Feedback inhibitor, cholesterol

Squalene Final acyclic intermediate in cholesterol synthesis, acts as feedback inhibitor of cholesterol synthesis... 

HMG-CoA reductase is the rate-determining enzyme of sterol synthesis, and its activity is regulated by competitive inhibition by compounds that bind to the same site as HMG-CoA. It is also regulated by substances that bind to other (allosteric) sites on the enzyme molecule. Inhibitors of this enzyme (e.g., simvastatin) are used as medicines to reduce cholesterol in patients whose cholesterol levels are too high. Through feedback inhibition, cholesterol is a strong inhibitor of the enzyme itself. No fungicides with this mode of action have yet been developed, but the possibility that they will be exists. 

As previously mentioned, the rate-limiting enzyme in the biosynthesis of cholesterol is HMG-CoA reductase. It catalyzes the reduction of 3-hydroxy-3-methyl-glutaryl-coen-zyme A to mevalonic acid (Fig. 11-4). The enzyme is also the point in the sequence where the end product cholesterol acts as its own feedback inhibitor. 7-Oxocholesterol, a nonbioactive steroid, retards the cell growth that cholesterol promotes and strongly inhibits HMG-Co-A reductase activity. The compound thus acts as a false feedback inhibitor. This inhibition is reversible by the addition of either cholesterol or mevalonic acid. 

Many strategies have been followed to control levels of serum cholesterol. A compound that incorporates the carbon skeleton of cholesterol itself, colestolone, is thought to inhibit cholesterol synthesis in a late step in its biosynthesis by acting as a product feedback inhibitor. The synthesis starts with bromination of the allylic C position in cholesterol benzoate 22-1 by means of A-bromosuccinimide (22-2) (Scheme 8.22). Dehydrobromination, for example with collidine, leads to the endocyclic 5,7-diene 22-3. In the presence of strong acid, the bonds migrate to form the transoid... 

In the mitochondrial matrix, acety-CoA molecules are condensed to produce 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). The next step, catalyzed by HMG-CoA reductase, is the major flux-controlling step. HMG-CoA reductase is modulated by both reversible phosphorylation and allosteric factors, and the activity of the enzyme even shows a circadian rhythm. The regulating influences are summarized in Fig. 12-11, but the most germane factor is the level of cholesterol itself, which acts as a negative feedback inhibitor. Therefore, cells respond to a lack of cholesterol both by expressing more LDL receptors and by increasing their own synthesis of cholesterol. 

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