Synthesis within the body starts with the mevalonate pathway where two molecules of acetyl CoA condense to form acetoacetyl-CoA. This is followed by a second condensation between acetyl CoA and acetoacetyl-CoA to form 3-hydroxy-3-methylglutaryl CoA (HMG-CoA). This molecule is then reduced to mevalonate by the enzyme HMG-CoA reductase. Production of mevalonate is the rate-limiting and irreversible step in cholesterol synthesis and is the site of action for statins.
Acetyl-CoA is coming from Citric Acid Cycle.
Mevalonate pathway
Acetoacetyl-CoA thiolase
Hydroxymethylglutaryl-CoA synthase or HMG-CoA synthase; EC 2.3.3.10
HMG-CoA Reductase
Mevalonate kinase
Phosphomevalonate kinase
- The Crystal Structure of Human Phosphomavelonate Kinase At 1.8 A Resolution 3ch4
Mevalonate-5-pyrophosphate decarboxylase
Diphosphomevalonate decarboxylase (EC 4.1.1.33), most commonly referred to in scientific literature as mevalonate diphosphate decarboxylase.
Isopentenyl pyrophosphate isomerase
Isopentenyl pyrophosphate isomerase (EC 5.3.3.2, IPP isomerase), also known as Isopentenyl-diphosphate delta isomerase
Mevalonate is finally converted to isopentenyl pyrophosphate.
Next steps of Cholesterol Biosynthesis
Geranyl transferase
Three molecules of isopentenyl pyrophosphate condense to form farnesyl pyrophosphate through the action of geranyl transferase. Other names in common use include:
- farnesyl-diphosphate synthase
- geranyl transferase I
- prenyltransferase
- farnesyl pyrophosphate synthetase
- farnesylpyrophosphate synthetase
Squalene synthase
Two molecules of farnesyl pyrophosphate then condense to form squalene by the action of squalene synthase in the endoplasmic reticulum.
Oxidosqualene cyclase
Oxidosqualene cyclase then cyclizes squalene to form lanosterol.
Finally, lanosterol is converted to cholesterol via either of two pathways, the Bloch pathway, or the Kandutsch-Russell pathway.
