Human Gene HMGCR (ENST00000287936.9) from GENCODE V44
  Description: Homo sapiens 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), transcript variant 3, mRNA. (from RefSeq NM_001364187)
RefSeq Summary (NM_000859): 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].
Gencode Transcript: ENST00000287936.9
Gencode Gene: ENSG00000113161.17
Transcript (Including UTRs)
   Position: hg38 chr5:75,337,220-75,362,101 Size: 24,882 Total Exon Count: 20 Strand: +
Coding Region
   Position: hg38 chr5:75,342,606-75,360,342 Size: 17,737 Coding Exon Count: 19 

Page IndexSequence and LinksUniProtKB CommentsPrimersMalaCardsCTD
RNA-Seq ExpressionMicroarray ExpressionRNA StructureProtein StructureOther SpeciesGO Annotations
mRNA DescriptionsPathwaysOther NamesMethods
Data last updated at UCSC: 2023-08-18 00:09:47

-  Sequence and Links to Tools and Databases
 
Genomic Sequence (chr5:75,337,220-75,362,101)mRNA (may differ from genome)Protein (888 aa)
Gene SorterGenome BrowserOther Species FASTAGene interactionsTable SchemaAlphaFold
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HGNCHPRDLynxMalacardsMGIneXtProt
OMIMPubMedReactomeUniProtKBWikipediaBioGrid CRISPR DB

-  Comments and Description Text from UniProtKB
  ID: HMDH_HUMAN
DESCRIPTION: RecName: Full=3-hydroxy-3-methylglutaryl-coenzyme A reductase; Short=HMG-CoA reductase; EC=1.1.1.34;
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.
CATALYTIC ACTIVITY: (R)-mevalonate + CoA + 2 NADP(+) = (S)-3- hydroxy-3-methylglutaryl-CoA + 2 NADPH.
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.
PATHWAY: Metabolic intermediate biosynthesis; (R)-mevalonate biosynthesis; (R)-mevalonate from acetyl-CoA: step 3/3.
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.
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane; Multi-pass membrane protein.
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.
SIMILARITY: Belongs to the HMG-CoA reductase family.
SIMILARITY: Contains 1 SSD (sterol-sensing) domain.

-  Primer design for this transcript
 

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Click here to load the transcript sequence and exon structure into Primer3Plus

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Click here to open Exonprimer with this transcript

To design primers for a non-coding sequence, zoom to a region of interest and select from the drop-down menu: View > In External Tools > Primer3


-  MalaCards Disease Associations
  MalaCards Gene Search: HMGCR
Diseases sorted by gene-association score: marek disease (18), hyperlipidemia, familial combined (18), cerebrotendinous xanthomatosis (17), mevalonic aciduria (16), familial hyperlipidemia (14), sitosterolemia (13), smith-lemli-opitz syndrome (13), hypercholesterolemia, familial (12), coronary artery disease (12), atherosclerosis (11), lichen planus pemphigoides (10), defective apolipoprotein b-100 (9), xanthomatosis (8), lipid metabolism disorder (8), arteriosclerosis (7), hemorrhage, intracerebral (7), homozygous familial hypercholesterolemia (6), chronic kidney failure (6), reye syndrome (6), spondylosis (6), creatine phosphokinase, elevated serum (6), 3-methylglutaconic aciduria (5), leukocyte adhesion deficiency, type iii (5), clopidogrel resistance (5), hyperlipoproteinemia, type iii (4), vascular disease (3), seizure disorder (3), myocardial infarction (3), myopathy (2), heart disease (2), osteoporosis (2), diabetes mellitus, noninsulin-dependent (2), stroke, ischemic (1)

-  Comparative Toxicogenomics Database (CTD)
  The following chemicals interact with this gene           more ... click here to view the complete list

-  RNA-Seq Expression Data from GTEx (53 Tissues, 570 Donors)
  Highest median expression: 33.02 RPKM in Skin - Not Sun Exposed (Suprapubic)
Total median expression: 479.43 RPKM



View in GTEx track of Genome Browser    View at GTEx portal     View GTEx Body Map

+  Microarray Expression Data
  Press "+" in the title bar above to open this section.

-  mRNA Secondary Structure of 3' and 5' UTRs
 
RegionFold EnergyBasesEnergy/Base
Display As
5' UTR -38.00104-0.365 Picture PostScript Text
3' UTR -455.001759-0.259 Picture PostScript Text

The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.

