3-hydroxy-3-methylglutaryl-coenzyme A reductase
GeneName
HMGCR
Summary
HMGCR, also known as HMG CoA reductase or HMGR, is a 97 kDa enzyme predominantly located in the endoplasmic reticulum and its membrane. It plays a pivotal role in the cholesterol biosynthetic process by catalysing the conversion of HMG-CoA to mevalonate, a key step in the mevalonate pathway. This enzyme is also involved in various metabolic processes including isoprenoid biosynthesis and coenzyme A metabolism. Additionally, HMGCR has been implicated in the regulation of long-term synaptic potentiation and the negative regulation of amyloid-beta clearance, linking it to neurodegenerative processes.
Importance
HMGCR is relevant to: - Cholesterol metabolism and its implications in cardiovascular diseases, as it is the target of statin drugs used to lower cholesterol levels - Neurodegenerative diseases, particularly Alzheimer’s, due to its role in amyloid-beta metabolism - Regulation of cellular signalling pathways, including the ERK1 and ERK2 cascade, which are important in various cellular functions - Potential therapeutic target in conditions related to dyslipidaemia and metabolic syndrome
Top Products
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Abcam Product Citation Summary
The data indicates that the HMGCR target is being investigated in the context of cholesterol homeostasis and metabolism, particularly in human U373 cells. Additionally, HMGCR is being studied in relation to focal cortical dysplasia in human cortical tissue, highlighting its relevance in neurological conditions.
Abcam Product Citation Table
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).
Involvement in disease
Muscular dystrophy, limb-girdle, autosomal recessive 28
LGMDR28
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.
None
The disease is caused by variants affecting the gene represented in this entry.
Pathway
Metabolic intermediate biosynthesis; (R)-mevalonate biosynthesis; (R)-mevalonate from acetyl-CoA: step 3/3.
Post-translational modifications
N-glycosylated. Deglycosylated by NGLY1 on release from the endoplasmic reticulum (ER) in a sterol-mediated manner.
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).
Phosphorylated. Phosphorylation at Ser-872 reduces the catalytic activity.
Sequence Similarities
Belongs to the HMG-CoA reductase family.
Tissue Specificity
Isoform 1
Ubiquitously expressed with the highest levels in the cerebellum, fetal brain, testis, skin and adrenal gland.
Isoform 2
Detected in the cerebellum, fetal brain, testis and adrenal gland.
Isoform 3
Low abundance except in skin, esophagus, and uterine cervix.
Cellular localization
- Endoplasmic reticulum membrane
- Multi-pass membrane protein
- Peroxisome membrane
- Multi-pass membrane protein
Alternative names
3-hydroxy-3-methylglutaryl-coenzyme A reductase, HMG-CoA reductase, HMGCR