Lovastatin, biosynthesis

Inhibit Enzymes Many drugs are competitive inhibitors of key enzymes in pathways. The statin drugs (lovastatin, simvastatin), used to control blood cholesterol levels, competitively inhibit 3-hvdroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase in cholesterol biosynthesis. Methotrexate, an antineoplastic drug, competitively inhibits dihydrofolate reductase, depriving the cell of active folate needed for purine and deoxythymidine synthesis, thus interfering with DNA replication during S phase. 

The most important class of cholesterol-lowering agents is the statins. These include lovastatin (Mevacor), simvastatin (Zocor), pravastatin (Pravachol), and atorvastatin (Lipitor), among others. These molecules work, in modest part, by inhibiting biosynthesis of cholesterol and, in larger part, by increasing the rate at which cholesterol is eliminated by the body. Let s have a look at this in more detail. 

After screening 8000 microorganisms, three novel inhibitors of HMG-CoA reductases were found at Sankyo (Tokyo, Japan), Mevastatin among them. The open form inhibits HMG-CoA reductase with a K value of 1 nM and influences dramatically the biosynthesis of cholesterol, just like the later developed analogs Lovastatin and Simvastatin (Figure 13.15, below). 

One class of antihyperlipidemic drugs is the statins. Statins interfere with the biosynthesis of cholesterol (A.103) and specifically inhibit the enzyme 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase (Scheme A.l). The statins that have been approved by the FDA include lovastatin (Mevacor, A.104), simvastatin (Zocor, A.105), pravastatin (Prava-chol, A.106), atorvastatin (Lipitor, A.107), rosuvastatin (Crestor, A.108), and fluvastatin (Lescol, A.109) (Figure A.29). All six compounds are drawn here to highlight the similarities between HMG-CoA (A.99) and mevalonic acid (A.100), and the top portion of the various statins. As a class, the statins have been extremely successful in terms of sales and effective in decreasing LDL cholesterol levels in the blood. 

HMG CoA reductase can be inhibited therapeutically by administering the drug lovastatin, based on the fungal products mevinolin and compactin, which competitively inhibit the enzyme and hence decrease the rate of cholesterol biosynthesis. Therefore, these compounds are routinely used for the treatment of hypercholesterolemia (high levels of blood cholesterol) (see Topic K6). 

Pravastatin (10) is another HMG-CoA reductase for the inhibition of cholesterol biosynthesis it is marketed by Sanyo and Bristol Myers Squibb under the trade names Mevalotin and Pravachol.87 It has a close structural relationship to lovastatin and simvastatin. It is produced by a two-step sequence. First, mevastatin (11), also known as ML-236B or compactin, is prepared by fermentation of Penicillium citrinum ss it is then enzymatically hydroxylated to produce 11 (Scheme 31.7).88-101... 

It is clear from Equation (19.4) that saturated fat, not cholesterol, is the single most important factor that raises serum cholesterol. Some cases of hyperlipoproteinemia type IV (high VLDL) respond to low-carbohydrate diets, because the excess of VLDL comes from intestinal cells, where it is produced from dietary carbohydrate. Resins, such as cholestyramine and cholestipol, bind and cause the excretion of bile salts, forcing the organism to use more cholesterol. Lovastatin decreases endogenous cholesterol biosynthesis (see later), and niacin (nicotinic acid) apparently decreases the production of VLDL and, consequently, LDL. It also results in an HDL increase. Antioxidants that inhibit the conversion of LDL to oxidized LDL have also been used with some success. These are high doses of vitamin E and the drug probucol. 

Uncovering the biochemical principles governing these mechanisms is therefore important for the rational biosynthesis of lovastatin and other fungal polyketides. It will also allow the enzymatic components of iterative PKSs to be used as tools in the combinatorial biosynthesis of entirely new polyketide scaffolds. 

Hajjaj, H., Niederberger, P., and Duboc, P. (2001). Lovastatin biosynthesis by Aspergillus terreus in a chemically defined medium. Appl Environ Microb 67 2596-2602. 

Sebti, S.M., Tkalcevic, G.T., and Jani, J.P. (1991). Lovastatin, a cholesterol biosynthesis inhibitor, inhibits the growth of human H-ras oncogene transformed cells in nude mice. Cancer Commun 3 141-147. 

Kennedy J, Auclair K, Kendrew SG, Park C, Vederas JC, Hutchinson CR. Modulation of polyketide synthase activity by accessory proteins during lovastatin biosynthesis. Science 1999 284 1368-1372. 

Xie X, Watanabe K, Wojcicki WA, Wang CCC, Tang Y. Biosynthesis of lovastatin analogues with a broadly specific acyl transferase. Chem. Biol. 2006 13 1161-1169. 

Although some Diels-Alder type natural products are isolated as a racemate through non-enzymatic process, an enzymatic reaction would be certainly involved in the case of chiral cycloadduct derived from an achiral precursor. Even in the cases of chiral precursors, enzymatic Diels-Alder reaction was shown in the biosynthesis of lovastatin, cholesterol-lowering drug (Section 6). 

The fungal metabolite lovastatin (128) and the related natural products have been used as cholesterol-lowering drugs which inhibit the activity of the enzyme (3S)-hydroxy-3-methylglutaryl-coenzyme A reductase, Fig. 34. Extensive studies on the biosynthesis of 128 in Aspergillus terreus indicate that it is formed through dihydromonaco-lin (127) in the polyketide pathway, in which includes an enzymatic... 

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