Polyketides with mixed origins

The very largest of the polyketides are the macrolide antibiotics, e.g. nystatin 3.106). Further examples are the ansamycins which derive by a mixed acetate-propionate pathway (Section 7.6.1). Intermediate in size are the cytochalasins which derive by an acetate (malo-nate) pathway (Section 7.6.2). Where propionate units account for C3 fragments in the ansamycins, methionine and acetate serve in the cytochalasins. The macrolide antibiotics discussed below all follow the former way of generating C3 units. It is clear that, if methyl groups are introduced by two different pathways, this is not adventitious. The methyl groups must have a function possibly like the double bonds in dictating the conformation of the macrocycle. 

For the biosynthesis of these complex polyketides, labelled precursors have been used to great advantage in plotting the origins of macrocyclic antibiotics. Little is known, however, of the mechanism of biosynthesis. (For a discussion on the possible significance of templates see [4].) 

Tylosin 3.102) is formed as indicated, the one C4 unit deriving from ethylmalonate (= butyrate) [76]. A similar origin is apparent for leucomycin 3.103) but the origin of C-3 and C-4 is obscure (not labelled by [1- C]-, [2- C]-acetate, [l- C]propionate or [1- C]butyrate) [77]. In both studies extensive catabolism of butyrate and ethylmalonate into propionyl fragments was observed, but by different pathways. 

Further reading [l]-[4] Biosynthesis (Specialist Periodical Reports) [ed. T. A. Geissman (vols. 1-3), J. D. Bu Lock (vols. 4 and 5)], The Chemical Society, London. 

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Attractive Compounds. With the exception of (Z)-3-dodecenyl ( )-2-butenoate 213 (Scheme 24), the female produced sex pheromone of the sweetpotato weevil Cylas formicarius [389], the structures of weevil pheromones are represented by oxygenated monoterpenes, polyketides produced from propanoate units, and branched alcohols and ketones, probably originating from a mixed acetate-propanoate biosynthesis [5]. 

Xanthones in higher plants are also formed by this mixed pathway, though the polyketide chain originates from a benzoic acid instead of the usual cinnamic acid. Cyclization now affords a benzophenone (691), rather than a chalcone, which subsequently cyclizes to the xanthone, a route used with considerable success in the laboratory (Scheme 280). Other xanthones are derived only from acetate, through ring opening, decarboxylation and cyclization of an anthraquinone precursor. 

Biosynthetic studies have indicated a mixed polyketide-terpenoid origin for the unusual fungal metabolite andobenin (51) (Scheme 8). The two extra methyl groups ( ) are derived from methionine. Andobenin co-occurs with andilesin (52) whose structure has been recently elucidated by X-ray and c.d. analysis. ... 

An example of such a polyketide is cubensic acid 76 from Xylaria cubensis [115]. From an initial viewing of this structure it could be considered to derive from a mixed acetate/propionate pathway. Feeding studies however clearly demonstrate that the underlying carbon chain is derived from eleven acetate units with all of the eight methyl branches having their origin in L-methionine (Fig. 8). 

Polyketides occuring in plants are not always exclusively synthesized from acetate units, but often are of mixed biosynthetic origin. Phenylpropanoid or terpenoid building blocks or sometimes both can be connected with the acetate-derived backbone. In addition, parts of the carbon skeleton can be derived from fatty acids or amino acids. This mixed assembly principle results in a plethora of structurally diverse compounds. Polyketide alkaloids obtained when nitrogen or nitrogen-containing precursors are incorporated into the polyketide backbone will also be discussed. 

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