UniProt functional annotation for P04035



	UniProt functional annotation for P04035

UniProt code: P04035.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Catalyzes the conversion of (3S)-hydroxy-3-methylglutaryl-CoA (HMG-CoA) to mevalonic acid, the rate-limiting step in the synthesis of cholesterol and other isoprenoids, thus plays a critical role in cellular cholesterol homeostasis (PubMed:2991281, PubMed:21357570, PubMed:6995544). HMGCR is the main target of statins, a class of cholesterol-lowering drugs (PubMed:11349148, PubMed:18540668). {ECO:0000269|PubMed:11349148, ECO:0000269|PubMed:18540668, ECO:0000269|PubMed:21357570, ECO:0000269|PubMed:2991281, ECO:0000269|PubMed:6995544}.

Catalytic activity: Reaction=(R)-mevalonate + CoA + 2 NADP(+) = (3S)-hydroxy-3- methylglutaryl-CoA + 2 H(+) + 2 NADPH; Xref=Rhea:RHEA:15989, ChEBI:CHEBI:15378, ChEBI:CHEBI:36464, ChEBI:CHEBI:43074, ChEBI:CHEBI:57287, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349; EC=1.1.1.34; Evidence={ECO:0000269|PubMed:21357570, ECO:0000269|PubMed:2991281, ECO:0000269|PubMed:6995544};

Activity regulation: Regulated by a negative feedback mechanism through sterols and non-sterol metabolites derived from mevalonate (PubMed:6995544). Phosphorylation at Ser-872 down-regulates the catalytic activity (By similarity). 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 (PubMed:11349148, PubMed:18540668). 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 (PubMed:11349148, PubMed:18540668). The first results can be seen after one week of statin use and the effect is maximal after four to six weeks (PubMed:11349148, PubMed:18540668). {ECO:0000250|UniProtKB:P00347, ECO:0000269|PubMed:11349148, ECO:0000269|PubMed:18540668, ECO:0000303|PubMed:6995544}.

Pathway: Metabolic intermediate biosynthesis; (R)-mevalonate biosynthesis; (R)-mevalonate from acetyl-CoA: step 3/3.

Subunit: Homotetramer (PubMed:10698924). Homodimer (PubMed:10698924). 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 (PubMed:12535518, PubMed:19458199). Interacts with UBIAD1 (PubMed:23169578). {ECO:0000269|PubMed:10698924, ECO:0000269|PubMed:11349148, ECO:0000269|PubMed:12535518, ECO:0000269|PubMed:19458199, ECO:0000269|PubMed:23169578}.

Subcellular location: Endoplasmic reticulum membrane {ECO:0000269|PubMed:17180682, ECO:0000305|PubMed:2991281}; Multi-pass membrane protein {ECO:0000250|UniProtKB:P00347}. Peroxisome membrane {ECO:0000269|PubMed:17180682}; Multi-pass membrane protein {ECO:0000250|UniProtKB:P00347}.

Tissue specificity: [Isoform 1]: Ubiquitously expressed with the highest levels in the cerebellum, fetal brain, testis, skin and adrenal gland. {ECO:0000269|PubMed:22989091}.

Tissue specificity: [Isoform 2]: Detected in the cerebellum, fetal brain, testis and adrenal gland. {ECO:0000269|PubMed:22989091}.

Tissue specificity: [Isoform 3]: Low abundance except in skin, esophagus, and uterine cervix. {ECO:0000269|PubMed:22989091}.

Ptm: N-glycosylated. Deglycosylated by NGLY1 on release from the endoplasmic reticulum (ER) in a sterol-mediated manner. {ECO:0000269|PubMed:19458199}.

Ptm: Undergoes sterol-mediated ubiquitination and ER-associated degradation (ERAD) (PubMed:12535518, PubMed:19458199, PubMed:21778231). Accumulation of sterols in the endoplasmic reticulum (ER) membrane, triggers binding of the reductase to the ER membrane protein INSIG1 or INSIG2 (PubMed:12535518, PubMed:19458199, PubMed:21778231, PubMed:22143767). The INSIG1 binding leads to the recruitment of the ubiquitin ligase, AMFR/gp78, RNF139 or RNF145, initiating ubiquitination of the reductase (PubMed:12535518, PubMed:19458199, PubMed:21778231). 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 (PubMed:12535518, PubMed:19458199, PubMed:21778231). The INSIG2-binding leads to the recruitment of the ubiquitin ligase RNF139, initiating ubiquitination of the reductase (PubMed:22143767). Lys-248 is the main site of ubiquitination (PubMed:19458199). Ubiquitination is enhanced by the presence of a geranylgeranylated protein (PubMed:21778231). {ECO:0000269|PubMed:12535518, ECO:0000269|PubMed:19458199, ECO:0000269|PubMed:21778231, ECO:0000269|PubMed:22143767}.

Ptm: Phosphorylated. Phosphorylation at Ser-872 reduces the catalytic activity. {ECO:0000250|UniProtKB:P00347}.

Similarity: Belongs to the HMG-CoA reductase family. {ECO:0000305}.

