In previous postings we learned how cholesterol is made from squalene and squalene is made from the six carbon compound mevalonate [How to Make Cholesterol] [Making Squalene].Today we'll cover the synthesis of melavonate from three molecules of the 2-carbon compound acetate.
When acetate is involved in biosynthesis reactions it is "activated" by forming a thioester linkage to coenzyme A ("thio" means sulfur). Coenzyme A was discovered by Nobel Laureate: Fritz Lipmann.
The first step in the pathway is the joining of two molecules of acetyl CoA to make the 4-carbon compound acetoacetyl CoA. Note that this molecule is still joined to coenzyme A. In the second step, another acetyl group is transferred to acetoacetyl CoA to make the 6-carbon molecule 3-hydroxyl-3-methylglutaryl CoA (HMG CoA). HMG-CoA was Monday's Molecule.
The last step is cleavage of the thioester linkage between the 6-carbon compound and CoA releasing mevalonate.
This last step is catalyzed by an enzyme called HMG-CoA reductase. This is an oxidation-reduction reaction where the reduction of HMG-CoA is coupled to the oxidation of NADPH. This enzyme is regulated inside the cell and this controls the biosynthesis of cholesterol since mevalonate is an essential intermediate in the pathway.
Lipitor® and similar drugs control cholesterol synthesis by inhibiting the enzyme HMG-CoA reductase. If we draw the substrate in a way that shows its structure, you can see that Lipitor® and Mevacor® resemble the business end of the molecule—the part that's cleaved by the enzyme. These drugs are effective inhibitors because they bind to the active site of the enzyme.
The class of HMG-CoA reductase inhibitors is called statins. They are used to control serum cholesterol levels in the hopes of reducing the risks of coronary heart disease. There don't seem to be any serious side effects to inhibiting mevalonate production in spite of the fact that mevalonate is required for synthesis of some hormones and of the essential cofactor ubiquinone [Ubiquinone and the Proton Pump].
I see in that Wikipedia article though that there's some thought that the rare but serious side effect of rhabdomyolysis might be associated with the reduction in ubiquinone levels and that attempts have been made to treat it with ubiquinone supplementation. (I take a bit of an interest in this stuff since I've been on pravastatin for some years now, though I've thankfully been free of any muscle-related side effects. Pravastatin is one of the least effective statins- though it works well enough for my mildly elevated cholesterol- but also has the lowest incidence of side effects, because it's less lipid-soluble and consequently is cleared from the body faster than other statins.)
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ReplyDeleteSome people said that lipitor causes Osteoporosis, is that true ?
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