Elucidation of the Biosynthetic Pathway Leading to the Complex Nonadride Phomoidride B

Abstract

In this Account we recall our studies into the biosynthesis of the complex fungal secondary metabolite phomoidride B (also known as 114). Our labeling studies revealed this natural product is produced by a remarkable dimerization of a sixteen-carbon anhydride. This unique biosynthetic pathway provides new opportunities in the area of combinatorial biosynthesis for the production of structurally novel unnatural products.

Secondary metabolites from entomopathogenic Hypocrealean fungi

“…100 Cordyanhydrides A and B (20) from C. pseudomilitaris 101 are novel maleic anhydrides that are the linear dimers or trimers, respectively, of formal C 9 anhydride units, analogous to the cyclic nonadrides. 102,103 We propose that the anhydride forms by the intermolecular aldol condensation of a short chain (C 6 ) unsaturated fatty acid from polyketide or fatty acid biosynthesis with oxaloacetate, or more likely a-ketoglutarate, based on the precedent of the biosynthesis of the dialkylmaleic anhydride in the Streptomyces metabolites tautomycetin 55 and tautomycin. 104 2.2 Nonribosomal peptides 2.2.1 Nonribosomal peptide biosynthesis.…”

Biosynthetic Study on Antihypercholesterolemic Agent Phomoidride: General Biogenesis of Fungal Dimeric Anhydrides

“…A previous report showed that the production of 2 was induced under low pH conditions . Therefore, we initially examined the expression of proposed phi genes under both nonproducing and producing conditions.…”

Structural and synthetic studies on maleic anhydride and related diacid natural products

“…18,19 More recent work has focussed on genome sequencing, knock out experiments and heterologous expression combined with isolation of intermediates leading to further insights into the biosynthesis of nonadrides. [20][21][22][23][24][25] Using heterologous expression in Aspergillus oryzae we have shown that the precursors for cyclisation are formed by an iterative highly reducing polyketide synthase supported by a hydrolase together with citrate-processing enzymes (Scheme 1). Carboxylic acids such as 9 have been shown to undergo spontaneous decarboxylation, yielding 11, and both isomers 10 and 11 may be formed in this fashion.…”