Sequence caution: Sequence=BAH12375.1; Type=Frameshift; Evidence={ECO:0000305};

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Catalyzes the conversion of (3S)-hydroxy-3-methylglutaryl-CoA (HMG-CoA) to mevalonic acid, the rate-limiting step in the synthesis of cholesterol and other isoprenoids, thus plays a critical role in cellular cholesterol homeostasis (PubMed:2991281, PubMed:21357570, PubMed:6995544). HMGCR is the main target of statins, a class of cholesterol-lowering drugs (PubMed:11349148, PubMed:18540668). {ECO:0000269\|PubMed:11349148, ECO:0000269\|PubMed:18540668, ECO:0000269\|PubMed:21357570, ECO:0000269\|PubMed:2991281, ECO:0000269\|PubMed:6995544}.


Catalytic activity:		Reaction=(R)-mevalonate + CoA + 2 NADP(+) = (3S)-hydroxy-3- methylglutaryl-CoA + 2 H(+) + 2 NADPH; Xref=Rhea:RHEA:15989, ChEBI:CHEBI:15378, ChEBI:CHEBI:36464, ChEBI:CHEBI:43074, ChEBI:CHEBI:57287, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349; EC=1.1.1.34; Evidence={ECO:0000269\|PubMed:21357570, ECO:0000269\|PubMed:2991281, ECO:0000269\|PubMed:6995544};
Activity regulation:		Regulated by a negative feedback mechanism through sterols and non-sterol metabolites derived from mevalonate (PubMed:6995544). Phosphorylation at Ser-872 down-regulates the catalytic activity (By similarity). 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 (PubMed:11349148, PubMed:18540668). 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 (PubMed:11349148, PubMed:18540668). The first results can be seen after one week of statin use and the effect is maximal after four to six weeks (PubMed:11349148, PubMed:18540668). {ECO:0000250\|UniProtKB:P00347, ECO:0000269\|PubMed:11349148, ECO:0000269\|PubMed:18540668, ECO:0000303\|PubMed:6995544}.
Pathway:		Metabolic intermediate biosynthesis; (R)-mevalonate biosynthesis; (R)-mevalonate from acetyl-CoA: step 3/3.
Subunit:		Homotetramer (PubMed:10698924). Homodimer (PubMed:10698924). 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 (PubMed:12535518, PubMed:19458199). Interacts with UBIAD1 (PubMed:23169578). {ECO:0000269\|PubMed:10698924, ECO:0000269\|PubMed:11349148, ECO:0000269\|PubMed:12535518, ECO:0000269\|PubMed:19458199, ECO:0000269\|PubMed:23169578}.
Subcellular location:		Endoplasmic reticulum membrane {ECO:0000269\|PubMed:17180682, ECO:0000305\|PubMed:2991281}; Multi-pass membrane protein {ECO:0000250\|UniProtKB:P00347}. Peroxisome membrane {ECO:0000269\|PubMed:17180682}; Multi-pass membrane protein {ECO:0000250\|UniProtKB:P00347}.
Tissue specificity:		[Isoform 1]: Ubiquitously expressed with the highest levels in the cerebellum, fetal brain, testis, skin and adrenal gland. {ECO:0000269\|PubMed:22989091}.
Tissue specificity:		[Isoform 2]: Detected in the cerebellum, fetal brain, testis and adrenal gland. {ECO:0000269\|PubMed:22989091}.
Tissue specificity:		[Isoform 3]: Low abundance except in skin, esophagus, and uterine cervix. {ECO:0000269\|PubMed:22989091}.
Ptm:		N-glycosylated. Deglycosylated by NGLY1 on release from the endoplasmic reticulum (ER) in a sterol-mediated manner. {ECO:0000269\|PubMed:19458199}.
Ptm:		Undergoes sterol-mediated ubiquitination and ER-associated degradation (ERAD) (PubMed:12535518, PubMed:19458199, PubMed:21778231). Accumulation of sterols in the endoplasmic reticulum (ER) membrane, triggers binding of the reductase to the ER membrane protein INSIG1 or INSIG2 (PubMed:12535518, PubMed:19458199, PubMed:21778231, PubMed:22143767). The INSIG1 binding leads to the recruitment of the ubiquitin ligase, AMFR/gp78, RNF139 or RNF145, initiating ubiquitination of the reductase (PubMed:12535518, PubMed:19458199, PubMed:21778231). 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 (PubMed:12535518, PubMed:19458199, PubMed:21778231). The INSIG2-binding leads to the recruitment of the ubiquitin ligase RNF139, initiating ubiquitination of the reductase (PubMed:22143767). Lys-248 is the main site of ubiquitination (PubMed:19458199). Ubiquitination is enhanced by the presence of a geranylgeranylated protein (PubMed:21778231). {ECO:0000269\|PubMed:12535518, ECO:0000269\|PubMed:19458199, ECO:0000269\|PubMed:21778231, ECO:0000269\|PubMed:22143767}.
Ptm:		Phosphorylated. Phosphorylation at Ser-872 reduces the catalytic activity. {ECO:0000250\|UniProtKB:P00347}.
Similarity:		Belongs to the HMG-CoA reductase family. {ECO:0000305}.
Sequence caution:		Sequence=BAH12375.1; Type=Frameshift; Evidence={ECO:0000305};