-  Protein Domain and Structure Information
  InterPro Domains: Graphical view of domain structure
IPR002202 - HMG_CoA_Rdtase
IPR023074 - HMG_CoA_Rdtase_cat
IPR023076 - HMG_CoA_Rdtase_CS
IPR004554 - HMG_CoA_Rdtase_eu_arc
IPR004816 - HMG_CoA_Rdtase_metazoan
IPR023282 - HMG_CoA_Rdtase_N
IPR009023 - HMG_CoA_Rdtase_NAD(P)-bd
IPR009029 - HMG_CoA_Rdtase_sub-bd
IPR000731 - SSD

Pfam Domains:
PF00368 - Hydroxymethylglutaryl-coenzyme A reductase

Protein Data Bank (PDB) 3-D Structure
MuPIT help
1DQ8 - X-ray MuPIT 1DQ9 - X-ray MuPIT 1DQA - X-ray MuPIT 1HW8 - X-ray MuPIT 1HW9 - X-ray MuPIT 1HWI - X-ray MuPIT 1HWJ - X-ray MuPIT 1HWK - X-ray MuPIT 1HWL - X-ray MuPIT 2Q1L - X-ray MuPIT 2Q6B - X-ray MuPIT 2Q6C - X-ray MuPIT 2R4F - X-ray MuPIT 3BGL - X-ray MuPIT 3CCT - X-ray MuPIT 3CCW - X-ray MuPIT 3CCZ - X-ray MuPIT 3CD0 - X-ray MuPIT 3CD5 - X-ray MuPIT 3CD7 - X-ray MuPIT 3CDA - X-ray MuPIT 3CDB - X-ray MuPIT


ModBase Predicted Comparative 3D Structure on P04035
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-  Orthologous Genes in Other Species
  Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
MouseRatZebrafishD. melanogasterC. elegansS. cerevisiae
Genome BrowserGenome BrowserNo orthologNo orthologNo orthologNo ortholog
Gene Details     
Gene Sorter     
MGIRGD    
Protein SequenceProtein Sequence    
AlignmentAlignment    

-  Gene Ontology (GO) Annotations with Structured Vocabulary
  Molecular Function:
GO:0004420 hydroxymethylglutaryl-CoA reductase (NADPH) activity
GO:0005515 protein binding
GO:0016491 oxidoreductase activity
GO:0016616 oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor
GO:0042282 hydroxymethylglutaryl-CoA reductase activity
GO:0042803 protein homodimerization activity
GO:0050661 NADP binding
GO:0050662 coenzyme binding
GO:0051721 protein phosphatase 2A binding
GO:0070402 NADPH binding

Biological Process:
GO:0006629 lipid metabolic process
GO:0006694 steroid biosynthetic process
GO:0006695 cholesterol biosynthetic process
GO:0006743 ubiquinone metabolic process
GO:0007568 aging
GO:0007584 response to nutrient
GO:0008202 steroid metabolic process
GO:0008203 cholesterol metabolic process
GO:0008284 positive regulation of cell proliferation
GO:0008299 isoprenoid biosynthetic process
GO:0008542 visual learning
GO:0010664 negative regulation of striated muscle cell apoptotic process
GO:0010666 positive regulation of cardiac muscle cell apoptotic process
GO:0015936 coenzyme A metabolic process
GO:0016126 sterol biosynthetic process
GO:0019216 regulation of lipid metabolic process
GO:0032874 positive regulation of stress-activated MAPK cascade
GO:0043066 negative regulation of apoptotic process
GO:0043407 negative regulation of MAP kinase activity
GO:0045445 myoblast differentiation
GO:0045471 response to ethanol
GO:0045540 regulation of cholesterol biosynthetic process
GO:0048643 positive regulation of skeletal muscle tissue development
GO:0048661 positive regulation of smooth muscle cell proliferation
GO:0051262 protein tetramerization
GO:0055114 oxidation-reduction process
GO:0061045 negative regulation of wound healing
GO:0061179 negative regulation of insulin secretion involved in cellular response to glucose stimulus
GO:0070374 positive regulation of ERK1 and ERK2 cascade

Cellular Component:
GO:0005778 peroxisomal membrane
GO:0005783 endoplasmic reticulum
GO:0005789 endoplasmic reticulum membrane
GO:0016020 membrane
GO:0016021 integral component of membrane
GO:0043231 intracellular membrane-bounded organelle


