Mevalonate inhibition

The statins lower cholesterol by inhibiting the en zyme 3 hydroxy 3 methylglutaryl coenzyme A reduc tase which is required for the biosynthesis of meva Ionic acid (see Section 26 10) Mevalonic acid is an obligatory precursor to cholesterol so less mevalonic acid translates into less cholesterol... 

Since GAs as diterpenes share many intermediates in the biosynthetic steps leading to other terpenoids, eg, cytokinins, ABA, sterols, and carotenoids, inhibitors of the mevalonate (MVA) pathway of terpene synthesis also inhibit GA synthesis (57). Biosynthesis of GAs progresses in three stages, ie, formation of / Akaurene from MVA, oxidation of /-kaurene to GA 2" hyde, and further oxidation of the GA22-aldehyde to form the different GAs more than 70 different GAs have been identified. 

The antiinflammatory effects of statins likely result from their ability to inhibit the formation of mevalonic acid. Downstream products of this molecule include not only the end product, cholesterol, but also several isoprenoid intermediates that covalently modify ( pre-nylate ) certain key intracellular signaling molecules. Statin treatment reduces leukocyte adhesion, accumulation of macrophages, MMPs, tissue factor, and other proinflammatory mediators. By acting on the MHC class II transactivator (CIITA), statins also interfere with antigen presentation and subsequent T-cell activation. Statin treatment can also limit platelet activation in some assays as well. All these results support the concept that in addition to their favorable effect on the lipid profile, statins can also exert an array of antiinflammatory and immunomodulatory actions. 

Statins lower plasma cholesterol levels by inhibiting HMG-CoA reductase in the mevalonate pathway (Fig. 4). Some research has shown that certain statins (but not all) stimulate BMP-2 expression in osteoblasts, increase bone formation and mimic N-BP in that they inhibit bone resorption. The use of statins in osteoporosis is presently being investigated. 

Figure 26-1. Biosynthesis of mevalonate. HMG-CoA reductase is inhibited by atorvastatin, pravastatin, and simvastatin. The open and solid circles indicate the fate of each of the carbons in the acetyl moiety ofacetyl-CoA.

Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, interrupting the conversion of HMG-CoA to mevalonate, the rate-limiting step in de novo cholesterol biosynthesis. Reduced synthesis of LDL and enhanced catabohsm of LDL mediated through LDL-Rs appear to be the principal mechanisms for lipid-lowering effects. 

ZEIDLER, J., SCHWENDER, J., MULLER, C WIESNER, J., WEIDEMEYER, C., BECK, E., JOMAA, H., LICHTENTHALER, H.K., Inhibition of the non-mevalonate 1-deoxy-D-xylulose 5-phosphate pathway of plant isoprenoid biosynthesis by fosmidomycin, Z. Naturforsch., 1998,53c, 980-986. 

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). 

The therapeutic class that uniquely exemplifies lactone prodrugs are the statins, i.e., the cholesterol-lowering agents that act by inhibiting 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase (EC 1.1.1.34). This microsomal enzyme catalyzes conversion of HMG-CoA to mevalonate, an important rate-limiting step in cholesterol biosynthesis. Cholesterol synthesis occurs mainly... 

Warfarin CoA to mevalonic acid for the synthesis of cholesterol Anticoagulant Inhibits synthesis of clotting factors II (prothrombin), VII, IX,... 

Hydroxy-3-methylglutaryl (HMG)-CoA reductase on the smooth endoplasmic reticulum (SER) is the rate-limiting enzyme. Insulin acth"ates the enzyme (dephosphorylation), and glucagon inhibits it. Mevalonate is the product, and the statin drugs competitively inhibit the enzyme. Cholesterol represses the expression o the HMG-CoA reductase gene and also increases degradation of the enzyme. 

Ethylphenoxy)triethylamine and 2-(3,4-dimethoxyphenoxy)triethylamine markedly reduce the biosynthesis of limonoids in citrus leaves, presumably by inhibition of cyclase activity. Radio-tracer studies have revealed that limonoids are synthesized in the leaves of citrus and transported to the fruit. The fruit tissue does not appear to be capable of the de novo synthesis of limonoids from acetate or mevalonate. 

HMG-CoA Reductase Inhibitors Statins inhibit HMG-CoA reductase, the enzyme synthesizing mevalonic acid (a key step in cholesterol biosynthesis). These drugs are indicated to treat hypercholesterolemia and to reduce LDL cholesterol. 

Mechanism of Action An antihyperlipidemicthat interferes with cholesterol biosynthesis by inhibiting the conversion of the enzyme hydroxymethylglutaryl-CoA (HMG-CoA) to mevalonate, a precursor to cholesterol. Therapeutic Effect Decreases LDL cholesterol, VLDL, and plasma triglyceride levels, increases HDL concentration. Pharmacokinetics Protein binding 88%. Minimal hepatic metabolism. Primarily eliminated in the feces. Half-life 19 hr (increased in patients with severe renal dysfunction). 

Mo, H., and Elson, C.E., Studies of the isoprenoid-mediated inhibition of mevalonate synthesis applied to cancer chemotherapy and chemoprevention, Exp. Biol Med. (Maywood), 229, 567, 2004. 

In contrast to these results, 25-hydroxycholesterol (and also, 20-hy-droxycholesterol, 7-ketocholesterol, and diosgenin) in aortic, smooth-muscle cells effectively blocks the incorporation of acetate into lipid-linked oligosaccharides (and, also, into cholesterol7). Thus, less of the lipid-linked oligosaccharides were available for glycosylation of proteins. In harmony with the presumed, inhibitory mechanism was the observation that incorporation of mevalonate into lipid-linked oligosaccharides was not inhibited, and that mevalonate itself (the product formed by HMG-CoA reductase from HMG-CoA and NADPH) could reverse the inhibition of glycosylation of protein (see Scheme 1). 

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). 

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