Pathways polymalonate

The fatty acid pathway or, as we should call it now, the acyl polymalonate pathway, also gives rise to an inexhaustible variety of aromatic and other compounds belonging to the family of the polyketides. You saw in Chapter 50 how the shikimic acid pathway makes aromatic compounds but the compounds below are from the polyketide route. 

This precise sequence was discovered only through very careful double labelling experiments and after the discovery of specific inhibitors for the enzyme. Since polyketides can be made from the acyl polymalonate pathway with or without reduction and elimination at any step, the number of possible structures is vast. With more reduction, no aromatic ring can be formed macrolide antibiotics such as brefeldin A come from this route. 

Olivetol has the characteristic 1,3-diOH pattern of a polyketide around the benzene ring but it has only 11 carbon atoms so CO2 was probably lost somewhere and the long side chain has certainly been reduced. The acyl-polymalonate pathway (pp. 1425-36) needs to be used. We start from... 

The plant families Ancistrocladaceae and Dioncophyllaceae are the only identifled sources of the unusual naphthylisoquinoline alkaloids (ref. 1). The family Ancistrocladaceae contains one genus, Ancistrocladus, which consists of approximately 20 species that are distributed in the Indian archipelago, tropical Asia and tropical West Africa. These isoquinoline alkaloids are structurally unique in that they appear to originate, biosynthetically, form the acetate-polymalonate pathway and not from amino acids (ref. 1). Another interesting structural feature of these compounds is that they exist as thermally stable atropisomers because of restricted rotation about the biaryl linkage. 

Lichen secondary metabolites are derived from three chemical pathways acetate-polymalonate pathway, shikimic acid pathway and mevalonic acid pathway (Fig. 1.3). 

Acetate-polymalonate pathway includes the most common lichen compounds such as... 

Lichen Secondary Metabolites of the Acetate-Polymalonate Pathway... 

The most common phenolic acid units derived by the acetate-polymalonate pathway and combined to form the characteristic lichen substances are of two types the orcinol-type units and p-orcinol-type units. While compounds formed from these two types of units are similar in many ways, differences in their structure and especially in their distributimi among the lichens suggest that the usual tendency to consider the orcinol and p-orcinol compounds separately probably has a biosynthetic justification. 

Miriquidic acid (206) 193) is structurally unique since the side chain ketonic group is not present in a position predicted from the normal acetate-polymalonate biogenetic pathway to these compounds. The depside (206) has been isolated from several Lecidea species 193). 

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. 

Most of the natural isocoumarins are derived biosynthetically from acetate via the acetate-polymalonate pathway 293, 294). Mellein (19) is formed from acetate and malonate, as in Scheme 3 140). The early reduction of two of the carbonyl groups in the polyketone chain has been indicated by results of CD3COOH feedings ). Loss of the oxygen function at C-6 of an isocoumarin is quite common but loss of the hydroxyl group at C-8 never occurs in those isocoumarins derived from acetate, presumably as a consequence of the cyclization mechanism 293). 

Diverse biosynthetic pathways are involved in the production of a wide range of secondary metabolites produced by lichens. Shikimic acid, polymalonate, and mevalonic acid pathways are known to be mainly responsible for the biosynthesis of secondary metabolites in lichens [43]. 

The polyene structure of citreoviridin suggested that this compound is derived from a polyketide e.g. (8) through the acetate polymalonate condensation pathway with the introduction of five Cj-units from methionine. In the biosynthetic studies, a strain of Penicillium pulvillorum was grown in Ushinsky medium at 25°C in stationary culture. Radioactive precursors were added to the culture 9-10 days after inoculation when the production of citreoviridin started to increase rapidly. Citreoviridin was then isolated and purified. The incorporation ratios obtained from [mc/Aj/- C]methionine and [2- " C]acetate were 70% and 5%, respectively. The radioactive citreoviridin was degraded as shown in Scheme 1. 

The results showed that the isocoumarin moiety of ochratoxin A is formed via the acetate-polymalonate pathway from one acetate and four malonate units, whereas the carbonyl carbon atom C(12) is derived from the Cj pool. 

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