HMGCoAreduktaasi

HMGCoAreduktaasi, commonly known in English as HMG-CoA reductase, is a membrane-bound enzyme of the endoplasmic reticulum that catalyzes the conversion of 3-hydroxy-3-methylglutaryl-CoA to mevalonate, a key early step in the mevalonate pathway leading to cholesterol and isoprenoid biosynthesis. The reaction uses NADPH and releases CoA and NADP+. The enzyme is encoded by the HMGCR gene in humans and is anchored to the endoplasmic reticulum membrane by an N-terminal transmembrane region, with the catalytic domain facing the cytosol.

Regulation of HMG-CoA reductase is tight and multilayered. Transcription of HMGCR is controlled by SREBP-2; low cellular cholesterol activates SREBP-2 and increases HMGCR expression, while high cholesterol suppresses it. Post-translationally, phosphorylation by AMP-activated protein kinase (AMPK) inhibits activity, linking energy status to cholesterol synthesis. The enzyme is also subject to feedback regulation by intermediates of the mevalonate pathway, ensuring balanced production of cholesterol and essential isoprenoids.

Clinical and pharmacological relevance is centered on its role as the primary target of statins, a class of lipid-lowering drugs. Statins competitively inhibit HMG-CoA reductase, reducing hepatic cholesterol synthesis and lowering plasma LDL cholesterol. Inhibition also decreases production of downstream isoprenoids, affecting processes such as protein prenylation. While statins are widely used to prevent cardiovascular disease, they can cause adverse effects in some individuals, including muscle symptoms and rare liver enzyme elevations.

In humans, the mevalonate pathway supplies precursors for ubiquinone, dolichol, and other biomolecules, making HMG-CoA reductase a pivotal enzyme in lipid and isoprenoid homeostasis.