Maleidride biosynthesis – construction of dimeric anhydrides – more than just heads or tails

Covering: up to early 2022 Maleidrides are a family of polyketide-based dimeric natural products isolated from fungi. Many maleidrides possess significant bioactivities, making them attractive pharmaceutical or agrochemical lead compounds. Their unusual biosynthetic pathways have fascinated scientists for decades, with recent advances in our bioinformatic and enzymatic understanding providing further insights into their construction. However, many intriguing questions remain, including exactly how the enzymatic dimerisation, which creates the diverse core structure of the maleidrides, is controlled. This review will explore the literature from the initial isolation of maleidride compounds in the 1930s, through the first full structural elucidation in the 1960s, to the most recent in vivo, in vitro, and in silico analyses

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

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. Ring cycle: The enzymes involved in the cyclization of the maleidride family of bioactive fungal natural products, including agnestadride A and byssochlamic acid, were identified. These previously unknown proteins show homology to ketosteroid isomerases (KI-like) and phosphatidylethanolamine-binding proteins (PEBP-like).BBSRCSyngent

Heterologe Produktion pilzlicher Maleidride enthüllt die kryptische Cyclisierung in ihrer Biosynthese

Die von Pilzen produzierten Maleidride sind eine wichtige Klasse bioaktiver Sekundarmetaboliten, die aus sieben-, acht- oder neungliedrigen Carbocyclen bestehen. Jeder Cyclus ist mit einem oder zwei anellierten Maleinsaureanhydridresten substituiert. Durch Gen-Knockouts und heterologe Expressionsexperimente wurde die Biosynthese von Byssochlaminsaure (ein Nonadrid) und Agnestadrid A (ein Heptadrid) untersucht. Unsere Experimente zeigen, dass der Vorlaufer der Cyclisierung von einer iterativen, vollstandig reduzierenden, pilzlichen Polyketidsynthase erzeugt wird, die durch eine Hydrolase und zwei Citrat-verarbeitende Enzyme unterstutzt wird. Die ungewohnliche Cyclisierung wird zum einen von zwei Proteinen katalysiert, die Homologien zu Ketosteroidisomerasen aufweisen, und zum anderen von zwei weiteren Proteinen mit Homologien zu Phosphatidylethanolamin-bindenden Proteinen

Novel nonadride, heptadride and maleic acid metabolites from the byssochlamic acid producer Byssochlamys fulva IMI 40021-an insight into the biosynthesis of maleidrides

The filamentous fungus Byssochlamys fulva strain IMI 40021 produces (+)-byssochlamic acid 1, its novel dihydroanalogue 2 and four related secondary metabolites. Agnestadrides A, 17 and B, 18 constitute a novel class of seven-membered ring, maleic anhydride-containing (hence termed heptadride) natural products. The putative maleic anhydride precursor 5 for both nonadride and heptadride biosynthesis was isolated as a fermentation product for the first time and its structure confirmed by synthesis. Acid 5 undergoes facile decarboxylation to anhydride 6. The generic term maleidrides is proposed to encompass biosynthetically-related compounds containing maleic anhydride moieties fused to an alicyclic ring, varying in size and substituents

Characterisation of the biosynthetic pathway to agnestins A and B reveals the reductive route to chrysophanol in fungi

Two new dihydroxy-xanthone metabolites, agnestins A and B, were isolated from Paecilomyces variotii along with a number of related benzophenones and xanthones including monodictyphenone. The structures were elucidated by NMR analyses and X-ray crystallography. The agnestin (agn) biosynthetic gene cluster was identified and targeted gene disruptions of the PKS, Baeyer-Villiger monooxygenase, and other oxido-reductase genes revealed new details of fungal xanthone biosynthesis. In particular, identification of a reductase responsible for in vivo anthraquinone to anthrol conversion confirms a previously postulated essential step in aromatic deoxygenation of anthraquinones, e.g. emodin to chrysophanol

Genetic and chemical characterisation of the cornexistin pathway provides further insight into maleidride biosynthesis

The biosynthetic gene cluster for the selective herbicide cornexistin 1 from the fungus Paecilomyces variotii has been identified and analysed.</p