【正文】 tal cholesterol (25%) and LDL (35%) in patients taking simvastatin, but more importantly, showed 42% decrease in death rate in this group. This and other impressive results drew other pharmaceutical panies into the statin market. Part of the efforts was directed at manufacturing synthetic statins, and fluvastatin (Sandoz AG, Lescol) was the first fully synthetic statin, followed by atorvastatin (Pfizer), better known by its trade name, Lipitor. This product later became the best selling drug (Kidd 2006).The structures of synthetic statins are dissimilar and quite different from the natural the HMG CoAlike moiety,responsible for HMG CoA reductase inhibition, is mon to both natural and synthetic statins (Manzoni and Rollini 2002). As mentioned before atorvastatin (Lipitor) is the most important synthetic statin,followed by fluvastatin (Lescol), rosuvastatin (Crestor), with a much smaller share of the market。 and pitavastatin that is presently mercialized in some oriental countries.Biosynthesis of lovastatinEarly research on Monascus ruber indicated that monacolin L and J were intermediates in the lovastatin biosynthetic pathway (Endo et al. 1985). It was shown that monacolin L is the first to be synthesized from nine molecules of acetate and is, in turn, converted to monacolin J by hydroxylation. In the hydroxylation reaction, 18O2 was incorporated into monacolin J through the action of a monooxygenase system involving cytochrome P450 present in the cellfree extract of M. ruber (Komagata et al. 1989). Subsequent experiments demonstrated the transformation of monacolin J to lovastatin (Kimura et al. 1990).Research with Aspergillus terreus, using labeled precursors (Chan et al. 1983。 Greenspan and Yudrovitz 1985。 Moore et al. 1985。 Shiao and Don 1987) indicated that the lovastatin biosynthetic pathway also starts from acetate units linked to each other in headtotail fashion to form two polyketide chains (Fig. 2). The methyl group is present in some statins in the side chain or at C6 derives from methionine, and is inserted in the structure before closure of the rings (Shiao and Don 1987). The main chain is then cylized and in some statins esterified by a side chain at C8. The oxygen atoms present in the main chain are inserted later by aerobic oxidation (Alberts et al. 1980。 Greenspan and Yudrovitz 1985。 Moore et al. 1985). Studies carried out in P. citrinum and M. ruber indicated a similar pathway (Endo 1985。 Chakravarti and Sahai1 (2004).Hence, it had been shown that lovastatin was derived from acetate via a polyketide pathway (Moore et al. 1985). Pioneering genetic research by Reeves, McAda, and workers atMDS Panlabs Inc., identified a type I polyketide synthase (PKS) gene essential for lovastatin biosynthesis by A. terreus (Hendrickson et al. 1999). Its product, now called lovastatin nonaketide synthase (LNKS) has been shown (Ma and Tang 2007) to contain seven active sites (in order:KS= ketosynthase。 MAT=malonylCoA:ACP acyltransferase。DH= dehydratase。 MT = methyltransferase。 KR = ketoreductase。 ACP = acyl carrier protein。 CON = condensation domain). Characterization of the LNKS (lovB) gene set the stage for understanding how the carbon skeleton of dihydromonacolin L and lovastatin are assembled. Moreover, since secondary metabolism genes are invariably clustered in microorganisms, this gene also provided a convenient entry into cloning and characterizing the other genes involved in lovastatin synthesis. Using it as a probe, Kennedy et al. (1999) isolated two cosmids, containing the plete lovastatin gene cluster, from a genomic library. They found the presence of 18 genes over 64 kb (Fig. 3). Of these genes, two (lovB and lovF) encoded PKSs. As previously noted, the lovB gene encodes LNKS, while lovF encodes a diketide synthase (DKS). The presence of methyltransferase domains in the LNKS and in the DKS indicated that in both cases the methyl groups are likely to be added (Sadenosylmethionine) while the polyketide is being synthesized. Furthermore, the function of the genes could be largely predicted by sequence parison. Additional understanding of their function was obtained by a lossoffunction mutation strategy, through disruptions of individual genes of the cluster.It is now clear that the lovastatin biosynthesis cluster contains two type I polyketide synthase genes (lovB and lovF). In addition,lovE encodes a transcription factor regulatory protein with the typical binuclear Zn++ finger motif. Its disruption mutants did not produce lovastatin or intermediates, while the overexpression resulted in increased metabolite production. It is assumed that lovE regulates lovastatin production at the transcriptional level. However, there is a second gene (lovH) with a similar structure (Hutchinson et ). It is not obvious how lovastatin biosynthesis uses two regulatory genes, since most other secondary metabolites clusters contain one dedicated regulatory gene (Keller and Hohn 1997). On the other hand, lovA and ORF 17 encode putative cytochrome 450 monooxygenases.Synthesis of the main nonaketidederive skeleton was found to require the LNKS (lovB), plus at least one additional protein (enoyl reductase lovC) that interacts with LNKS, and is necessary for the correct processing of the growing chain, and production of dihydromonacolin L. In the absence of LovC, LNKS forms the conjugated pyrones 3 and 4 as truncated PKS products (Burr et al. 2007).LNKS is a multidomain enzyme that contains seven activities, and functions in a way similar to animal fatty acid synthases (FAS) and bacterial type I PKS,., the ketosynthase (KS) performs decarboxylative claisen condensation for chain elongation (Kennedy et al. 1999)。 the malonylCoA:ACP acyltransferase (MAT) selects and transfers the extender unit in the form of malonic esters, while the acyl carrier protein (ACP) serves as the tether (or bind) fo