Biosynthesis of cholesterol: Difference between revisions
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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]])'> | <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 <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. | 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. | ||
'''Mevalonate pathway''' | '''Mevalonate pathway''' | ||
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<scene name='92/929923/Cv/2'>3-hydroxy-3-methylglutaryl CoA (HMG-CoA)</scene> => <scene name='92/929923/Cv/3'>mevalonate</scene> | <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 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'' | ||
*[[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'' | ''Phosphomevalonate kinase'' | ||
*The Crystal Structure of Human Phosphomavelonate Kinase At 1.8 A Resolution [[3ch4]] | *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'' | ''Mevalonate-5-pyrophosphate decarboxylase'' | ||
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*[[Sandbox Reserved 333|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'' | ||
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*[[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''' | '''Next steps of Cholesterol Biosynthesis''' | ||
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''Geranyl transferase'' | ''Geranyl transferase'' | ||
Three molecules of isopentenyl pyrophosphate condense to form farnesyl pyrophosphate through the action of geranyl transferase. Other names in common use include: | 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 | *farnesyl-diphosphate synthase | ||
*geranyl transferase I | *geranyl transferase I | ||
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''Squalene synthase'' | ''Squalene synthase'' | ||
Two molecules of farnesyl pyrophosphate then condense to form squalene by the action of squalene synthase in the endoplasmic reticulum. | 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]] | *[[Squalene synthase]] | ||