Biosynthesis of Polyketides

Detailed descriptions of the historical development of this biosynthetic route and experimental evidence supporting some of its basic features have been provided in several reviews and books. In addition, an excellent new text, which provides a record of achievement in this area, has been published recently. The present Report describes the results of biosynthetic investigations published during the period Jan 1971—Dec 1972.For convenience, the aromatic 

Exciting progress - has been made in the enzymology of systems which elaborate phenolic compounds by the acetate-poly maionate pathway. The purification and properties of 6-MSA (6-methylsalicylic acid) (4) synthetase were reported in 1970 and recent work has provided further information on this enzymic system. Thus it has been reported that an ammonium sulphate protein fraction from P. patulum catalyses the synthesis of 6-MSA, TAL (triacetic acid lactone) (2), and fatty acids in the presence of malonyl-coenzyme A and NADPH. The derivation of 6-MSA from one acetate and three maionate 

Further investigations on the enzymology of conversion of 6-MSA (4) into patulin (10) are described in a recent report which records the isolation and 

The bacterial biosynthesis of 6-methylsalicylic acid (6-MSA) (4) has been studied in detail and the administration of radioactive malonate to Mycobacterium phlei has provided 6-MSA with a labelling pattern consistent with its derivation by the acetate-polymalonate biosynthetic route. Some activity from malonate was incorporated into the acetate-derived C-methyl group and this partial conversion of malonate into acetate has been recorded previously in fungal studies. Related studies on the biosynthesis of 6-MSA and salicylic acid by Mycobacterium fortuitum have shown that acetate was much more efficiently incorporated into the former compound. It has been concluded, therefore, that these structurally similar phenolic acids are derived by different biosynthetic pathways. 

The sequence of reactions involved in the bios)mthesis of mycophenolic acid (23) has been the subject of recent investigations by several research groups. Previous studies had established that the basic carbocyclic skeleton of the molecule was acetate-derived and that methionine provided the 

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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. 

Staunton, J. and Wilkinson, B. (2001) Combinatorial biosynthesis of polyketides and nonribosomal peptides. Current Opinion in Chemical Biology, 5, 159. 

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]. 

RAWLINGS, B.J., Biosynthesis of polyketides (other than actinomycete macrolides), Nat. Prod. Rep., 1999,16,425-484. 

The chemoenzymatic synthesis of dTDP-p-L-olivose and dTDP-a-L-olivose, donor substrates for the biosynthesis of polyketides and other drugs, has been described. Starting from 2-deoxy-D- ra/u o-hexose 6-phosphate, dTDP D-oliose was also synthesized.174... 

Biosynthesis of Polyketides Phenolic Compounds derived from Shikimate. The Biosynthesis of CB - Cjg Terpenoid Compounds Trrterpenoids Steroids, and Carotenoids Non-protein Amino-acids, Cyanogenic Glycosides, and Glucosinolates Biosynihesis of Alkaloids. 

R Pieper, G Luo, DE Cane, C Khosla. Cell-free biosynthesis of polyketides by recombinant erythromycin polyketide synthases. Nature 378 263-266, 1995. 

The biosynthesis of polyketides is analogous to the formation of long-chain fatty acids catalyzed by the enzyme fatty acid synthase (FAS). These FASs are multi-enzyme complexes that contain numerous enzyme activities. The complexes condense coenzyme A (CoA) thioesters (usually acetyl, propionyl, or malonyl) followed by a ketoreduction, dehydration, and enoylreduction of the [3-keto moiety of the elongated carbon chain to form specific fatty acid products. These subsequent enzyme activities may or may not be present in the biosynthesis of polyketides. 

By the methods presented for the combinatorial biosynthesis of polyketides, a multitude of modified and artificial polyketide substances should be available. New antibiotics, potentially with fewer side effects and consequently broader applicability, are desperately needed in the light of increasing resistance of bacteria towards established medications. 

The power of combinatorial biosynthesis has been best demonstrated through the engineered biosynthesis of polyketides." Polyketides consist of a structurally diverse family of natural products and are mostly biosynthesized by soil-bome actinomyces as secondary metabolites. Fungi and plants have also been sources of polyketides. 

For a review on polyether biosynthesis in dinoflagellates Rein KS, Snyder RV. The biosynthesis of polyketide metabolites by dinoflagellates. Adv. Appl. Microbiol. 2006 50 93-125. 

Biodiversity New Leads for the Pharmaceutical and Agrochemical Industries reviews and discusses aspects of modern natural products research. The central theme of many articles is the sustainable use of global biodiversity. Microbial, plant and marine products are presented as the sources of new drugs, including anti-fungal products, antibiotics, anti-cancer agents and animal health products. There is also coverage of the biosynthesis of polyketides and the chemical synthesis of natural products and their derivatives. 

Two chapters in section five describe different aspects of the biosynthesis of polyketides, which are numerically the most abimdant and structurally diverse class of natural products. The first chapter reports in vivo and in vitro studies aimed at enhancing our understanding of the basic pathways of polyketide assembly with a view to producing novel compounds. In the second chapter, a consistent difference in the modes of cyclisation of the fused ring polyketides of fungi and streptomycetes is described, which provides the basis for a new biosynthetic classification of these metabolites. 

In their simplest form, polyketides are natural compounds containing alternating carbonyl and methylene groups ( p-polyketones ). The biosynthesis of polyketides begins with the condensation of a starter unit (typically, acetyl-CoA or propionyl-CoA) with an extender unit (commonly malonyl-CoA or methylmalonyl-CoA, followed by decarboxylation of the extender unit (/, 2) (Fig. 1). Repetitive decarboxylative condensations result in lengthening of the polyketide carbon chain, and additional modifications such as ketoreduction, dehydratation, and enoylreduction may also occur (discussed below). 

The Biosynthesis of Polyketides, Tetramic Acids, and Pyridones in Fungi... 

Biosynthesis of polyketide-terpenoid (meroterpenoid) metabolites, andibenin A... 

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