthesis, conserved biosystemTerpenoids, also known as isoprenoids, are a large class of natural products consisting of isoprene (C5) units. There are two biosynthetic pathways, the mevalonate pathway [MD:M00095] and the non-mev...
mevalonate pathway I, organism-specific biosystem (from BIOCYC)
mevalonate pathway I, organism-specific biosystemGeneral Background The biosynthesis of : DELTA3-ISOPENTENYL-PP (IPP) occurs via the : PWY-922 (MVA pathway, this pathway). IPP is synthesized from the condensation of three acetyl-CoA molecules. ...
mevalonate pathway I, conserved biosystem (from BIOCYC)
mevalonate pathway I, conserved biosystemGeneral Background The biosynthesis of |FRAME: DELTA3-ISOPENTENYL-PP| (IPP) can occur via two distinct routes: the |FRAME: PWY-922| (MVA pathway, this pathway) and the |FRAME:NONMEVIPP-PWY| (MEP pa...
superpathway of cholesterol biosynthesis, organism-specific biosystem (from BIOCYC)
superpathway of cholesterol biosynthesis, organism-specific biosystem
superpathway of cholesterol biosynthesis
superpathway of cholesterol biosynthesis, conserved biosystem (from BIOCYC)
superpathway of cholesterol biosynthesis, conserved biosystemThe sequence of reactions in the cholesterol biosynthetic pathway may vary. This superpathway gives an overview of three possible routes of cholesterol biosynthesis. These routes exist because redu...
superpathway of geranylgeranyldiphosphate biosynthesis I (via mevalonate), organism-specific biosystem (from BIOCYC)
superpathway of geranylgeranyldiphosphate biosynthesis I (via mevalonate), organism-specific biosystem
superpathway of geranylgeranyldiphosphate biosynthesis I (via mevalonate)
superpathway of geranylgeranyldiphosphate biosynthesis I (via mevalonate), conserved biosystem (from BIOCYC)
superpathway of geranylgeranyldiphosphate biosynthesis I (via mevalonate), conserved biosystem|FRAME: GERANYLGERANYL-PP| (also known as geranylgeranyl pyrophosphate, or GGPP) is a crucial compound involved in the biosynthesis of a variety of terpenes and terpenoids, including central compound...

General gene information

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Markers

RH47294 (e-PCR)
- UniSTS:36389

GDB:177804 (e-PCR)
- UniSTS:154965

GDB:181537 (e-PCR)
- UniSTS:155263

D5S2670 (e-PCR)
- UniSTS:67513

D5S2478 (e-PCR)
- UniSTS:8158

EST7D6 (e-PCR)
- UniSTS:263414

Homology

Homologs of the HMGCR gene: The HMGCR gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, fruit fly, mosquito, C.elegans, S.cerevisiae, K.lactis, E.gossypii, S.pombe, M.oryzae, N.crassa, A.thaliana, and rice.
Map Viewer (Mouse, Rat)
OrthoDB: The Hierarchical Catalog of Eukaryotic Orthologs

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
NADPH binding	IDA Inferred from Direct Assay more info	PubMed
coenzyme binding	IDA Inferred from Direct Assay more info	PubMed
hydroxymethylglutaryl-CoA reductase (NADPH) activity	IEA Inferred from Electronic Annotation more info
hydroxymethylglutaryl-CoA reductase activity	IDA Inferred from Direct Assay more info	PubMed
protein homodimerization activity	IEA Inferred from Electronic Annotation more info

Process	Evidence Code	Pubs
aging	IEA Inferred from Electronic Annotation more info
cellular lipid metabolic process	TAS Traceable Author Statement more info
cholesterol biosynthetic process	TAS Traceable Author Statement more info
coenzyme A metabolic process	IEA Inferred from Electronic Annotation more info
embryo development	IEA Inferred from Electronic Annotation more info
isoprenoid biosynthetic process	IEA Inferred from Electronic Annotation more info
myoblast differentiation	IEA Inferred from Electronic Annotation more info
negative regulation of MAP kinase activity	IEA Inferred from Electronic Annotation more info
negative regulation of insulin secretion involved in cellular response to glucose stimulus	IEA Inferred from Electronic Annotation more info
negative regulation of striated muscle cell apoptotic process	IEA Inferred from Electronic Annotation more info
negative regulation of vasodilation	IEA Inferred from Electronic Annotation more info
negative regulation of wound healing	IEA Inferred from Electronic Annotation more info
positive regulation of ERK1 and ERK2 cascade	IEA Inferred from Electronic Annotation more info
positive regulation of cardiac muscle cell apoptotic process	IEA Inferred from Electronic Annotation more info
positive regulation of skeletal muscle tissue development	IEA Inferred from Electronic Annotation more info
positive regulation of smooth muscle cell proliferation	IEA Inferred from Electronic Annotation more info
positive regulation of stress-activated MAPK cascade	IEA Inferred from Electronic Annotation more info
protein tetramerization	IDA Inferred from Direct Assay more info	PubMed
response to ethanol	IEA Inferred from Electronic Annotation more info
response to nutrient	IEA Inferred from Electronic Annotation more info
small molecule metabolic process	TAS Traceable Author Statement more info
ubiquinone metabolic process	IEA Inferred from Electronic Annotation more info
visual learning	IEA Inferred from Electronic Annotation more info