-  Descriptions from all associated GenBank mRNAs
  AK296499 - Homo sapiens cDNA FLJ59310 complete cds, highly similar to 3-hydroxy-3-methylglutaryl-coenzyme A reductase (EC 1.1.1.34).
M62627 - Human 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase mRNA, 3' flank.
LF209869 - JP 2014500723-A/17372: Polycomb-Associated Non-Coding RNAs.
MA445446 - JP 2018138019-A/17372: Polycomb-Associated Non-Coding RNAs.
BC024180 - Homo sapiens cDNA clone IMAGE:4824506, containing frame-shift errors.
AX069418 - Sequence 82 from Patent WO0102600.
AX229787 - Sequence 20 from Patent WO0162968.
AK299655 - Homo sapiens cDNA FLJ55363 complete cds, highly similar to 3-hydroxy-3-methylglutaryl-coenzyme A reductase (EC 1.1.1.34).
BC033692 - Homo sapiens 3-hydroxy-3-methylglutaryl-Coenzyme A reductase, mRNA (cDNA clone MGC:45281 IMAGE:5212903), complete cds.
AK292892 - Homo sapiens cDNA FLJ78605 complete cds, highly similar to Homo sapiens 3-hydroxy-3-methylglutaryl-Coenzyme A reductase (HMGCR), mRNA.
M11058 - Human 3-hydroxy-3-methylglutaryl coenzyme A reductase mRNA, complete cds.
AB527413 - Synthetic construct DNA, clone: pF1KB3947, Homo sapiens HMGCR gene for 3-hydroxy-3-methylglutaryl-Coenzyme A reductase, without stop codon, in Flexi system.
DQ890855 - Synthetic construct clone IMAGE:100003485; FLH166504.01X; RZPDo839H0786D 3-hydroxy-3-methylglutaryl-Coenzyme A reductase (HMGCR) gene, encodes complete protein.
DQ894009 - Synthetic construct Homo sapiens clone IMAGE:100008469; FLH166500.01L; RZPDo839H0785D 3-hydroxy-3-methylglutaryl-Coenzyme A reductase (HMGCR) gene, encodes complete protein.
KJ891361 - Synthetic construct Homo sapiens clone ccsbBroadEn_00755 HMGCR gene, encodes complete protein.
AK312437 - Homo sapiens cDNA, FLJ92784, highly similar to Homo sapiens 3-hydroxy-3-methylglutaryl-Coenzyme A reductase (HMGCR), mRNA.
LF332352 - JP 2014500723-A/139855: Polycomb-Associated Non-Coding RNAs.
MA567929 - JP 2018138019-A/139855: Polycomb-Associated Non-Coding RNAs.
LF332351 - JP 2014500723-A/139854: Polycomb-Associated Non-Coding RNAs.
MA567928 - JP 2018138019-A/139854: Polycomb-Associated Non-Coding RNAs.
JD027108 - Sequence 8132 from Patent EP1572962.
AY429542 - Homo sapiens HMGCRv_2 mRNA sequence; alternatively spliced.
LF332348 - JP 2014500723-A/139851: Polycomb-Associated Non-Coding RNAs.
MA567925 - JP 2018138019-A/139851: Polycomb-Associated Non-Coding RNAs.
LF332347 - JP 2014500723-A/139850: Polycomb-Associated Non-Coding RNAs.
MA567924 - JP 2018138019-A/139850: Polycomb-Associated Non-Coding RNAs.
LF332346 - JP 2014500723-A/139849: Polycomb-Associated Non-Coding RNAs.
MA567923 - JP 2018138019-A/139849: Polycomb-Associated Non-Coding RNAs.
LF332345 - JP 2014500723-A/139848: Polycomb-Associated Non-Coding RNAs.
MA567922 - JP 2018138019-A/139848: Polycomb-Associated Non-Coding RNAs.
LF332344 - JP 2014500723-A/139847: Polycomb-Associated Non-Coding RNAs.
MA567921 - JP 2018138019-A/139847: Polycomb-Associated Non-Coding RNAs.
LF332343 - JP 2014500723-A/139846: Polycomb-Associated Non-Coding RNAs.
MA567920 - JP 2018138019-A/139846: Polycomb-Associated Non-Coding RNAs.
AY429541 - Homo sapiens HMGCRv_1 mRNA sequence; alternatively spliced.
LF332342 - JP 2014500723-A/139845: Polycomb-Associated Non-Coding RNAs.
MA567919 - JP 2018138019-A/139845: Polycomb-Associated Non-Coding RNAs.
LF332341 - JP 2014500723-A/139844: Polycomb-Associated Non-Coding RNAs.
MA567918 - JP 2018138019-A/139844: Polycomb-Associated Non-Coding RNAs.
LF332339 - JP 2014500723-A/139842: Polycomb-Associated Non-Coding RNAs.
MA567916 - JP 2018138019-A/139842: Polycomb-Associated Non-Coding RNAs.
LF332338 - JP 2014500723-A/139841: Polycomb-Associated Non-Coding RNAs.
MA567915 - JP 2018138019-A/139841: Polycomb-Associated Non-Coding RNAs.
AY429543 - Homo sapiens HMGCRv_3 mRNA sequence; alternatively spliced.
LF332337 - JP 2014500723-A/139840: Polycomb-Associated Non-Coding RNAs.
MA567914 - JP 2018138019-A/139840: Polycomb-Associated Non-Coding RNAs.
LF332336 - JP 2014500723-A/139839: Polycomb-Associated Non-Coding RNAs.
MA567913 - JP 2018138019-A/139839: Polycomb-Associated Non-Coding RNAs.
DL492553 - Novel nucleic acids.
M62633 - Human 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase mRNA, 3' flank.
LF332335 - JP 2014500723-A/139838: Polycomb-Associated Non-Coding RNAs.
MA567912 - JP 2018138019-A/139838: Polycomb-Associated Non-Coding RNAs.
JD305621 - Sequence 286645 from Patent EP1572962.
JD386469 - Sequence 367493 from Patent EP1572962.
JD357111 - Sequence 338135 from Patent EP1572962.
LF332334 - JP 2014500723-A/139837: Polycomb-Associated Non-Coding RNAs.
MA567911 - JP 2018138019-A/139837: Polycomb-Associated Non-Coding RNAs.
JD284903 - Sequence 265927 from Patent EP1572962.
JD162854 - Sequence 143878 from Patent EP1572962.
JD287613 - Sequence 268637 from Patent EP1572962.
JD510534 - Sequence 491558 from Patent EP1572962.
JD091067 - Sequence 72091 from Patent EP1572962.
JD449185 - Sequence 430209 from Patent EP1572962.
JD280468 - Sequence 261492 from Patent EP1572962.
JD059450 - Sequence 40474 from Patent EP1572962.
LF332333 - JP 2014500723-A/139836: Polycomb-Associated Non-Coding RNAs.
MA567910 - JP 2018138019-A/139836: Polycomb-Associated Non-Coding RNAs.
JD203002 - Sequence 184026 from Patent EP1572962.
JD073205 - Sequence 54229 from Patent EP1572962.
JD348263 - Sequence 329287 from Patent EP1572962.
JD546139 - Sequence 527163 from Patent EP1572962.
JD154644 - Sequence 135668 from Patent EP1572962.
JD307484 - Sequence 288508 from Patent EP1572962.
LF332332 - JP 2014500723-A/139835: Polycomb-Associated Non-Coding RNAs.
MA567909 - JP 2018138019-A/139835: Polycomb-Associated Non-Coding RNAs.
JD202723 - Sequence 183747 from Patent EP1572962.

