Functional replacement of the ketosynthase domain of FUM1 for the biosynthesis of fumonisins, a group of fungal reduced polyketides

Zhu, Xia; Yu, Fei; Bojja, Ravi S.; Zaleta-Rivera, Kathia; Du, Liangcheng

doi:10.1007/s10295-006-0137-9

Cited by 14 publications

(24 citation statements)

References 33 publications

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“…Fum1p and PKS1 share a sequence similarity of 44.1% and identity of 34.2% for the entire amino acid sequence [84]. When the KS domain of FUM1 was replaced with the KS domain of PKS1, the F. verticillioides strain produced fumonisins [88]. The result shows that the heterologous KS is able to functionally interact with the six other domains of Fum1p.…”

Section: Genetic Manipulations Of the Pks For Sphinganineanalog Mycotmentioning

confidence: 84%

“…This represents the Wrst successful domain swapping in fungal HR-PKS. To further test if the whole fumonisin PKS could be functionally replaced by a PKS that has a similar domain architecture, we replaced entire FUM1 with PKS1 [88]. This F. verticillioides strain did not produce any fumonisin or new metabolites.…”

Section: Genetic Manipulations Of the Pks For Sphinganineanalog Mycotmentioning

confidence: 99%

“…Our laboratory has been studying the biosynthesis of SAMT and using it as a model system for the biosynthesis of fungal highly reduced polyketides [28,88,89]. This system has several advantages.…”

Section: Sphinganine-analog Mycotoxins As a Model System To Study Thementioning

confidence: 99%

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Biosynthesis of sphinganine-analog mycotoxins

Zhu

Gerber

et al. 2008

J Ind Microbiol Biotechnol

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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.

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Section: Genetic Manipulations Of the Pks For Sphinganineanalog Mycotmentioning

confidence: 84%

Section: Genetic Manipulations Of the Pks For Sphinganineanalog Mycotmentioning

confidence: 99%

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Biosynthesis of sphinganine-analog mycotoxins

Zhu

Gerber

et al. 2008

J Ind Microbiol Biotechnol

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“…128 Therefore, the accessory releasing enzyme FUM8p plays an important role in terminating PKS function and controlling the chain length, which may explain the production of 9 with identical chain length when the KS domain of FUM1p in F. verticilliodes is swapped with that from C. heterostrophus ChPKS1 of T-toxin pathway. 80 …”

Section: Highly-reducing Polyketide Synthasesmentioning

confidence: 99%

Navigating the Fungal Polyketide Chemical Space: From Genes to Molecules

2012

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The iterative type I polyketide synthases (IPKSs) are central to the biosynthesis of an enormously diverse array of natural products in fungi. These natural products, known as polyketides, exhibit a wide range of biological activities and include clinically important drugs as well as undesirable toxins. The PKSs synthesize these structurally diverse polyketides via a series of decarboxylative condensations of malonyl-CoA extender units and β-keto modifications in a highly programmed manner. Significant progress has been made over the past few years in understanding the biosynthetic mechanism and programming of fungal PKSs. The continuously expanding fungal genome sequence data have sparked genome-directed discoveries of new fungal PKSs and associated products. The increasing number of fungal PKSs that have been linked to their products along with in-depth biochemical and structural characterizations of these large enzymes have remarkably improved our knowledge on the molecular basis for polyketide structural diversity in fungi. This perspective highlights the recent advances and examines how the newly expanded paradigm has contributed to our ability to link fungal PKS genes to chemical structures and vice versa. The knowledge will help us navigate through the logarithmically expanding seas of genomic information for polyketide compound discovery and provided opportunities to reprogram these megasynthases to generate new chemical entities.

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“…Very recently, an exchange of the KS domain in FUM1 with that of the PKS1 from C. heterostrophus resulted in active fumonisin production and represents the first successful domain swapping for fungal reduced polyketides. 79 Fumonisin biosynthesis is controlled by a cyclin C-type protein whose gene (FCC1) is not associated within the fum cluster. 80 Also, repression in the presence of nitrogen and stimulation by amylopectin was found.…”

Section: Fumonisinmentioning

confidence: 99%