HMGCR
entrez
3156
canonical
uniprot
P04035
canonical
ensembl
ENSG00000113161
resolver
ensp
ENSP00000287936
resolver
ensp
ENSP00000340816
resolver
ensp
ENSP00000505805
resolver
ensp
ENSP00000534025
resolver
ensp
ENSP00000589749
resolver
genesymbol
HMGCR
resolver
hgnc
HGNC:5006
resolver
uniprot
B7Z3Y9
resolver
uniprot
Q8N190
resolver
uniprot_entry
HMDH_HUMAN
resolver
uniprot_sec
B7Z3Y9
resolver
uniprot_sec
Q8N190
resolver
activity_regulation
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). Inhibited by pravastatin (PubMed:36745799). {ECO:0000250|UniProtKB:P00347, ECO:0000269|PubMed:11349148, ECO:0000269|PubMed:18540668, ECO:0000269|PubMed:36745799, ECO:0000303|PubMed:6995544}.
uniprot
proteins
amino_acid_sequence
MLSRLFRMHGLFVASHPWEVIVGTVTLTICMMSMNMFTGNNKICGWNYECPKFEEDVLSSDIIILTITRCIAILYIYFQFQNLRQLGSKYILGIAGLFTIFSSFVFSTVVIHFLDKELTGLNEALPFFLLLIDLSRASTLAKFALSSNSQDEVRENIARGMAILGPTFTLDALVECLVIGVGTMSGVRQLEIMCCFGCMSVLANYFVFMTFFPACVSLVLELSRESREGRPIWQLSHFARVLEEEENKPNPVTQRVKMIMSLGLVLVHAHSRWIADPSPQNSTADTSKVSLGLDENVSKRIEPSVSLWQFYLSKMISMDIEQVITLSLALLLAVKYIFFEQTETESTLSLKNPITSPVVTQKKVPDNCCRREPMLVRNNQKCDSVEEETGINRERKVEVIKPLVAETDTPNRATFVVGNSSLLDTSSVLVTQEPEIELPREPRPNEECLQILGNAEKGAKFLSDAEIIQLVNAKHIPAYKLETLMETHERGVSIRRQLLSKKLSEPSSLQYLPYRDYNYSLVMGACCENVIGYMPIPVGVAGPLCLDEKEFQVPMATTEGCLVASTNRGCRAIGLGGGASSRVLADGMTRGPVVRLPRACDSAEVKAWLETSEGFAVIKEAFDSTSRFARLQKLHTSIAGRNLYIRFQSRSGDAMGMNMISKGTEKALSKLHEYFPEMQILAVSGNYCTDKKPAAINWIEGRGKSVVCEAVIPAKVVREVLKTTTEAMIEVNINKNLVGSAMAGSIGGYNAHAANIVTAIYIACGQDAAQNVGSSNCITLMEASGPTNEDLYISCTMPSIEIGTVGGGTNLLPQQACLQMLGVQGACKDNPGENARQLARIVCGTVMAGELSLMAALAAGHLVKSHMIHNRSKINLQDLQGACTKKTA
uniprot
proteins
disease_involvement
DISEASE: Muscular dystrophy, limb-girdle, autosomal recessive 28 (LGMDR28) [MIM:620375]: An autosomal recessive form of limb girdle muscular dystrophy, a group of genetically heterogeneous muscular disorders that share proximal muscle weakness as the major attribute. Most limb girdle muscular dystrophies present with elevated creatinine kinase and myopathic electromyographic features. Disease is usually progressive to a variable degree, ranging from minor disability to complete inability to ambulate, and can involve the large proximal muscles, as well as axial and facial muscles. Different disease forms may exhibit skeletal muscle hypertrophy, kyphoscoliosis, and contractures or involve other muscle groups and manifest with distal weakness, cardiomyopathy, dysphagia, and respiratory difficulties. LGMDR28 is characterized by progressive muscle weakness affecting the proximal and axial muscles of the upper and lower limbs, and highly variable age at onset. Most patients have limited ambulation or become wheelchair-bound within a few decades, and respiratory insufficiency commonly occurs. {ECO:0000269|PubMed:36745799, ECO:0000269|PubMed:37167966}. Note=The disease is caused by variants affecting the gene represented in this entry.
