Biosynthesis of cholesterol: Difference between revisions

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Alexander Berchansky

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 <StructureSection load='' size='350' side='right' scene='HMG-CoA_Reductase/1dq8_starting_scene/1' caption='Crystal Structure of HMG-CoA, (PDB code [[1dq8]])'>
-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.
+Synthesis within the body starts with the mevalonate pathway where two molecules of <scene name='43/430893/Cv/2'>acetyl-CoA</scene> condense to form <scene name='92/929923/Cv/1'>acetoacetyl-CoA</scene>. This is followed by a second condensation between acetyl CoA and acetoacetyl-CoA to form <scene name='92/929923/Cv/2'>3-hydroxy-3-methylglutaryl CoA (HMG-CoA)</scene>. This molecule is then reduced to <scene name='92/929923/Cv/3'>mevalonate</scene> 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'''
-''Step 1 Acetoacetyl-CoA thiolase''
+''Acetoacetyl-CoA thiolase''
 *[[Acetoacetyl-CoA thiolase]]
+<scene name='43/430893/Cv/2'>acetyl-CoA</scene> => <scene name='92/929923/Cv/1'>acetoacetyl-CoA</scene>.
-''Step 2 hydroxymethylglutaryl-CoA synthase or HMG-CoA synthase; EC 2.3.3.10''
+''Hydroxymethylglutaryl-CoA synthase or HMG-CoA synthase; EC 2.3.3.10''
 *[[1xpk]]
+<scene name='43/430893/Cv/2'>Acetyl-CoA</scene> + <scene name='92/929923/Cv/1'>acetoacetyl-CoA</scene> => <scene name='92/929923/Cv/2'>3-hydroxy-3-methylglutaryl CoA (HMG-CoA)</scene>.
+''HMG-CoA Reductase''
+*[[HMG-CoA Reductase]]
+<scene name='92/929923/Cv/2'>3-hydroxy-3-methylglutaryl CoA (HMG-CoA)</scene> => <scene name='92/929923/Cv/3'>mevalonate</scene>
+The HMG binding pocket is the site of catalysis in HMGR. <scene name='HMG-CoA_Reductase/1dqa_cis_loop2/2'> The “cis-loop” that bends over the top of HMG </scene> ([[1dqa]]) is a critical structural element of this binding site. Residues <scene name='HMG-CoA_Reductase/1dqa_e_and_d/2'>E559 and D767</scene> and are positioned in the active site as is <scene name='HMG-CoA_Reductase/1dqa_k691/2'>K691 which is only 2.7 angstroms from the HMG O2 carbonyl oxygen</scene>. 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 <scene name='HMG-CoA_Reductase/1dqa_h866/2'>H866, which is within hydrogen bonding distance of the thiol group</scene>.  It is then believed that the close proximity of <scene name='HMG-CoA_Reductase/1dqa_e_and_d/2'>E559 and D767</scene> increases the pKA of E559, allowing it to be a proton donor for the reduction of mevaldehyde into mevalonate.
+''Mevalonate kinase''
+*[[Mevalonate kinase]]
+<scene name='92/929923/Cv/3'>mevalonate</scene> => <scene name='92/929923/Cv/6'>mevalonate-5-phosphate</scene>
+The 3D structure of MK complex with mevalonate shows the enzyme composed of <scene name='86/864102/Cv/2'>2 domains</scene>: The N-terminal and the C-terminal. The mevalonate binds in a <scene name='86/864102/Cv/7'>deep cleft</scene> between the 2 domains forming <scene name='86/864102/Cv/6'>H-bonds and hydrophobic interactions</scene><ref>PMID:17397541</ref>. Water molecules are shown as red spheres.
+''Phosphomevalonate kinase''
+*The Crystal Structure of Human Phosphomavelonate Kinase At 1.8 A Resolution [[3ch4]]
+<scene name='92/929923/Cv/6'>mevalonate-5-phosphate</scene> => <scene name='92/929923/Cv/7'>mevalonate-5-pyrophosphate</scene>
+''Mevalonate-5-pyrophosphate decarboxylase''
+Diphosphomevalonate decarboxylase (EC 4.1.1.33), most commonly referred to in scientific literature as mevalonate diphosphate decarboxylase.
+*[[Sandbox Reserved 333|Mevalonate Diphosphate Decarboxylase]]
+<scene name='92/929923/Cv/7'>mevalonate-5-pyrophosphate</scene> => <scene name='92/929923/Cv/8'>isopentenyl pyrophosphate</scene>
+''Isopentenyl pyrophosphate isomerase''
+Isopentenyl pyrophosphate isomerase (EC 5.3.3.2, IPP isomerase), also known as Isopentenyl-diphosphate delta isomerase
+*[[Isopentenyl-diphosphate delta-isomerase]]
+<scene name='92/929923/Cv/8'>isopentenyl pyrophosphate</scene> => <scene name='92/929923/Cv/9'>dimethylallyl pyrophosphate</scene>
+'''Next steps of Cholesterol Biosynthesis'''
+''Geranyl transferase''
+Three molecules of <scene name='92/929923/Cv/8'>isopentenyl pyrophosphate</scene> condense to form <scene name='92/929923/Cv/10'>farnesyl pyrophosphate</scene> 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 <scene name='92/929923/Cv/10'>farnesyl pyrophosphate</scene> then condense to form <scene name='92/929923/Cv/11'>squalene</scene> 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, <scene name='92/929923/Cv/5'>lanosterol</scene> is converted to <scene name='92/929923/Cv/4'>cholesterol</scene> via either of two pathways, the Bloch pathway, or the Kandutsch-Russell pathway.
 </StructureSection>
 == References ==
 <references/>