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. 2016 Jun 1;55(23):6784-8.
doi: 10.1002/anie.201511882. Epub 2016 Apr 21.

Heterologous Production of Fungal Maleidrides Reveals the Cryptic Cyclization Involved in their Biosynthesis

Katherine Williams  1 , Agnieszka J Szwalbe  2 , Nicholas P Mulholland  3 , Jason L Vincent  3 , Andrew M Bailey  4 , Christine L Willis  2 , Thomas J Simpson  2 , Russell J Cox  5   6
Affiliations

Heterologous Production of Fungal Maleidrides Reveals the Cryptic Cyclization Involved in their Biosynthesis

Katherine Williams et al. Angew Chem Int Ed Engl. .

Abstract

Fungal maleidrides are an important family of bioactive secondary metabolites that consist of 7, 8, or 9-membered carbocycles with one or two fused maleic anhydride moieties. The biosynthesis of byssochlamic acid (a nonadride) and agnestadride A (a heptadride) was investigated through gene disruption and heterologous expression experiments. The results reveal that the precursors for cyclization are formed by an iterative highly reducing fungal polyketide synthase supported by a hydrolase, together with two citrate-processing enzymes. The enigmatic ring formation is catalyzed by two proteins with homology to ketosteroid isomerases, and assisted by two proteins with homology to phosphatidylethanolamine-binding proteins.

Keywords: biosynthesis; cyclization; enzymes; maleidride; polyketides.

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Figures

Figure 1
Figure 1
Examples of maleidrides and the hypothesized precursor.
Scheme 1
Scheme 1
Proposed general pathway to maleidrides.
Figure 2
Figure 2
Top: transcriptome analysis of the byssochlamic acid (1) biosynthetic gene cluster in B. fulva IMI 40021 under producing (green) and non‐producing (black) conditions. Bottom: comparative genomic analysis of other putative maleidride BGCs.
Figure 3
Figure 3
HPLC (DAD, 210–600 nm) chromatograms. A) Extract from WT B. fulva; B) extract from B. fulva Δpks1; C) extract from untransformed A. oryzae NSAR1; D) extract from A. oryzae transformant BF‐PMCH; E) extract from A. oryzae transformant BF‐PMCH+KIs; F) extract from A. oryzae transformant BF‐PMCH+KIs+PEBPs; G) Purified agnestadride A (8); H) Purified byssochlamic acid (1). Compounds 12, 12′, and 13 are cometabolites of 1 and have been previously identified and characterized.10
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