Reactome | HMGCR dimer binds statins

HMGCR dimer binds statins

Stable Identifier

R-HSA-9705584

Type

Reaction [binding]

Species

Homo sapiens

Compartment

cytosol, endoplasmic reticulum membrane

ReviewStatus

5/5

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Dimeric 3-hydroxy-3-methyl glutaryl coenzyme A reductase (HMGCR dimer) is the key enzyme in the cholesterol biosynthetic pathway and catalyzes the committed step of the reduction of beta-hydroxy-3-methylglutaryl CoA (bHMG-CoA) to mevalonate. HMGCR is regarded as one of the most important drug targets in the treatment of hypercholesterolemia. HMGCR inhibitors, commonly referred to as statins, are among the most widely prescribed drugs in the world. Statins work by their similarity to the substrate (bHMG-CoA), leading to competition towards the HMG binding site on the enzyme between substrate and statins (Istvan & Deisenhofer 2001). As statins also block the access of the substrate to the binding site, the affinity of HMGCR for statins is slightly higher than its affinity for the substrate (Istvan 2002, Carbonell & Ernesto Freire 2005, Gesto et al. 2020). Statins can be divided in two types, according to their origin. Type I statins e.g. lovastatin, pravastatin and simvastatin, are natural fungal products and Type II statins e.g. atorvastatin, rosuvastatin and fluvastatin, are fully synthetic.

Literature References

PubMed ID	Title	Journal	Year
12486413	Structural mechanism for statin inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase Istvan, ES	Am Heart J	2002
16128575	Binding thermodynamics of statins to HMG-CoA reductase Carbonell, T, Freire, E	Biochemistry	2005
32859023	An Atomic-Level Perspective of HMG-CoA-Reductase: The Target Enzyme to Treat Hypercholesterolemia Gesto, DS, Pereira, CMS, Cerqueira, NMFS, Sousa, SF	Molecules	2020
11349148	Structural mechanism for statin inhibition of HMG-CoA reductase Istvan, ES, Deisenhofer, J	Science	2001