mevalonate

Mevalonate, also known as mevalonic acid in its protonated form, is a six-carbon carboxylic acid that serves as a central intermediate in the mevalonate pathway, a conserved route for the biosynthesis of isoprenoids such as cholesterol, ubiquinone, dolichols, and prenyl groups. The molecule is produced from acetyl-CoA through a series of enzymatic steps that include the action of HMG-CoA synthase and HMG-CoA reductase.

In the canonical eukaryotic mevalonate pathway, two acetyl-CoA molecules condense to form acetoacetyl-CoA, which combines with another acetyl-CoA to form HMG-CoA. HMG-CoA reductase reduces HMG-CoA to mevalonate, a key regulatory step. Mevalonate is then phosphorylated by mevalonate kinase to mevalonate-5-phosphate, further phosphorylated by phosphomevalonate kinase to mevalonate-5-diphosphate, and finally decarboxylated to isopentenyl pyrophosphate (IPP). IPP can be isomerized to dimethylallyl pyrophosphate (DMAPP); these five-carbon units are the building blocks for a wide range of isoprenoids.

Mevalonate-derived IPP and DMAPP feed into the synthesis of cholesterol and other essential biomolecules, including ubiquinone and dolichols, and are also involved in protein prenylation. The pathway is tightly regulated; the rate-limiting step is the HMG-CoA reductase-catalyzed conversion of HMG-CoA to mevalonate. Pharmacological inhibition of this enzyme by statins reduces cholesterol synthesis and has a major role in cardiovascular disease management.

Defects in the mevalonate pathway, such as mevalonate kinase deficiency, can cause metabolic disorders including mevalonic aciduria, featuring fever, immune dysregulation, and developmental issues. In nature, organisms may utilize either the mevalonate pathway or the non-mevalonate (MEP/DOXP) pathway to produce IPP and DMAPP, with distribution varying across taxa.