Complex polyketides

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

Figure 12.1 The biosynthesis of 6dEB catalyzed by DEBS [58]. (From B.A. Pfeifer, S.J. Admiraal, H. Gramajo et al. Biosynthesis of complex polyketides in a metabolically engineered strain of E. coli. Science 291 1790-1792. Washington, DC AAAS. 2001 AAAS. Reprinted with permission from AAAS.)...

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. 

The use of crotylsilanes instead of allylsilanes in both the alkene and alkyne tandem reactions allows the creation of a third and a second stereocenter respectively (Scheme 5.25) [39]. These reactions allow extremely rapid and efficient access to stereochemi-cally complex polyketide chains, as demonstrated by the five-step conversion of alcohol 65 to triol 66 in 31% overall yield. The conversion of 67 to both 68 and 69 establishes the scope of this chemistry to allow access to different structural and stereochemical motifs. 

Few examples have been reported of the preparation of oligomers by C-C bond formation. Reggelin described a synthetic protocol that enables the sequential stereo-controlled assembly of polyketides on cross-linked polystyrene (Figure 16.29 see also [273]). Flowever, this strategy involves many steps and only short polyketides have so far been prepared. Shorter and more efficient synthetic protocols will probably have to be developed to give access to larger and structurally more complex polyketides. 

Many of the unusual compounds that indicate the exciting chemistry to be discovered in marine natural products are polyketides. Polyketides are a family of structurally complex natural products that include a number of important pharmaceuticals. They are produced primarily by microorganisms through a specialized metabolism that is a variation of fatty acid biosynthesis [430]. Polyketides fall into two structural classes aromatic and complex. Polyketides are formed by enzyme complexes... 

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. 

Like the related fatty acid synthases (FASs), polyketide synthases (PKSs) are multifunctional enzymes that catalyze the decarboxylative (Claisen) condensation of simple carboxylic acids, activated as their coenzyme A (CoA) thioesters. While FASs typically use acetyl-CoA as the starter unit and malonyl-CoA as the extender unit, PKSs often employ acetyl- or propionyl-CoA to initiate biosynthesis, and malonyl-, methylmalonyl-, and occasionally ethylmalonyl-CoA or pro-pylmalonyl-CoA as a source of chain-extension units. After each condensation, FASs catalyze the full reduction of the P-ketothioester to a methylene by way of ketoreduction, dehydration, and enoyl reduction (Fig. 3). In contrast, PKSs shortcut the FAS pathway in one of two ways (Fig. 4). The aromatic PKSs (Fig. 4a) leave the P-keto groups substantially intact to produce aromatic products, while the modular PKSs (Fig. 4b) catalyze a variable extent of reduction to yield the so-called complex polyketides. In the latter case, reduction may not occur, or there may be formation of a P-hydroxy, double-bond, or fully saturated methylene additionally, the outcome may vary between different cycles of chain extension (Fig. 4b). This inherent variability in keto reduction, the greater variety of... 

Figure 4 (a) The aromatic polyketide biosynthetic cycle (ACP, acyl carrier protein KS, P-ketoacyl synthase KR, P-ketoacyl reductase DH, dehydratase ER, enoyl reductase), (b) The complex polyketide biosynthetic cycle. 

Purified DEBS 1-TE has also been used to investigate another interesting aspect of polyketide biosynthesis the control of stereochemistry. As noted by W. D. Celmer in 1965, the macrolide polyketides (the class of complex polyketide to which erythromycin belongs) have the same absolute configuration at all comparable stereocenters (Fig. 12) [40,41], These homologies suggest that there exists... 

Figure 12 Stereochemical model for the complex polyketides. This figure shows the Celmer model for the structure and stereochemistry of the macrolides and its comparison to actual polyketide structures.

To the extent that they are covalently linked, the complex polyketide synthases are less reliant on association for function. In most systems, however, transient docking between multienzymes is required. Recently, it has been demonstrated that the regions of sequence upstream from N-terminal modules and downstream from C-terminal modules (referred to as interpolypeptide linkers) play a crucial role in the assembly of functional modules in vivo [78]. Clearly, the presence of such linkers will also be important for productive biosynthesis in vitro using multiprotein systems. 

J Staunton. Combinatorial biosynthesis of erythromycin and complex polyketides. Curr Opin Chem Biol 2 339-345, 1998. 

Donadio S, Staver MJ, McAlpine JB, Swanson SJ, Katz L (1991) Modular Organization of Genes Required for Complex Polyketide Biosynthesis. Science 252 675... 

Gene clusters (or parts thereof) controlling the biosynthesis of several other complex polyketides, including avermectin [25],rapamycin [26], oleandomycin [164], and soraphen [165], have been isolated and sequenced. In aU cases, the PKSs have been found to be organized into individual modules with each module containing the appropriate sets of active sites. Thus, the modular hypothesis appears to be well-substantiated now in several model systems. Intriguingly, in the case of rapamycin, biosynthesis of the entire macrocycle involves activity of a 12-module PKS as well as a peptide synthetase module (see below). 

Structurally diverse compounds like the undecapeptide cyclosporin A and the complex polyketide FK506 bind similar biological target molecules, the immuno-philins, and interfere with identical T cell signaling pathways. 

There is no major distinction between the avermectins and milbemycins, which are based on the same complex polyketide macrocycle (168) the avermectins are oxygenated at C-13 and bear a disaccharide on this oxygen. They have been isolated from cultures of a... 

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