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.
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.
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.
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
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Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
