HMG-CoA reductase pathway

HMG-CoA reductase pathway

HMG-CoA reductase pathway is a crucial metabolic pathway involved in the production of cholesterol, coenzyme Q10, and other important isoprenoids. The pathway is named after the key enzyme, HMG-CoA reductase, which catalyzes the conversion of HMG-CoA to mevalonate, a critical step in the biosynthesis of cholesterol.

Overview

The HMG-CoA reductase pathway, also known as the mevalonate pathway, begins with the condensation of acetyl-CoA and acetoacetyl-CoA to form HMG-CoA. This reaction is catalyzed by the enzyme HMG-CoA synthase. HMG-CoA is then reduced to mevalonate by HMG-CoA reductase. This step is the rate-limiting step of the pathway and is therefore the primary site of regulation.

Mevalonate is then converted to isopentenyl pyrophosphate (IPP) through a series of enzymatic reactions. IPP is a key intermediate in the pathway and serves as the building block for the synthesis of higher isoprenoids. IPP can be converted to dimethylallyl pyrophosphate (DMAPP), which can then be combined with another molecule of IPP to form geranyl pyrophosphate (GPP). GPP can be further elongated to form farnesyl pyrophosphate (FPP), which is a precursor to squalene, the direct precursor to cholesterol.

Regulation

The HMG-CoA reductase pathway is tightly regulated to ensure proper levels of cholesterol and other isoprenoids. The primary site of regulation is the HMG-CoA reductase enzyme, which is controlled by a variety of mechanisms, including feedback inhibition, covalent modification, and gene expression.

Clinical significance

Given its central role in cholesterol biosynthesis, the HMG-CoA reductase pathway is a major target for cholesterol-lowering drugs, known as statins. Statins work by inhibiting the HMG-CoA reductase enzyme, thereby reducing the production of cholesterol.

See also

• Cholesterol biosynthesis
• Statins
• Isoprenoid biosynthesis