Polyketide biosynthesis

Figure 1 Polyketide biosynthesis. Polyketide backbones are formed via condensations from acyl-CoA thioesters of carboxylic acids. The (3-ketone which results from each condensation can undergo a series of reductive steps analogous to fatty acid biosynthesis. However, either none or only some of the reductive activities may occur in a given cycle. This allows PKSs to generate diversity through selection of priming and extender units, variation of the reductive cycle, and stereoselectivity. (ACP, acyl carrier protein AT, acyl transferase KS, ketosynthase DH, dehydratase ER, enoylreductase KR, ketoreductase TE, thioesterase.) The structure depicted in the lower right-hand corner is representative of the possible structural variations that can arise during polyketide biosynthesis.

A final example of metabolic pathway engineering is based on polyketide and nonribosomal peptide biosynthesis. Polyketides and nonribosomal peptides are complex natural products with numerous chiral centers, which are of substantial economic benefit as pharmaceuticals. These natural products function as antibiotics [erythromycin A (65), vancomycin (66)], antifungals (rapamycin, amphotericin B), antiparasitics [avermectin Ala (67)], antitumor agents [epothiolone A (68), calicheamicin yj, and immunosuppressants [FK506 (69), cyclosporin A], Because this exponentially growing and intensely researched field has developed, the reader is directed to review articles for additional details.347-359 Also with the potential economic benefit to develop the next blockbuster pharmaceutical, a number of patents and patent applications have been published.360-366... 

Polyketide Biosynthesis, Polyketide Biosynthesis, Polyketide Biosynthesis, Polyketide Biosynthesis, Polyketides as Drugs... 

Keywords Aliphatic polyketides Biosynthesis Polyketide Synthase Genetic Engineering Erythromycin A Rapamycin. 

Keywords Anthracycline Combinatorial biosynthesis Polyketide Streptomyces... 

P. A. Frey and A. D. Hegeman, Enzymatic Reaction Mechanisms, Oxford University Press, Oxford, 2007. A more basic treatment is in two Oxford Primers by J. Mann, Chemical Aspects of Biosynthesis, OUP, 1994 and by T. Bugg, Introduction to Enzyme and Coenzyme Chemistry, OUP, Oxford, 2004. A more comprehensive treatment is in J. E. McMurry and T. P. Begley, The Organic Chemistry of Biological Pathways, Roberts, 2005. For an introduction to biosynthesis, see F. J. keeper and J. C. Vederas, Biosynthesis Polyketides and Vitamins, Springer, 2000. 

The ansa-chain of the ansamycins streptovaricins (4), rifamycins (263), geldanamycin (4), and herbimycin (32) has been shown to be polyketide in origin, being made up of propionate and acetate units with the 0-methyl groups coming from methionine. The remaining aromatic C N portion of the ansamacroHdes is derived from 3-amino-5-hydroxybenzoic acid (264—266) which is formed via shikimate precursors. Based on the precursors of the rifamycins and streptovaricins isolated from mutant bacteria strains, a detailed scheme for the biosynthesis of most of the ansamacroHdes has been proposed (95,263). 

Role of polyketide synthases in biosynthesis of some heterocycles, in particular macrolides 97CRV2465. 

Cytochrome P450 enzymes have been the subject of a number of recent reviews in which their mechanism and scope of action are covered in much detail [1, 6, 10, 11]. The reader is referred to these articles for a more thorough account of the mechanism and reactivity of cytochrome P450 enzymes, while we present a few representative examples of cytochrome P450-catalyzed epoxidation below. The enzymes we chose are all involved in the biosynthesis of polyketide natural products. Polyketides are a large, structurally diverse family of compounds and have provided a wealth of therapeutically useful drugs and drug leads. 

The acetate labeling results clearly demonstrated a polyketide origin for the naphthoate fragment. This resulted in the hypothesis that the first enzyme-free intermediate in azinomycin biosynthesis would be naphthoate 102, with condensation to fonn a polyketone chain, reduction, cyclization, and dehydration/aromati-... 

It is likely that the biosynthesis of 113 is directed by a hybrid polyketide syn-thase/nonribosomal peptide synthetase enzyme system, as indicated in Figure 11.19. 

The biosynthesis of maduropeptin has not been studied in detail, but an iterative type I polyketide synthase gene predicted to be responsible for forming the enediyne core structure has been identified [188]. 

Sheiko SS, Moller M (2001) Hyperbranched Macromolecules Soft Particles with Adjustable Shape and Capability to Persistent Motion. 212 137-175 Shen B (2000) The Biosynthesis of Aromatic Polyketides. 209 1-51 Shinkai S, see James TD (2002) 218 159-200 Shirakawa E, see Hiyama T (2002) 219 61-85 Shogren-Knaak M, see Imperial B (1999) 202 1-38 Sinou D (1999) Metal Catalysis in Water. 206 41-59... 

The biosynthesis of two major classes of red tide toxins, saxitoxin analogs and brevetoxins, have been studied. It was shown that saxitoxin is biosynthesized from arginine, acetate, and methionine methyl group. Brevetoxins were shown to be unique polyketides, which are probably biosynthesized from dicarboxylic acids. Some details of the biosynthetic mechanism have been elucidated. 

Quinones represent a very large and heterogeneous class of biomolecules. Three major biosynthetic pathways contribute to the formations of various quinones. The aromatic skeletons of quinones can be synthesized by the polyketide pathway and by the shikimate pathway. The isoprenoid pathways are involved in the biosynthesis of the prenyl chain and in the formation of some benzoquinones and naphthoquinones. ... 

Hopwood D.A. and Sherman, D.H., Molecular genetics of polyketides and its comparison with fatty acid biosynthesis, Anna. Rev. Genet., 24, 37, 1990. 

Schneider, G., Enzymes in the biosynthesis of aromatic polyketide antibiotics, Curr. Opin. Struct. Biol., 15, 629, 2005. 

Kim, J.E. et ah. Putative polyketide synthase and laccase for biosynthesis of auro-fusarin in Gibberella zea, Appl. Environ. Microbiol., 71, 1701, 2005. 

A series of hypocholesteremic agents were isolated from Monascus and named monacolin J, K, and L. These polyketides were first isolated from cultures of Penicillium citrinum and they can inhibit specifically the enzyme controlling the rate of cholesterol biosynthesis. They are currently used in China in traditional and modem medicine. 

The late cannabinoid pathway starts with the alkylation of ohvetolic acid (3.2 in Fig. 4) as polyketide by geranyl diphosphate (3.1) as the terpenoid unit. Terpenoids can be found in all organisms, and in plants two terpenoid pathways are known, the so called mevalonate (MEV) and non-mevalonate (DXP) pathway as described by Eisenrich, lichtenthaler and Rohdich [23,24,29,30]. The mevalonate pathway is located in the cytoplasm of the plant cells [30], whereas the DXP pathway as major pathway is located in the plastids of the plant cells [29] and delivers geranyl diphosphate as one important precursor in the biosynthesis. 

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