Biosynthesis of cholesterol

Synthesis within the body starts with the mevalonate pathway where two molecules of condense to form . This is followed by a second condensation between acetyl CoA and acetoacetyl-CoA to form . This molecule is then reduced to 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

2 => .

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

• 1xpk

+ => .

HMG-CoA Reductase

• HMG-CoA Reductase

=>

The HMG binding pocket is the site of catalysis in HMGR. (1dqa) is a critical structural element of this binding site. Residues and are positioned in the active site as is . It is this K691 that likely stabilizes the negatively charged oxygen of the first mevaldyl-CoA intermediate. The mevaldyl CoA intermediate is subsequently converted to Mavaldehyde with added stabilization from . It is then believed that the close proximity of increases the pKA of E559, allowing it to be a proton donor for the reduction of mevaldehyde into mevalonate.

Mevalonate kinase

• Mevalonate kinase

=>

The 3D structure of MK complex with mevalonate shows the enzyme composed of : The N-terminal and the C-terminal. The mevalonate binds in a between the 2 domains forming ^[1]. Water molecules are shown as red spheres.

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