Lovastatin biosynthetic pathway

Regioselective esterification of the 8-hydroxyl group of accumulated monacolin J, produced using a truncated lovastatin biosynthetic pathway, could provide a viable biocatalytic route to simvastatin. With this aim, Xie and Tang cloned and expressed the acyl transferase LovD from the lovastatin biosynthetic pathway into E. colv, they found... 

LovD acyltransferase from the lovastatin biosynthetic pathway... 

Lewis, K.A., Holstein, S.A., and Hohl, R.J. (2005). Lovastatin alters the isoprenoid biosynthetic pathway in acute myelogenous leukemia cells in vivo. Leuk Res 29 527-533. 

Lovastatin works by inhibiting 3-hydroxy-3-methylglutary 1 coenzyme A (HMG-(3oA) reductase, a key rate-limitingenzyme in the cholesterol biosynthetic pathway. However, the first specific inhibitors of this enzyme were discovered several years earlier by Endo et al. at Sankyo (157). The compounds, which are structurally related to lovastatin, were isolated from Penicillium citrinum and shown to block cholesterol synthesis in rats and lower cholesterol levels in the blood. Development of the most active compound, designated ML-236B (123), is believed to have been curtailed because of toxicity problems (158). 

The reabsorption of bile is impeded by oral administration of positively charged polymers, such as cholestyramine, that bind negatively charged bile salts and are not themselves absorbed. Cholesterol synthesis can be effectively blocked by a class of compounds called statins (e.g., lovastatin, which is also called mevacor Figure 26.22). These compounds are potent competitive inhibitors (AT j < 1 nM) of HMG-CoA reductase, the essential control point in the biosynthetic pathway. Plasma cholesterol levels decrease by 50% in many patients given both lovastatin and inhibitors of bile-salt reabsorption. Lovastatin and other inhibitors of HMG-CoA reductase are widely used to lower the plasma cholesterol level in people who have atherosclerosis, which is the leading cause of death in industrialized societies. 

Statins are the secondary metaboKtes of a number of different filamentous fungi. Their medical importance and commercial value stem from their ability to inhibit the enzyme (3S)-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase. Since this enzyme catalyzes a key step in the endogenous cholesterol biosynthetic pathway, statins have become the widely used an-tihypercholesterolemic drugs. Along with some synthetic statins, the most prominent examples are lovastatin, mainly from Aspergillus terreus, and mevastatin produced by Penicillium citrinum, which was the first statin to be discovered [92, 93]. 

Figure 10.5 Lovastatin biosynthetic pathway. LovB and LovC, a nonaketide synthase and enoyl reductase, respectively, generate the first stable intermediate, dihydromonacolin L. Monacolin L and Monacolin J are recognized pathway intermediates, however enzymes that catalyze these conversions have not been identified. LovF is a diketide synthase generating 2-methylbutyryl-CoA. This molecule is esterified to Monacolin J by LovD, generating Lovastatin.

The discovery of these early statins paved the way for the worldwide development of other drugs based on the statin chemical structure (Figure 8.2). Sankyo and Merck directed their later efforts at manufacturing synthetic analogs. Many different statins are currently available for therapeutic use, but lovastatin and mevastatin remain the only fermentation-derived statins. The lovastatin biosynthetic pathway in A. terreus is well understood. This pathway was the first example of a polyketide synthetic pathway in which two fungal type I polyketide synthases work in combination to produce a product (Hendrickson et al., 1999 Kennedy et al., 1999). Since then several statins, including simvastatin, pravastatin, fluvastatin and atorvastatin, have been approved in many countries and are currently used by millions. 

Lovastatin is a member of a class of drugs (atorvastatin and simvastatin are others in this class) called statins that are used to treat hypercholesterolemia. The statins act as competitive inhibitors of the enzyme HMG-CoA reductase. These molecules mimic the structure of the normal substrate of the enzyme (HMG-CoA) and act as transition state analogues. While the statins are bound to the enzyme, HMG-CoA cannot be converted to mevalonic acid, thus inhibiting the whole cholesterol biosynthetic process. Recent studies indicate that there may be important secondary effects of statin therapy because some of the medical benefits of statins are too rapid to be a result of decreasing atherosclerotic lesions. Statin therapy has been associated with reduced risks of dementia, Alzheimer disease, ischemic cerebral stroke, and other diseases that are not correlated with high cholesterol levels. Although this is still an active area of research, it appears that the pleiotropic effects of statins may be a result of a reduction in the synthesis of isoprenoid intermediates that are formed in the pathway of cholesterol biosynthesis. 

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