Biosynthesis of cholesterol

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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.
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Acetyl-CoA is coming from [[Citric Acid Cycle]].
 
'''Mevalonate pathway'''
'''Mevalonate pathway'''
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*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]]
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<scene name='92/929923/Cv/7'>Mevalonate-5-pyrophosphate</scene>
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<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]]
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<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]]
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<scene name='92/929923/Cv/8'>isopentenyl pyrophosphate</scene> => <scene name='92/929923/Cv/9'>dimethylallyl pyrophosphate</scene>
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Mevalonate is finally converted to isopentenyl pyrophosphate.
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'''Next steps of Cholesterol Biosynthesis'''
'''Next steps of Cholesterol Biosynthesis'''
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''Geranyl transferase''
''Geranyl transferase''
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Three molecules of isopentenyl pyrophosphate condense to form farnesyl pyrophosphate through the action of geranyl transferase. Other names in common use include:
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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''
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Two molecules of farnesyl pyrophosphate then condense to form squalene by the action of squalene synthase in the endoplasmic reticulum.
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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]]

Current revision

Crystal Structure of HMG-CoA, (PDB code 1dq8)

Drag the structure with the mouse to rotate

References

  1. ↑ Sgraja T, Smith TK, Hunter WN. Structure, substrate recognition and reactivity of Leishmania major mevalonate kinase. BMC Struct Biol. 2007 Mar 30;7:20. PMID:17397541 doi:10.1186/1472-6807-7-20

Proteopedia Page Contributors and Editors (what is this?)

Alexander Berchansky

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