Polyketides, metabolites built primarily from combinations of acetate units, are described. The biosynthesis of saturated and unsaturated fatty acids is covered, together with prostaglandins, thromboxanes, and leukotrienes. Cyclization of polyketides to give aromatic structures is then rationalized in terms of aldol and Claisen reactions. More complex structures formed via pathways involving alkylation reactions, phenolic oxidative coupling, oxidative cleavage of aromatic rings, and employing starter groups other than acetate are developed. The use of extender groups other than malonate gives rise to macrolides and polyethers, whilst further cyclization of polyketide structures may be achieved through Diels-Alder reactions. The application of genetic engineering to modify products from the acetate pathway is discussed. Monograph topics giving more detailed information on medicinal agents include fixed oils and fats, evening primrose oil, echinacea, prostaglandins and isoprostanes, thromboxanes, leukotrienes, senna, cascara, frangula and allied drugs, St John's wort, mycophenolic acid, khellin and cromoglicate, griseofulvin, poison ivy and poison oak, aflatoxins, cannabis, tetracyclines, anthracycline antibiotics, macrolide antibiotics, avermectins, polyene antifungals, tacrolimus and sirolimus, ansa macrolides, mevastatin and other statins.
Polyketides constitute a large class of natural products grouped together on purely biosynthetic grounds. Their diverse structures can be explained as being derived from poly-P-keto chains, formed by coupling of acetic acid (C2) units via condensation reactions, i.e. nCH3CO2H-> —[CH2CO]„ —
Included in such compounds are the fatty acids, polyacetylenes, prostaglandins, macrolide antibiotics and many aromatic compounds, e.g. anthraquinones and tetracyclines.
The formation of the poly-P-keto chain could be envisaged as a series of Claisen reactions, the reverse of which are involved in the P-oxidation sequence for the metabolism of fatty acids (see page 18). Thus, two molecules of acetyl-CoA could participate in a Claisen condensation giving acetoacetyl-CoA, and this reaction could be repeated to generate a poly-P-keto ester of appropriate chain length (Figure 3.1). However, a study of the enzymes involved in fatty acid biosynthesis showed this simple rationalization could not be correct, and a more complex series of reactions was operating. It is now known that fatty acid biosynthesis involves initial carboxylation of acetyl-CoA to malonyl-CoA, a reaction involving ATP, CO2 (as bicarbonate, HCO—), and the coen-zyme biotin as the carrier of CO2 (see page 17).
The conversion of acetyl-CoA into malonyl-CoA increases the acidity of the a-hydrogens, and thus provides a better nucleophile for the Claisen condensation. In the biosynthetic sequence, no acy-lated malonic acid derivatives are produced, and no label from [14C]bicarbonate is incorporated, so the carboxyl group introduced into malonyl-CoA is simultaneously lost by a decarboxylation reaction during the Claisen condensation (Figure 3.1). Accordingly, the carboxylation step helps to activate the a-carbon and facilitate Claisen condensation, and the carboxyl is immediately removed on completion of this task. An alternative rationalization is that decarboxylation of the malonyl ester is used to generate the acetyl enolate anion without any requirement for a strong base.
The pathways to fatty acids and aromatic polyketides branch early. The chain extension process of Figure 3.1 continues for aromatics,
CH3 — C — SCoA —^—C^-C-C^-C-SCoA —^—-CH3CO-[cH2 - c]^- CH2COSCoA
acetyl-CoA Claisen acetoacetyl-CoA Umnm poly ß kefo es,er reaction reaction poly-ß-keto ester
Claisen reaction acetyl-CoA
nucleophilic attack on malonyl-CoA
carbonyl with simultaneous loss of CO2
CH3CO -[cH2 - C7 CH2COSCoA poly-ß-keto ester repeat of Claisen reaction generating a highly reactive poly-ß-keto chain, which has to be stabilized by association with groups on the enzyme surface until chain assembly is complete and cyclization reactions occur. However, for fatty acids, the carbonyl groups are reduced before attachment of the next malonate group. Partial reduction processes, leading to a mixture of methylenes, hydroxyls, and carbonyls, are characteristic of macrolides (see page 92).
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