HMGCoA
3-hydroxy-3-methylglutaryl-coenzyme A - pathways
Adapted from figures on page 402 and 405 of Biochemistry of Lipids, Lipoproteins, and Membranes 5th Edition 2008 eds: Vance and Vance
This is the molecular synthesis cascade interrupted by statins, HMG-CoA Reductase inhibitors, which attach to HMG-CoA Reductase and block further synthesis in order to reduce serum cholesterol and reduce atherosclerotic plaque and vascular disease. This stems from observations that red rice yeast reduced cholesterol, and that oxysterol deposits are associated with plaque deposits, inflammation, and infarction (in overfed westerners).
But correlation is not causation. The inflammation may be due to stress and too many calories. The plaque may be the bodie's way of patching over the inflammation. Too many tire patches will render a tire stiff (hypertension), and too many inside patches will plug the pipe they are patching from the inside. But then, reasoning by analogy isn't really reasoning either, is it?
molecule |
made by |
from molecule |
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Acetyl-CoA |
Acetoacetyl-CoA Thiolase |
Acetoacetyl-CoA |
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HMG-CoA |
HMG-CoA Synthase |
Acetyl-CoA |
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Mevalonate |
HMG-CoA Reductase |
HMG-CoA |
statins block this step |
Mevalonate-5-P |
Mevalonate Kinase |
Mevalonate |
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Mevalonate-5-PP |
Phosphomeavalonate Kinase |
Mevalonate-5-P |
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Isopentenyl-PP |
Mevalonate-5-PP Decarboxylase |
Mevalonate-5-PP |
makes Isopentyl adenosome tRNAs |
Dimethylallyl-PP |
Isopentenyl-PP Isomerase |
Isopentenyl-PP |
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Geranyl-PP |
Farnesyl Diphosphate Synthase |
Dimethylallyl-PP |
makes Prenylated proteins, Heme A, Dolichol |
Farnesyl-PP |
Farnesyl Diphosphate Synthase |
Geranyl-PP |
makes Ubiquinone/CoQ10 |
Squalene |
Squalene Synthase |
Farnesyl-PP |
why not block this step instead??? |
Squalene epoxide |
Squalene Epoxidase |
Squalene |
or block this step? |
Lanosterol |
Oxidosqualene Cyclase |
Squalene epoxide |
or block this step? |
Zymosterol |
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Lanosterol |
or block this step? |
postulated alternative pathway 1 |
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Cholest-8(9)-en-3β-ol |
Δ24-reductase |
Zymosterol |
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Lathosterol |
Δ8Δ7-isomerase |
Cholest-8(9)-en-3β-ol |
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7-Dehydrocholesterol |
Lanosterol Oxidase |
Lathosterol |
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Cholesterol |
Δ7-DHC Reductase |
7-Dehydrocholesterol |
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postulated alternative pathway 2 |
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Cholesta-7,24-dien-3β-ol |
Δ8Δ7-isomerase |
Zymosterol |
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7-Dehydrodesmosterol |
Δ5-desaturase |
Cholesta-7,24-dien-3β-ol |
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Desmosterol |
Δ7-reductase |
7-Dehydrodesmosterol |
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Cholesterol |
Desmosterol Δ24-reductase |
Desmosterol |
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Isopentenyl ? |
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adenosine ? |
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tRNAs ? |
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