Inhibition of HMG-CoA reductase

Acetyl-CoA is first transferred through many steps to HMG-CoA, which is then reduced to mevalonate by HMG-CoA reductase  

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. 

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Experiments with fibroblasts in vitro have shown that even a very high concentration of LDL in the culture medium does not achieve more than approximately 85% inhibition of HMG-CoA reductase. Only when mevalonate was also added did the activity of the enzyme fall to very low levels. These results indicate that cells require at least two end products of the pathway to bring about repression. This observation should not be surprising, given the proximity to yet another metabolic crossroad (pathway branch point). 

Lipitor molecule at active site. Source. Istvan ES, Deisenhofer J. Structural mechanism for statin inhibition of HMG—CoA reductase, Science 292 1160 (2001). http //www.fda. gov/medwatch/SAFETY/2004/jul PI/Lipitor PI.pdf [accessed August 20, 2007]. Used with permission.)... 

Inhibition of HMG-CoA reductase. Top The HMG-CoA intermediate that is the immediate precursor of mevalonate, a critical compound in the synthesis of cholesterol. Bottom The structure of lovastatin and its active form, showing the similarity to the normal HMG-CoA intermediate (shaded areas). 

So far, most microorganisms and enzymes derived therefrom have been used in the reduction of a single keto group of p-keto or a-keto compounds [68-71], Recently, Patel et al. [72] have demonstrated the stereoselective reduction of 3,5-dioxo-6-(benzyloxy)hexanoic acid, ethyl ester (41), to (3,S, 5R)-dihydroxy-6-(benzyloxy)hexanoic acid, ethyl ester (42a) (Fig. 14). The compound (42a) is a key chiral intermediate required for the chemical synthesis of [4-[4a,6P(E)]]-6-[4,4-bis(4-fluorophenyl)-3-(l-methyl-lH-tetrazol-5-yl)-l,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one, compound R-( + )-(43), a new anticholesterol drug that acts by inhibition of HMG CoA reductase [73], Among various microbial cultures evaluated for the stereoselective reduction of diketone (41), cell suspensions of Aci-... 

As an example the inhibition of HMG-CoA reductase (HMGR) will be discussed. HMGR is the target for drugs lowering the plasma total and low-density lipoprotein... 

Menon, G.K., Feingold, K.R., Mao-Qiang, M., Schaude, M., and Elias, P.M., Structural basis for the barrier abnormality following inhibition of HMG CoA reductase in murine epidermis, J. Invest. Dermatol., 98, 209, 1992. 

The weight of evidence supports the conclusion that the more expressed inhibition of HMG-CoA reductase by a higher statin blood level reduces the concentrations of other essential products, primarily of isoprenylated proteins and possibly ubiquinone, synthetized downstream from mevalonic acid within the peripheral cells. In parallel, it was also recognized that statins exert pleiotropic effects in various cells far beyond the originally described inhibition of hepatic cholesterol synthesis. All of these effects are considered to be class-specific for the statins. It is important to emphasize that the frequency of untoward side effects observed with the various statins can be related to their potency, the number of metabolic inter-... 

Istvan E. Statin inhibition of HMG-CoA reductase a 3-dimensional view. Atherosclerosis, 2003 (Suppl. 4, Issue 1), 3-8. 

Statins, HMG-CoA reductase inhibitors, form a class of hypolipidaemic drug used to lower cholesterol levels. Inhibition of HMG-CoA reductase stimulates LDL receptors, resulting in an increased clearance of LDL from the bloodstream, with a concomitant decrease in blood cholesterol levels. Drug effect is maximal after four to six weeks of use (see also Section 5.15). 

The first "statin" was discovered by Endo and coworkers at Sankyo in Tokyo in 1976. After testing over 8,000 microbial extracts, they found a compound, named mevastatin (ML-236B) (Figure 9), from Penicillium citrinum which showed specific inhibition of HMG CoA reductase and functioned in vivo, lowering serum cholesterol levels. Further development of mevastatin was curtailed because inhibition of cholesterol biosynthesis was not restricted to the liver. The compound enters the lens and adrenals, where it blocks the essential biosynthesis of cholesterol. The same compound was also isolated by a team at the Beecham Research Laboratories in Brockham Park, Surrey. Whilst screening for antifungal activity, they isolated the compound, which they named compactin, from Pencillium brevicompactum, but apparently failed to recognise it as a potent inhibitor of HMG CoA reductase. 

E.S. Istvan and J. Deisenhofer. 2001. Structural mechanism for statin inhibition of HMG-CoA reductase Science 292 1160-1164. (PubMed)... 

Despite inhibition of HMG-CoA reductase by statins, cells compensate by increasing enzyme expression several fold. However, the total body cholesterol is reduced by 20-40% due to increased expression of LDL-receptors after statin administration this enhances LDL (the major cholesterol carrying lipoprotein) clearance from serum with a net reduction of serum cholesterol (Chapter 20). Individuals who lack functional LDL-receptors (homozygous familial hypercholesterolemia. Chapter 20) do not benefit from statin therapy. However, statin therapy is useful in the treatment of heterozygous familial hypercholesterolemia. Since HMG-CoA reductase plays a pivotal role in the synthesis of many products vital for cellular metabolism, inhibitors of the enzyme may have toxic effects. Monitoring of liver and muscle function may be necessary to detect any toxicity of statin drug therapy. A decreased risk of bone fractures with statin therapy has been observed in subjects age 50 years or older, who are being treated for hypercholesterolemia. The mechanism of action of statins in bone metabolism may involve inhibition of prenylation... 

Among more recent successes of this approach one can mention the discovery of lovastatin, also called mevino-lin (Figure 6.7), which was the basis of a new generation of hypocholesterolemic agents, acting by inhibition of HMG-CoA reductase. 

Two other totally synthetic variants are of interest. Fluvastatin (Lescol) (marketed in 1993) has been shown to lower LDL cholesterol significantly via competitive inhibition of HMG-CoA reductase. Here an indole ring replaces the decalin structure of lovastatin. With the additional phenyl ring it easily supersedes the hydrophobic requirement for the reductase inhibition. The para-fluorine atom undoubtedly enhances potency. Another experimental entry in this effort is RG12561. 

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