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.

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

=>

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.