Component	Evidence Code	Pubs
endoplasmic reticulum	IDA Inferred from Direct Assay more info	PubMed
endoplasmic reticulum membrane	TAS Traceable Author Statement more info	PubMed
integral to membrane	IEA Inferred from Electronic Annotation more info
peroxisomal membrane	IDA Inferred from Direct Assay more info	PubMed

General protein information

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Preferred Names: 3-hydroxy-3-methylglutaryl-Coenzyme A reductase

Names: 3-hydroxy-3-methylglutaryl-Coenzyme A reductase; HMG-CoA reductase; hydroxymethylglutaryl-CoA reductase; 3-hydroxy-3-methylglutaryl CoA reductase (NADPH)

NP_000850.1

EC 1.1.1.34

NP_001124468.1

EC 1.1.1.34

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

NG_011449.1 RefSeqGene

Range

5001..29934

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

NM_000859.2 → NP_000850.1 3-hydroxy-3-methylglutaryl-Coenzyme A reductase isoform 1

Status: REVIEWED

Description

Transcript Variant: This variant (1) encodes the longer isoform (1).

Source sequence(s)

AA648735, BC033692, CN278665, M11058, M62627

Consensus CDS

CCDS4027.1

UniProtKB/Swiss-Prot

P04035

Related

ENSP00000287936, OTTHUMP00000128250, ENST00000287936, OTTHUMT00000219877

Conserved Domains (3) summary

cd00643
Location:465 – 871
Blast Score: 1776

HMG-CoA_reductase_classI; Class I hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase (HMGR)

TIGR00920
Location:1 – 888
Blast Score: 3905

2A060605; 3-hydroxy-3-methylglutaryl-coenzyme A reductase

cl14618
Location:88 – 218
Blast Score: 139

SecD_SecF; Protein export membrane protein
NM_001130996.1 → NP_001124468.1 3-hydroxy-3-methylglutaryl-Coenzyme A reductase isoform 2

Status: REVIEWED

Description

Transcript Variant: This variant (2) lacks an in-frame coding exon in the middle region, as compared to variant 1. The resulting isoform (2) is shorter than isoform 1.

Source sequence(s)

AA648735, BC033692, CN278665, M62627

Consensus CDS

CCDS47234.1

UniProtKB/Swiss-Prot

P04035

Related

ENSP00000340816, OTTHUMP00000222063, ENST00000343975, OTTHUMT00000369021

Conserved Domains (4) summary

cd00643
Location:522 – 818
Blast Score: 1379

HMG-CoA_reductase_classI; Class I hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase (HMGR)

TIGR00920
Location:1 – 835
Blast Score: 3535

2A060605; 3-hydroxy-3-methylglutaryl-coenzyme A reductase

cl14618
Location:88 – 218
Blast Score: 139

SecD_SecF; Protein export membrane protein

cl00205
Location:465 – 520
Blast Score: 115

HMG-CoA_reductase; Hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase (HMGR)

RefSeqs of Annotated Genomes: Homo sapiens Annotation Release 104

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh37.p10 Primary Assembly

Genomic

NC_000005.9 Reference GRCh37.p10 Primary Assembly

Range

74632993..74657926

Download

GenBank, FASTA, Sequence Viewer (Graphics)

Alternate HuRef

Genomic

AC_000137.1 Alternate HuRef

Range

69838165..69863098

Download

GenBank, FASTA, Sequence Viewer (Graphics)

Alternate CHM1_1.0

Genomic

NC_018916.1 Alternate CHM1_1.0

Range

74925992..74950924

Download

GenBank, FASTA, Sequence Viewer (Graphics)

Nucleotide		Protein
Heading	Accession and Version	Protein
genomic	ABBA01061944.1 (66107..91040)	None
genomic	AC008897.7 (39595..64421)	None
genomic	AF273765.1	AAG21343.1
genomic	AMYH01015409.1 (130603..155535)	None
genomic	AY321356.1	AAP72015.1
genomic	CH471084.1	EAW95754.1
		EAW95755.1
		EAW95756.1
genomic	HB386655.1	CAZ64465.1
mRNA	AA648735.1	None
mRNA	AK292892.1	BAF85581.1
mRNA	AK296499.1	BAH12375.1
mRNA	AK299655.1	BAG61573.1
mRNA	AK312437.1	BAG35346.1
mRNA	AY429541.1	None
mRNA	AY429542.1	None
mRNA	AY429543.1	None
mRNA	BC024180.1	None
mRNA	BC033692.1	AAH33692.1
mRNA	CN278665.1	None
mRNA	M11058.1	AAA52679.1
mRNA	M62627.1	None
mRNA	M62633.1	None
other-genetic	DQ890855.2	ABM81781.1
other-genetic	DQ894009.2	ABM84935.1