The Polyketides

Biosynthetic studies using acetate (Ac), propionate (Pr), and butyrate (Bu) revealed the polyketide nature of aurodox which has the composition Pr(Ac)g for the goldinamine skeleton C-7 to C-25 and the composition Bu(Ac) for the C-27 to C-39 carbon chain of goldinonic acid. In contrast to the methyl branch at C-8, those at C-19 and C-21 are methionine-derived as are all remaining methyl groups (52,53). The biogenetic origin of the pyridone moiety is not clear. 

The overall biosynthetic pathway to the tetracychnes has been reviewed (74). Studies (75—78) utilising labeled acetate and malonate and nmr analysis of the isolated oxytetracycline (2), have demonstrated the exclusive malonate origin of the tetracycline carbon skeleton, the carboxamide substituent, and the folding mode of the polyketide chain. Feeding experiments using [1- 02] acetate and analysis of the nmr isotope shift effects, led to the location of... 

It is very likely that a similar Type I polyketide synthase constructs the naphthoate fragment of azinomycin B. This will be a very interesting enzyme to study, since it will need to perform an unprecedented three regioselective reduction reactions, as well as controlling the polyketide chain length and directing its cycliza-tion. 

Three other portions of the molecule which do not fit the polyketide combination pattern (Scheme 7B a,f,n) can be also explained by assuming they are derived from a dicarboxylic acid such as 3-hydroxy-3-methylglutaric acid (Scheme 8b). If that is the case, brevetoxins are a new type of mbced polyketides which are formed by condensation on both ends of dicarboxylic acids (Scheme 8c). In order to prove further the hypothesis, feeding experiments with such putative precursors as succinate, acetoacetate, and propionate are in progress. 

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. ... 

Anthraquinones occur as their oxygenated derivatives, with the substitution pattern reflecting their origins from the polyketide or shikunate pathway [13,18-20]. They are typically rather polar and, in many cases, their polarity is increased by their glycosidation. Although dimeric forms are known, most of the compounds identified are monomeric and have a relatively simple substitution of the central nucleus. Figure... 

The biosynthesis of polyketides (including chain initiation, elongation, and termination processes) is catalyzed by large multi-enzyme complexes called polyketide synthases (PKSs). The polyketides are synthesized from starter units such as acetyl-CoA, propionyl-CoA, and other acyl-CoA units. Extender units such as malonyl-CoA and methylmalonyl-CoA are repetitively added via a decarboxylative process to a growing carbon chain. Ultimately, the polyketide chain is released from the PKS by cleavage of the thioester, usually accompanied by chain cyclization [49]. 

There are at least three types of PKS. Type I PKSs catalyze the biosynthesis of macrolides such as erythromycin and rapamycin. As modular enzymes, they contain separate catalytic modules for each reaction catalyzed sequentially in the polyketide biosynthetic pathway. Type II PKSs have only a few active sites on separate polypeptides, and the active sites are used iteratively, catalyzing the biosynthesis of bacterial aromatic polyketides. Type III are fungal PKSs they are hybrids of type I and type II PKSs [49,50]. 

Ward, S.L., Desai, R.P., Hu, Z. et al. (2007) Precursor-directed biosynthesis of 6-deoxyerythronolide B analogues is improved by removal of the initial catalytic sites of the polyketide synthase. Journal of Industrial Microbiology and Biotechnology, 34, 9-15. 

Ikeda, H., Nonomiya, T., Usami, M. et aL (1999) Organization of the biosynthetic gene cluster for the polyketide anthelmintic macrolide avermectin in Streptomyces avermitilis. Proceedings of the National Academy of Sciences of the United States of America, 96, 9509-9514. 

Figure 12.2 Schematic representation of the CHS and STS reactions. The reaction pathway highlights the initiation, elongation, and termination phases of the polyketide extension reaction.

O HAGAN, D., The Polyketide Metabolites, Horwood, Chichester, United Kingdom, 1991. 

BANGERA, M.G., THOMASHOW, L.S., Identification and characterization of a gene cluster for the synthesis of the polyketide antibiotic 2,4-diacetylphloroglucinol from Pseudomonas fluorescens Q2-87, J. Bacteriol., 1999,181,3155-3163. 

The second largest class of compounds reported from macroalgae is the polyketides, which comprise approximately a quarter of known algal compounds (Blunt et al. 2007). Polyketides are polymers of acetate (C2) and occasionally propionate (C3) and are very similar to fatty acids in their biosynthetic origin. Polyketides can be found in plants, animals, bacteria, and fungi. With a range of activities as broad as their structures, the polyketides are a diverse family of natural products classified based upon the polyketide synthases (PKSs) responsible for their biosynthesis, primarily type I and type II. 

The Polyketide Pathway One metabolic process that has received much attention from natural product chemists is the production of secondary metabolites via polyketide synthase (PKS) enzymes. Polyketide synthases condense small starting... 

C domains can display functions that deviate from typical amide bond formation. Several C domains are postulated to act as ester synthases, catalyzing ester formation instead of amide formation. NRPS modules containing C domains that display this activity are present in the biosynthetic pathways for the kutznerides, cryptophycins, " cereulide, valinomycin, hectochlorin, and beauvericin. Each of these C domains likely utilizes a PCP-bound a-hydroxyl acceptor in the condensation reaction. Another NRPS C domain that catalyzes ester bond formation is involved in the biosynthesis of the polyketide-derived mycotoxins known as the fiimonisins. Du and coworkers have shown that a recombinant PCP-C didomain of an NRPS involved in the biosynthetic pathway of the fnmonisins can catalyze ester bond formation between hydroxyfumonisins and the A-acetylcysteamine thioester of tricarballylic acid, even though PCP-bound tricarballylic acid is not... 

The challenge lay in the stereochemicaUy correct synthesis of the polyketide part of the molecule. Starting from L-serine (89) (Chart 6) by C2-elongation steps, reduction of the obtained keto functions including adequate protection and deprotection, and introduction of the salicylic acid residue the four stereoisomeric 3,5-diols (90) were obtained. Comparison of the H-NMR data with those of anachelin (10) showed that the isomer with 3R,5S,6S) configuration was the correct starting material. 

The framework of coccinelline-type alkaloids may be generated by linear combination of seven acetate units, as illustrated in Scheme 57 (330,336). An intermediate such as 456 would explain the existence of the different ladybug alkaloids. Support for the polyketide origin has been provided by feeding experiments ( " CHjCOONa and CHg COONa) with Coccinella septempunctata (330). 

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