Cholesterol Biosynthesis (Mevalonate Pathway)

Multi-step synthesis of cholesterol from acetyl-CoA via the mevalonate pathway.

Overview

Cholesterol synthesis begins with condensation of 3 acetyl-CoA to HMG-CoA, reduced by HMG-CoA reductase (the rate-limiting enzyme) to mevalonate. Mevalonate is phosphorylated and decarboxylated to isopentenyl pyrophosphate (IPP), which is the precursor for all isoprenoids. Six IPP units are condensed to squalene, cyclized to lanosterol, and converted to cholesterol through ~19 additional enzymatic steps. SREBP-2 transcriptionally regulates pathway enzymes in response to cholesterol levels.

Cellular Location

Cytoplasm and ER (liver primarily)

Clinical Significance

Statins (HMG-CoA reductase inhibitors) are among the most prescribed drugs globally for cardiovascular disease; SREBP pathway is a master regulator of lipid homeostasis; Smith-Lemli-Opitz syndrome = DHCR7 deficiency.

Key Molecules

Acetyl-CoA HMG-CoA Mevalonate IPP FPP Squalene Lanosterol Cholesterol SREBP-2 SCAP Insig

Key Enzymes

HMG-CoA reductase HMG-CoA synthase Squalene synthase Squalene epoxidase Lanosterol synthase DHCR7

Related Pathways

De Novo Fatty Acid Synthesis

Cytoplasmic synthesis of palmitate from acetyl-CoA and malonyl-CoA.

Bile Acid Synthesis

Hepatic conversion of cholesterol to bile acids for lipid digestion and signaling.