Lovastatin, biosynthesis structure

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... 

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. 

Figure 1 Bulk drugs from natural sources Paclitaxel (antileukemic and antitumor) and lovastatin (inhibitor of cholesterol biosynthesis) are examples of the diverse and complex structures made by plant and microbial cell biosyntheses, respectively. In most instances of such compounds having desirable biological activities, their structural and chiral complexities make chemical synthesis not competitive with isolation from biosynthesis.

Lovastatin, because a part of its structure resembles mevalonate ion, can apparently bind at the active site ot HMGA-CoA-reductase and act as a competitive inhibitor ot this enzyme and thereby reduce cholesterol biosynthesis. 

The interplay of two PKSs is a common theme in fungal polyketide biosynthesis [22]. This strategy allows to expand the structural space covered by such PKSs without further complicating the programmed teamwork of domains within a single iterative PKS. Lovastatin (4) biosynthesis thereby represents an example of convergent PKS interactions, where two independently acting PKSs assemble their products that finally get fused by action of an additional enzyme, in this case the ACP LovD. However, there are also many... 

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