Biosynthesis of sphinganine-analog mycotoxins

Abstract

Sphinganine-analog mycotoxins (SAMT) are polyketide-derived natural products produced by a number of plant pathogenic fungi and are among the most economically important mycotoxins. The toxins are structurally similar to sphinganine, a key intermediate in the biosynthesis of ceramides and sphingolipids, and competitive inhibitors for ceramide synthase. The inhibition of ceramide and sphingolipid biosynthesis is associated with several fatal diseases in domestic animals and esophageal cancer and neural tube defects in humans. SAMT contains a highly reduced, acyclic polyketide carbon backbone, which is assembled by a single module polyketide synthase. The biosynthesis of SAMT involves a unique polyketide chain-releasing mechanism, in which a pyridoxal 5'-phosphate-dependent enzyme catalyzes the termination, offloading and elongation of the polyketide chain. This leads to the introduction of a new carbon-carbon bond and an amino group to the polyketide chain. The mechanism is fundamentally different from the thioesterase/cyclase-catalyzed polyketide chain releasing found in bacterial and other fungal polyketide biosynthesis. Genetic data suggest that the ketosynthase domain of the polyketide synthase and the chain-releasing enzyme are important for controlling the final product structure. In addition, several post-polyketide modifications have to take place before SAMT become mature toxins.

Quantitative molecular networking to profile marine cyanobacterial metabolomes

“…As shown in Supplementary Figure S3, it is conceivable that the enolic form of an enzyme-tethered δ-keto intermediate is involved in coincident carbocyclic ring formation and off-loading from the enzyme. Although there is some precedence for carbon–carbon bond formation during PKS off-loading, 24 to our knowledge this would represent the first occasion wherein a carbocyclic ring is directly formed. Because a defined protocol was employed in the analysis of the 20 cyanobacterial extracts and equal masses of extract were introduced for each species, the chromatogram areas for specific compounds (nodes) occurring in multiple extracts were comparable, and allowed relative quantitation.…”

Identification of Early Fumonisin Biosynthetic Intermediates by Inactivation of the FUM6 Gene in Fusarium verticillioides

“…11,12,14 Thus, a possible consequence of FUM6 gene deletion would be accumulation of 2-amino-12,16-dimethylicosane-3-one (molecular mass = 339 Da). A compound affording protonated molecular ions at m/z 340 was evident from the LC-MS chromatograms of extracts of cultures of the f um6 mutants and likely corresponded to the 2-amino-12,16-dimethylicosane-3-one.…”

“…11,12 In gene inactivation studies, FUM cluster genes were subjected to standard gene deletion or disruption strategies, and the resulting mutant strains were characterized for their ability to produce fumonisin analogues. 15,16 Precursor feeding studies with these analogues have provided evidence that at least some are fumonisin biosynthetic intermediates.…”

Proteome analysis of Aspergillus niger: Lactate added in starch-containing medium can increase production of the mycotoxin fumonisin B2 by modifying acetyl-CoA metabolism

“…The fumonisin B-series group contains up to three hydroxyl groups and the degree of hydroxylation gives rise to the designations B 1 -B 4 [13,14]. These are classified as mycotoxins as they have been shown to be cytotoxic and carcinogenic [14,15] and fumonisins have been suspected to be involved in oesophageal cancer in South Africa and China [16-19].…”