Biosynthesis of cholesterol
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. Mevalonate pathway Acetoacetyl-CoA thiolase 2 acetyl-CoA => acetoacetyl-CoA. Hydroxymethylglutaryl-CoA synthase or HMG-CoA synthase; EC 2.3.3.10 Acetyl-CoA + acetoacetyl-CoA => 3-hydroxy-3-methylglutaryl CoA (HMG-CoA). HMG-CoA Reductase 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) => mevalonate The HMG binding pocket is the site of catalysis in HMGR. The “cis-loop” that bends over the top of HMG (1dqa) is a critical structural element of this binding site. Residues E559 and D767 and are positioned in the active site as is K691 which is only 2.7 angstroms from the HMG O2 carbonyl oxygen. 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 H866, which is within hydrogen bonding distance of the thiol group. It is then believed that the close proximity of E559 and D767 increases the pKA of E559, allowing it to be a proton donor for the reduction of mevaldehyde into mevalonate. Mevalonate kinase mevalonate => mevalonate-5-phosphate The 3D structure of MK complex with mevalonate shows the enzyme composed of 2 domains: The N-terminal and the C-terminal. The mevalonate binds in a deep cleft between the 2 domains forming H-bonds and hydrophobic interactions[1]. Water molecules are shown as red spheres. Phosphomevalonate kinase
mevalonate-5-phosphate => mevalonate-5-pyrophosphate Mevalonate-5-pyrophosphate decarboxylase Diphosphomevalonate decarboxylase (EC 4.1.1.33), most commonly referred to in scientific literature as mevalonate diphosphate decarboxylase. mevalonate-5-pyrophosphate => isopentenyl pyrophosphate Isopentenyl pyrophosphate isomerase Isopentenyl pyrophosphate isomerase (EC 5.3.3.2, IPP isomerase), also known as Isopentenyl-diphosphate delta isomerase isopentenyl pyrophosphate => dimethylallyl 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:
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.
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