Polyketides lovastatin

It was proposed that a Diels-Alder cyclization occurred during a polyketide synthase assembly of the bicyclic core of Lovastatin by Aspergillus terreus MF 4845." In vitro Diels-Alder cyclization of the corresponding model compounds generated two analogous diastere-omers in each case, under either thermal or Lewis-acid-catalyzed conditions (Eq. 12.37). As expected, the Diels-Alder reaction occurred faster in aqueous media. The cyclization half-life in chloroform at room temperature is 10 days while in aqueous media at either pH 5 or 7, the half-life drops to two days. 

Additionally, the study demonstrated that there are fatty acid metabolism genes that were positively associated with lovastatin production and tended to encode catabolic enzymes that are predicted to promote formation of the polyketide precursors acetyl-CoA and malonyl-CoA, whereas fatty acid metabolism genes that are negatively associated with secondary metabolite production encode anabolic enzymes, i.e., acyl-CoA oxidase, fatty acid desaturase, and fatty acid synthases. 

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. 

Lovastatin and mevastatin are synthesized via polyketide pathways. Polyketides are a large group of structurally diverse secondary metabolites produced by bacteria, fungi, and plants. The factors influencing production of lovastatin or mevastatin have not been fuUy elucidated. Studies of Aspergillus terreus grown in chemically defined media indicate that... 

Squalestatin SI 29 is a potent inhibitor of mammalian squalene synthase. It is produced by Phoma species, and like lovastatin, consists of two polyketide chains a main chain hexaketide and a sidechain tetraketide. Like lovastatin, both chains are methylated, but unusually for a fungal HR polyketide, the main chain is formed from a non-acetate starter unit— benzoate is incorporated at this position. 

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. 

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... 

An additional problem is that polyketide formation requires acetyl-CoA, malonyl-CoA, and NADPH generated by primary metabolic pathways. These precursors and the cofactor are also used for fatty acid biosynthesis. An inverse relationship between the synthesis of fatty acids and polyketide compounds has been found in the mevinolin (lovastatin)-producing species ot Aspergillus (Dutton, 1988 Greenspan and Yudkovitz, 1985). Thus, any regulatory factor that substantially alters the rate or extent of formation of these precursors and cofactor may affect polyketide formation. 

Initially identified from Monascus spp., monacolin K (C24H36O5) is a polyketide, which is structurally identical to lovastatin (Endo, 1979, 1980). In addition to monacolin K, there are several other minor monacolins (Ma et al., 2000). At least six structurally related monacolins have been identified from the genus Monascus, namely monacolin J, K, L, and X, dihydromonacolin K, and dihydromonacolin L (Endo et al., 1985a,b). 

Hendrickson, L., Davis, C. R., Roach, C. D., Nguyen, K., Aldrich McAda, T. P. C., and Reeves, C. D. 1999. Lovastatin biosynthesis in Aspergillus terreus Characterization of blocked mutants, enzyme activities and a multifunctional polyketide synthase gene. Chem. Biol. 6, 429-439. 

A number of total syntheses of decalin polyketides have been reported, supporting the feasibility of biosynthetic cycloadditions. Actual involvement of PKS (lovastatin PKS and chlorothricin PKS) and PKS-NRPS (cheaoglobosin PKS-NRPS and equisetin PKS-NRPS) as Diels-Alderases is discussed in Section 8.08.4. Intramolecular Diels-Alder reaction could occur either during or after chain elongation of polyketide chain. 

Other medically important polyketides include the antibiotics doxorubicin (14-hydroxydaunomycin Fig. 5-23), rifamycin (Box 28-and the antifimgal pimaricin, griseofulvin, and amphotericin (Fig. 21-10), the HMG-CoA reductase inhibitor lovastatin, the 2-butanyl-4-methylthreonine of cyclosporin A (Box 9-F), and other immunosuppressants such as rapamycin. Many characteristic plant products, including stilbenes and chalcones (Box 21-E), are polyketides. A variety of different polyketides serve as phytoalexins. Some such as aflatoxin are dangerous toxins. Ants and ladybird beetles make toxic polyamine alkaloids using a polyketide pathway. ... 

Lovastatin is an inhibitor of the enzyme (35)-hydrooxymethylglutaryl-CoA (HMG-CoA) reductase tliat catalyzes the reduction of HMG-CoA to mevalonate, a key step in cholesterol biosynthesis. Tliis activity confers on lovastatin its medically important anti-hyperchoilesterolemic activity and other potentially important uses. It is a secondary metabolite from the filamentous fungus Aspergillus terreus and has been shown to be derived from acetate via a polyketide pathway. 

Tlie sequential reactions in elongating acyl transfers in the synthesis of polyketide natural products and non-ribosomal peptide antibiotics such as erythromycin, rapamycin, epotliilone, lovastatin, penicillins, cyclosporin and vancomycin resemble molecular solid-state assembly lines. Such multimodular enzymes may be utilized in combinatorial biosynthesis by way of reprogramming for the manufacture of unnaUiral analogs of natural products. 

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