Biosynthesis polyketides

Nature gives us some illustrative examples of iterative methodologies in its biochemical mechanisms. The fatty acid-polyketide biosynthesis is one of them. The assembly of acyl units by sequential Claisen-type condensations to form a polyketide or fatty acid takes place at a multi-enzyme complex, at which the initial molecule is lengthened by one C2-unit per pass of a reaction cycle (Fig. 2). 

Shen, B. (2003) Polyketide biosynthesis beyond the type I, II and III polyketide synthase paradigms. Current Opinion in Chemical Biology, 7, 285. 

Staunton, J. and Weissman, K.J. (2001) Polyketide biosynthesis a millennium review. Natural Product Reports,... 

Donadio, S., Staver, M.J., McAlpine, J.B. et al. (1991) Modular organization of genes required for complex polyketide biosynthesis. Science, 252, 675. 

Novel polyketides could also be generated by blocking certain catalytic domains of PKSs to allow bypass of the early steps in polyketide biosynthesis. In one example, the Cys729 —> Ala... 

Mutka, S.C., Bondi, S.M., Carney, J.R. et al. (2006) Metabolic pathway engineering for complex polyketide biosynthesis in Saccharomyces cerevisiae. FEMS Yeast Research, 6, 4047. 

Leadlay, P.F., Staunton, J., Oliynyk, M. et al. (2001) Engineering of complex polyketide biosynthesis — insights from sequencing of the monensin biosynthetic gene cluster. Journal of Industrial Microbiology Biotechnology, 27 (6), 360-367. 

FUJII, I., Polyketide biosynthesis in filamentous fungi. In Comprehensive Natural Products Chemistry, Vol. 1, Polyketides and Other Secondary Metabolites Including Fatty Acids and Their Derivatives (U. Sankawa ed.), Elsevier, Amersterdam, 1999, pp. 409-441. 

Stachowicz JJ (2001) Ecological perspectives on marine natural product biosynthesis. In McClintock JB, Baker BJ (eds) Marine chemical ecology. CRC, Boca Raton, FL Staunton J, Weissman KJ (2001) Polyketide biosynthesis a millennium review. Nat Prod Rep 18 380 116... 

Ferrer JL, Jez JM, Bowman ME, Dixon RA, Noel JP (1999) Structure of chalcone synthase and the molecular basis of plant polyketide biosynthesis. Nat Struct Biol 6(8) 775-784... 

Of the four major classes of biochemicals (carbohydrates, proteins, nucleic acids and lipids), experiments have shown that the first three classes could have arisen through prebiotic chemistry. Although the biosynthesis of many natural products can be traced back to acetate (e.g. fatty acids, terpenes and polyketide biosynthesis) or amino acids (e.g. alkaloid biosynthesis), there are many whose biosynthetic origins are either obscure or result from a complex combination of pathways (Fig. 2). 

Pederin (147) has been considered to be derived via polyketide biosynthesis, based on the result of feeding experiments with [ l- " C]acetate and [2- C]acetate in Paederus fuscipes (483). 

Shen B, Du L, Sanchez C, Chen M and Edwards DJ (1999) Bleomycin biosynthesis in Streptomyces ver-ticillus ATCC15003 a model of hybrid peptide and polyketide biosynthesis. Bioorg Chem 27, 155-171. 

Abe I (2008) Engineering of plant polyketide biosynthesis. Chem Pharm Bull 56 1505-1514... 

S Donadio, MJ Staver, JB McAlpine, SJ Swanson, L Katz. Modular organization of the genes required for complex polyketide biosynthesis. Science 252 675-679, 1991. 

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.

MJ Bibb, S Biro, H Motamedi, JF Collins, CR Hutchinson. Analysis of the nucleotide sequence of the Streptomyces glaucescens tcml genes provides key information about the enzymology of polyketide biosynthesis. EMBO J 8 2727-2736, 1989. 

This chapter describes the progress toward the one-pot total synthesis of the complex natural products called polyketides, molecules that hold a preeminent position in human medicine. It also details from this perspective the significant insights into polyketide biosynthesis that have been gained by studying the purified proteins in vitro. 

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