Biosynthesis of cholesterol

Synthesis within the body starts with the mevalonate pathway where two molecules of 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

• Acetoacetyl-CoA thiolase

Hydroxymethylglutaryl-CoA synthase or HMG-CoA synthase; EC 2.3.3.10

• 1xpk

HMG-CoA Reductase

• HMG-CoA Reductase

Mevalonate kinase

• 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.

• Mevalonate Diphosphate Decarboxylase

Isopentenyl pyrophosphate isomerase

Isopentenyl pyrophosphate isomerase (EC 5.3.3.2, IPP isomerase), also known as Isopentenyl-diphosphate delta isomerase

• 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

• Farnesyl diphosphate synthase

Squalene synthase

Two molecules of farnesyl pyrophosphate then condense to form squalene by the action of squalene synthase in the endoplasmic reticulum.

• Squalene synthase

Oxidosqualene cyclase

Oxidosqualene cyclase then cyclizes squalene to form lanosterol.

• Squalene-hopene cyclase

Finally, lanosterol is converted to cholesterol via either of two pathways, the Bloch pathway, or the Kandutsch-Russell pathway.