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.
Highlights
Nonribosomal peptide synthesis – mechanistic aspectsNonribosomal peptide synthesis (NRPS) is a key mechanism responsible for the biosynthesis of bioactive metabolites in bacteria and fungi (Mootz et al, 2002; Reiber et al, 2005) (Fig. 1)
NRP synthetases are composed of discrete domains [adenylation (A), thiolation (T) or peptidyl carrier protein (PCP) and condensation (C) domains] which when grouped together are referred to as a single module as shown for the putative Aspergillus fumigatus NRP synthetase encoded by pesM (Fig. 2, Table 1)
Post-translational phosphopantetheinylation of 49-phosphopantetheine-dependent carrier proteins is essential for metabolite production in NRPS, polyketide biosynthesis, fatty acid biosynthesis and lysine biosynthesis. 49-PPTase is responsible for the conversion of the peptidyl carrier protein (PCP in NRP synthetases), acyl carrier protein (ACP in polyketide and fatty acid biosynthesis) and a-aminoadipate semialdehyde reductase from an inactive apo-form to an active holo- configuration, in an Mg2+-dependent reaction (Walsh et al, 1997)
Summary
Nonribosomal peptide synthesis (NRPS) is a key mechanism responsible for the biosynthesis of bioactive metabolites in bacteria and fungi (Mootz et al, 2002; Reiber et al, 2005) (Fig. 1). In linear NRP synthetases, the three core domains are organized in the order adenylation, thiolation and condensation (A-T-C)n to form an elongation module that adds one amino acid to the growing chain. Variations on this structure include the iterative NRP synthetases characteristic of siderophore synthetases (Mootz et al, 2002; Reiber et al, 2005) or nonlinear NRP synthetases which deviate in their domain organization from the standard (A-T-C)n architecture (Fig. 2). The emergence of fungal genome sequences has led to the identification of multiple ORFs predicted to encode NRP synthetase genes (e.g. in Cochliobolus heterostrophus, Claviceps purpurea and Fusarium graminearum: Lee et al, 2005; Haarmann et al, 2005; Varga et al, 2005; Tobiasen et al, 2007)
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