uniprot
proteins
ec_number
1.1.1.34
uniprot
proteins
function
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:21357570, PubMed:2991281, PubMed:36745799, PubMed:6995544). HMGCR is the main target of statins, a class of cholesterol-lowering drugs (PubMed:11349148, PubMed:18540668, PubMed:36745799). {ECO:0000269|PubMed:11349148, ECO:0000269|PubMed:18540668, ECO:0000269|PubMed:21357570, ECO:0000269|PubMed:2991281, ECO:0000269|PubMed:36745799, ECO:0000269|PubMed:6995544}.
uniprot
proteins
mass_dalton
97476
uniprot
proteins
mutagenesis
MUTAGEN 75..77; /note="YIY->AIA: Reduced sterol-mediated release from the ER. Not deglycosylated in response to sterols."; /evidence="ECO:0000269|PubMed:19458199"; MUTAGEN 89; /note="K->R: Abolishes sterol-mediated ubiquitination and degradation; when associated with R-248."; /evidence="ECO:0000269|PubMed:19458199"; MUTAGEN 248; /note="K->R: Abolishes sterol-mediated ubiquitination and degradation; when associated with R-89."; /evidence="ECO:0000269|PubMed:19458199"; MUTAGEN 807; /note="G->D: Does not affect hydroxymethylglutaryl-CoA reductase activity."; /evidence="ECO:0000269|PubMed:21357570
uniprot
proteins
pathway_participation
PATHWAY: Metabolic intermediate biosynthesis; (R)-mevalonate biosynthesis; (R)-mevalonate from acetyl-CoA: step 3/3.
uniprot
proteins
post_translational_modification
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}.
uniprot
proteins
protein_family
HMG-CoA reductase family
uniprot
proteins
pubmed
10391209
uniprot
proteins
pubmed
10698924
uniprot
proteins
pubmed
11349148
uniprot
proteins
pubmed
12535518
uniprot
proteins
pubmed
14702039
uniprot
proteins
pubmed
15372022
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
17180682
uniprot
proteins
pubmed
18193044
uniprot
proteins
pubmed
18354102
uniprot
proteins
pubmed
18540668
uniprot
proteins
pubmed
19458199
uniprot
proteins
pubmed
20686565
uniprot
proteins
pubmed
21357570
uniprot
proteins
pubmed
21778231
uniprot
proteins
pubmed
22143767
uniprot
proteins
pubmed
22989091
uniprot
proteins
pubmed
23169578
uniprot
proteins
pubmed
23186163
uniprot
proteins
pubmed
24275569
uniprot
proteins
pubmed
2991281
uniprot
proteins
pubmed
36745799
uniprot
proteins
pubmed
37167966
uniprot
proteins
pubmed
6995544
uniprot
proteins
sequence_length
888
uniprot
proteins
subcellular_location
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}.
uniprot
proteins
transmembrane_region
TRANSMEM 10..39; /note="Helical"; /evidence="ECO:0000250|UniProtKB:P00347"; TRANSMEM 57..78; /note="Helical"; /evidence="ECO:0000250|UniProtKB:P00347"; TRANSMEM 90..114; /note="Helical"; /evidence="ECO:0000250|UniProtKB:P00347"; TRANSMEM 124..149; /note="Helical"; /evidence="ECO:0000250|UniProtKB:P00347"; TRANSMEM 160..187; /note="Helical"; /evidence="ECO:0000250|UniProtKB:P00347"; TRANSMEM 192..220; /note="Helical"; /evidence="ECO:0000250|UniProtKB:P00347"; TRANSMEM 249..275; /note="Helical"; /evidence="ECO:0000250|UniProtKB:P00347"; TRANSMEM 315..339; /note="Helical"; /evidence="ECO:0000250|UniProtKB:P00347
uniprot
proteins