Identification of a hybrid PKS/NRPS required for pseurotin A biosynthesis in the human pathogen Aspergillus fumigatus.
The genome sequence of Aspergillus fumigatus revealed the presence of a single hybrid polyketide synthase-non-ribosomal peptide synthetase (PKS/NRPS) gene that is present within a cluster of five genes suggestive of its involvement in secondary metabolism. Here, we present evidence that it is required for the biosynthesis of pseurotin A, a compound with an unusual heterospirocyclic gamma-lactam structure. We have confirmed that the genome reference strain A. fumigatus Af293 produces pseurotin A, a compound previously reported to be a competitive inhibitor of chitin synthase and an inducer of nerve-cell proliferation. Deletion or overexpression of the PKS/NRPS gene psoA in A. fumigatus leads to the absence or accumulation of pseurotin A, respectively; this indicates that this gene is essential for the biosynthesis of pseurotin A. It is likely that the first product of psoA is converted to pseurotin A by the products of other genes in this cluster.
Maiya
Shubha
S
University of Sheffield, Department of Molecular Biology and Biotechnology, S10 2TN, Sheffield, UK.
Grundmann
Alexander
A
Li
Xiang
X
Li
Shu-Ming
SM
Turner
Geoffrey
G
D000818:Animals; D001232:Aspergillus fumigatus / Q000378:metabolism*; D049109:Cell Proliferation; D017931:DNA Primers / Q000737:chemistry; D005798:Genes, Bacterial; D016678:Genome; D007769:Lactams / Q000737:chemistry; D008956:Models, Chemical; D008957:Models, Genetic; D010453:Peptide Synthases / Q000737:chemistry*; D010957:Plasmids / Q000378:metabolism; D048630:Polyketide Synthases / Q000737:chemistry*; D011760:Pyrrolidinones / Q000737:chemistry*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013053:Spectrophotometry / Q000379:methods
D017931:DNA Primers; D007769:Lactams; D011760:Pyrrolidinones; C012013:pseurotin; D048630:Polyketide Synthases; D010453:Peptide Synthases; C104385:non-ribosomal peptide synthase