HMGCoAreduktase

HMGCoAReduktase, also known as HMG-CoA reductase, is the enzyme that catalyzes the first committed step in the mevalonate pathway, converting 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) to mevalonate, using NADPH as a cofactor. This step is rate-limiting for cholesterol synthesis and for the production of isoprenoids essential for cell membranes and protein prenylation.

In humans, the enzyme is encoded by the HMGCR gene and mainly resides in the endoplasmic reticulum as a membrane-bound protein, with a catalytic cytosolic domain. In other organisms there are two main classes: class I (eukaryotes and some archaea) as membrane-associated homodimers; class II (bacteria) are soluble cytosolic enzymes with distinct properties.

Regulation: Expression is controlled by sterol regulatory element-binding proteins (SREBP). The enzyme is regulated post-translationally by phosphorylation by AMP-activated protein kinase (AMPK), which inactivates the enzyme during energy stress; dephosphorylation activates it. Cholesterol and its derivatives provide feedback inhibition. Hormones such as insulin and glucagon also influence activity and expression.

Function and clinical aspects: The mevalonate pathway produces cholesterol and nonsterol isoprenoids such as ubiquinone and dolichol; HMG-CoA reductase is a key control point. Statins are competitive inhibitors of HMG-CoA reductase used to lower LDL cholesterol and reduce cardiovascular risk. Genetic variation in HMGCR can affect statin response and risk of adverse effects; rare variants may influence cholesterol metabolism.

History and notes: Statins were developed following the discovery that fungal metabolites could inhibit cholesterol synthesis, leading to drugs such as simvastatin and atorvastatin.