|
Size: 5013
Comment:
|
Size: 6078
Comment:
|
| Deletions are marked like this. | Additions are marked like this. |
| Line 9: | Line 9: |
'''In any case''', if what we are attempting to do is limit serum cholesterol, we should be blocking the synthesis of '''squaline''', not mevalonate. If what we are ''actually'' trying to do is lower LDL and VLDL cholesterol particles (which are cholesterol '''containers''', not merely cholesterol), we should inhibit the formation of those containers, while protecting cholesterol in HDL containers. Stopping mevalonate synthesis at the beginning of this tree of molecular synthesis is like reducing traffic accidents by bombing steel mills; without cars there are fewer traffic accidents, without steel there are fewer cars, but there are more direct causes of those accidents than either cars or steel. We know a hell of a lot more about molecular biology than we did in 1971, when Akira Endo began studying Penicillium citrinum and the mevalonate it produced. The statins are poisons used by fungi to defend themselves from other organisms by damagining synthesis of cell walls and cytoskeletons. Which seem to be useful parts of my own body. |
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?
In any case, if what we are attempting to do is limit serum cholesterol, we should be blocking the synthesis of squaline, not mevalonate. If what we are actually trying to do is lower LDL and VLDL cholesterol particles (which are cholesterol containers, not merely cholesterol), we should inhibit the formation of those containers, while protecting cholesterol in HDL containers.
Stopping mevalonate synthesis at the beginning of this tree of molecular synthesis is like reducing traffic accidents by bombing steel mills; without cars there are fewer traffic accidents, without steel there are fewer cars, but there are more direct causes of those accidents than either cars or steel.
We know a hell of a lot more about molecular biology than we did in 1971, when Akira Endo began studying Penicillium citrinum and the mevalonate it produced. The statins are poisons used by fungi to defend themselves from other organisms by damagining synthesis of cell walls and cytoskeletons. Which seem to be useful parts of my own body.
molecule |
made by |
from molecule |
|
|
|||
Acetyl-CoA |
Acetoacetyl-CoA Thiolase |
Acetoacetyl-CoA |
|
HMG-CoA |
HMG-CoA Synthase |
Acetyl-CoA |
|
Mevalonate |
HMG-CoA Reductase |
HMG-CoA |
statins block this step |
Mevalonate-5-P |
Mevalonate Kinase |
Mevalonate |
|
Mevalonate-5-PP |
Phosphomeavalonate Kinase |
Mevalonate-5-P |
|
Isopentenyl-PP |
Mevalonate-5-PP Decarboxylase |
Mevalonate-5-PP |
makes Isopentyl adenosome tRNAs |
Dimethylallyl-PP |
Isopentenyl-PP Isomerase |
Isopentenyl-PP |
|
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 |
|
Lanosterol |
or block this step? |
postulated alternative pathway 1 |
|||
Cholest-8(9)-en-3β-ol |
Δ24-reductase |
Zymosterol |
|
Lathosterol |
Δ8Δ7-isomerase |
Cholest-8(9)-en-3β-ol |
|
7-Dehydrocholesterol |
Lanosterol Oxidase |
Lathosterol |
|
Cholesterol |
Δ7-DHC Reductase |
7-Dehydrocholesterol |
|
postulated alternative pathway 2 |
|||
Cholesta-7,24-dien-3β-ol |
Δ8Δ7-isomerase |
Zymosterol |
|
7-Dehydrodesmosterol |
Δ5-desaturase |
Cholesta-7,24-dien-3β-ol |
|
Desmosterol |
Δ7-reductase |
7-Dehydrodesmosterol |
|
Cholesterol |
Desmosterol Δ24-reductase |
Desmosterol |
|
|
|||
|
|
||
Isopentenyl ? |
|
|
|
adenosine ? |
|
|
|
tRNAs ? |
|
|
|
? |
|
|
|
|
|
||
|
|
||
|
|
||
|
|
|
|
|
|
||
|
|
||
|
|
||
|
|
|
|
|
|
|
|
|
|
|
|
