Polyketides polyketide lactones

Guerriero, A., D Ambrosio, M., Cuomo, V., and Pietra, F., A novel, degraded polyketidic lactone, leptosphaerolide, and its likely diketone precursor, leptosphaerodione. Isolation from cultures of the marine ascomycete Leptosphaeria oraemaris (Linder), Helv. Chim. Acta, 74, 1445, 1991. 

Epothilones A (56) and B (57), 16-membered macrocyclic polyketide lactones, were first isolated from the cellulose-degrading myxobac-terium Sorangium cellulosum by Hoefle, Reichenbach, and coworkers (86) as narrow-... 

Tylosin is a polyketide lactone substituted with three deoxyhexose sugars. It is used as an antimicrobial growth promoter in animals. Acquired resistance has been observed in potentially human pathogenic strains isolated from animals (1). Of further concern is the fact that tylosin confers cross-resistance on erythromycin (2). 

Recently, it has been noticed that natural products with polyketide units can be potent immunosuppressive agents as well as antitumor agents. Two structurally different polyketide lactones, discodermolide and pironetin belong to this group of compounds (Fig. 1). Due to the potential therapeutic applications and the extreme scarcity of discodermolide and pironetin, interest in the chemical synthesis of these two natural products and in their analogues continues unabated. 

Kao, C.M., Luo, G.L., Katz, L. et al. (1995) Engineered biosynthesis of a triketide lactone from an incomplete modular polyketide synthase. Journal of the American Chemical Society, 117, 9105. 

All polyketides use the same general mechanism for chain elongation. Acetyl coenzyme A provides acetate (C2) units, which are condensed by a ketosynthase (KS). This in turn catalyzes condensation of the growing chain onto an acyl carrier protein (ACP), as generalized in Fig. 1.4. Enzymes such as ketoreductase (KR), enoyl reductase (ER), and dehydratase (DH) establish the oxidation state of caibon during translation, imparting structural diversity. Successive translation of each module leads to a chain of the required length that is eventually passed to thioeste-rase (TE), which releases the chain as a free acid or lactone. 

Common substructural motifs in polyketide natural products are six-membered ring lactones, lactols, and tetrahydropyrans. It was recognized by Wuts and co-workers that hydroformylation of readily available homoaUyhc alcohols would provide a direct and efficient entry into these ring systems. Such an approach was employed in a synthesis of Prelog-Djerassi lactone (Scheme 5.11) [13]. 

In 1997 (-)-callystatin A (Fig. 1.2.2), a potent cytotoxic polyketide, was isolated from the marine sponge Callyspongia truncata and structurally elucidated by Ko-bayashi et al. [20] shortly afterward its absolute configuration was confirmed by the same authors by total synthesis [21]. The structure of (-)-callystatin A shows a polypropionate chain and a lactone ring connected to each other by two diene systems separated by two sp carbon atoms (Fig. 1.2.2). Since this arrangement is structurally related to several antitumor antibiotics and due to the fact that only very small amounts can be isolated from natural sources, callistatin A has been... 

Coumarins and isocoumarins appear to be of varied origins. Simple coumarins, such as umbelliferone, are formed by the shikimic acid pathway in which hydroxylation of p-hydroxycinnamic acid occurs. Other coumarins, for example alternariol (690), are derived from a polyketide unit, as are a number of chromanones, chromones, pyranones and isocoumarins (B-78MI22400). The biosynthesis of 5-hydroxy-2-methylchromone has been shown to involve the chromanone (60JCS654). However, isocoumarins are also derived from the mixed acetate-shikimate route, through initial cyclization of the polyketide and subsequent lactonization. 

Chemical study of a marine-derived Penicillium brocae, obtained from a tissue sample of a Fijian Zyzzya sp. sponge, resulted in the isolation and characterization of three novel cytotoxic polyketides, brocaenols A-C 136, 137a, and 137b, possessing an unusual enolized oxepine lactone ring system <2003JOC2014>. 

CM Kao, M McPherson, RN McDaniel, HFu, DE Cane, C Khosla. Gain of function mutagenesis of a modular polyketide synthase II. Engineered biosynthesis of an eight-membered ring tetraketide lactone. J Am Chem Soc 119 11339-11340,... 

The original DEBS 1-TE cell-free system allowed several other features of polyketide chain extension to be examined by using well-known inhibitors of specific enzyme activities. Incubation of DEBS 1 -TE with the serine protease inhibitor phenylmethylsulfonyl fluoride (PMSF) resulted in a significant decrease in biosynthetic activity. This result emphasized the mechanistic similarity between the targeted TE domain and the serine protease enzymes. Addition of the fatty acid inhibitor cerulenin [38] also reduced production of the lactone, consistent with the evolutionary kinship between these two classes of enzymes. Inhibition of DEBS 1+TE by cerulenin was also reported [33],... 

The DEBS 1-TE multienzyme was purified to 90-95% homogeneity and then used in another series of experiments to establish the extent to which alternative starter units could be used by the polyketide synthase [36], Substantial amounts of lactones were obtained in the presence of acetyl-, n-butyryl-, and isobutyryl-CoA, illustrating that the loading didomain exhibits a relaxed specificity for the starter unit (Fig. 10). The utilization of acetyl-CoA and -butyryl-CoA by DEBS 1 + TE was demonstrated in a cell-free system [39], Additionally, in the absence of the reducing cofactor NADPH, cell-free DEBS 1+TE converted... 

Figure 9 Construction of bimodular polyketide synthases, (a) Chromosomal repositioning of the thioesterase domain from the C-terminus of module 6 to the end of module 2 in the erythromycin PKS leads to production of triketide lactones and the disruption of erythromycin biosynthesis, (b) DEBS 1-TE contains a fusion within the ACP domains of modules 2 and 6. In Saccharopolyspora erythraea and Streptomyces coelicolor the construct produced both propionate and acetate-derived lactones, (c) DEBS 1+TE contains a fusion between ACP2 and the thioesterase domain. In S. coelicolor, the protein biosynthesized the same lactones.

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