Abstract
Maleidrides are a family of structurally related fungal natural products, many of which possess diverse, potent bioactivities. Previous identification of several maleidride biosynthetic gene clusters, and subsequent experimental work, has determined the ‘core’ set of genes required to construct the characteristic medium-sized alicyclic ring with maleic anhydride moieties. Through genome mining, this work has used these core genes to discover ten entirely novel putative maleidride biosynthetic gene clusters, amongst both publicly available genomes, and encoded within the genome of the previously un-sequenced epiheveadride producer Wicklowia aquatica CBS 125634. We have undertaken phylogenetic analyses and comparative bioinformatics on all known and putative maleidride biosynthetic gene clusters to gain further insights regarding these unique biosynthetic pathways.
Highlights
Maleidrides are an important family of bioactive polyketide-derived secondary metabolites, produced by diverse filamentous fungi and are characterised by a mediumsized alicyclic ring with one or two fused maleic anhydride moieties
Identification of maleidride BGCs Previously identified maleidride BGCs In fungi the genes required for the biosynthesis, regulation and transport of a specific natural product are generally co-located as a single biosynthetic gene cluster (BGC) [20,21,22]
Scheme 1 Proposed biosynthesis of maleidride monomers and dimerisations required to construct the diverse structures of known maleidrides of Fungi has recommended that Paecilomyces be used to replace Byssochlamys, we refer to this strain as Paecilomyces fulvus ( see phylogenetic analysis of internal transcribed spacer regions (ITS) in Additional file 1: Fig. S53) [23]
Summary
Maleidrides are an important family of bioactive polyketide-derived secondary metabolites, produced by diverse filamentous fungi and are characterised by a mediumsized alicyclic ring with one or two fused maleic anhydride moieties. It is interesting to note that minor structural changes can lead to significant shifts in potency or target, for example, the γ-hydroxybutenolide motif present in the PP2A inhibitor rubratoxin A 8 makes it ~ 100 times more potent than its anhydride analogue rubratoxin B 9 [8]. Another rubratoxin analogue, ceramidastin 10, which lacks the α,βunsaturated lactone moiety of the rubratoxins, is a novel inhibitor of bacterial ceramidase, [9] an enzyme thought to contribute to skin infections of patients with atopic dermatitis [10]
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