-  Biochemical and Signaling Pathways
  KEGG - Kyoto Encyclopedia of Genes and Genomes
hsa00900 - Terpenoid backbone biosynthesis
hsa01100 - Metabolic pathways

BioCyc Knowledge Library
PWY-5910 - superpathway of geranylgeranyldiphosphate biosynthesis I (via mevalonate)
PWY-922 - mevalonate pathway
PWY66-5 - superpathway of cholesterol biosynthesis

Reactome (by CSHL, EBI, and GO)

Protein P04035 (Reactome details) participates in the following event(s):

R-HSA-191352 Reduction of HMG-CoA produces mevalonate
R-HSA-1989781 PPARA activates gene expression
R-HSA-2426168 Activation of gene expression by SREBF (SREBP)
R-HSA-400206 Regulation of lipid metabolism by Peroxisome proliferator-activated receptor alpha (PPARalpha)
R-HSA-1655829 Regulation of cholesterol biosynthesis by SREBP (SREBF)
R-HSA-556833 Metabolism of lipids
R-HSA-8957322 Metabolism of steroids
R-HSA-191273 Cholesterol biosynthesis
R-HSA-1430728 Metabolism
R-HSA-191352 Reduction of HMG-CoA produces mevalonate
R-HSA-191273 Cholesterol biosynthesis
R-HSA-8957322 Metabolism of steroids
R-HSA-556833 Metabolism of lipids
R-HSA-1430728 Metabolism

-  Other Names for This Gene
  Alternate Gene Symbols: ENST00000287936.1, ENST00000287936.2, ENST00000287936.3, ENST00000287936.4, ENST00000287936.5, ENST00000287936.6, ENST00000287936.7, ENST00000287936.8, HMDH_HUMAN, NM_001364187, P04035, Q8N190, uc003kdp.1, uc003kdp.2, uc003kdp.3, uc003kdp.4, uc003kdp.5
UCSC ID: ENST00000287936.9
RefSeq Accession: NM_000859
Protein: P04035 (aka HMDH_HUMAN)
CCDS: CCDS4027.1

-  Methods, Credits, and Use Restrictions
  Click here for details on how this gene model was made and data restrictions if any.