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 . 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 condense to form 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 then condense to form 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.

spinqualitylabelsall models Crystal Structure of HMG-CoA, (PDB code 1dq8) Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image