title: Nonribosomal peptide synthesis in Aspergillus fumigatus and other fungi.
abstract: In fungi, nonribosomal peptide synthetases (NRP synthetases) are large multi-functional enzymes containing adenylation, thiolation (or peptidyl carrier protein, PCP) and condensation domains. These enzymes are often encoded within gene clusters. Multiple NRP synthetase ORFs have also been identified in fungi (14 in Aspergillus fumigatus). LeaA, a methyltransferase, is involved in secondary metabolite gene cluster regulation in Aspergillus spp. The NRP synthetases GliP and FtmA respectively direct the biosynthesis of the toxic metabolites gliotoxin and brevianamide F, a precursor of bioactive prenylated alkaloids. The NRP synthetase Pes1 has been shown to mediate resistance to oxidative stress, and in plant-pathogenic ascomycetes (e.g. Cochliobolus heterostrophus) an NRP synthetase, encoded by the NPS6 gene, significantly contributes to virulence and resistance to oxidative stress. Adenylation (A) domains within NRP synthetases govern the specificity of amino acid incorporation into nonribosomally synthesized peptides. To date there have only been limited demonstrations of A domain specificity (e.g. A. fumigatus GliP and in Beauveria bassiana) in fungi. Indeed, only in silico prediction data are available on A domain specificity of NRP synthetases from most fungi. NRP synthetases are activated by 4'-phosphopantetheinylation of serine residues within PCP domains by 4'-phosphopantetheinyl transferases (4'-PPTases). Coenzyme A acts as the 4'-phosphopantetheine donor, and labelled coenzyme A can be used to affinity-label apo-NRP synthetases. Emerging fungal gene disruption and gene cluster expression strategies, allied to proteomic strategies, are poised to facilitate a greater understanding of the coding potential of NRP synthetases in fungi.
authors.affiliation: Department of Biology and National Institute for Cellular Biotechnology, National University of Ireland, Maynooth, Co. Kildare, Ireland.
authors.forename: Deirdre
authors.initials: D
authors.lastname: Stack
authors.affiliation: Department of Biology and National Institute for Cellular Biotechnology, National University of Ireland, Maynooth, Co. Kildare, Ireland.
authors.forename: Claire
authors.initials: C
authors.lastname: Neville
authors.affiliation: Department of Biology and National Institute for Cellular Biotechnology, National University of Ireland, Maynooth, Co. Kildare, Ireland.
authors.forename: Sean
authors.initials: S
authors.lastname: Doyle
mesh_terms: D001232:Aspergillus fumigatus / Q000201:enzymology* / Q000235:genetics; D005658:Fungi / Q000201:enzymology* / Q000235:genetics; D046908:Peptide Biosynthesis, Nucleic Acid-Independent / Q000235:genetics / Q000502:physiology*; D010453:Peptide Synthases / Q000235:genetics* / Q000378:metabolism*
chemical_list: D010453:Peptide Synthases; C104385:non-ribosomal peptide synthase