Abstract
Chemical probes were devised and evaluated for the capture of biosynthetic intermediates involved in the bio-assembly of the nonribosomal peptide echinomycin. Putative intermediate peptide species were isolated and characterised, providing fresh insights into pathway substrate flexibility and paving the way for novel chemoenzymatic approaches towards unnatural peptides.
Highlights
Chemical probes were devised and evaluated for the capture of biosynthetic intermediates involved in the bio-assembly of the nonribosomal peptide echinomycin
Key domains utilised in peptide elaboration throughout assembly include methyltransferases, epimerases[4] and heterocyclases, whereas tailoring enzymes acting in post-nonribosomal peptide synthetases (NRPSs) processes comprise oxidases,[5] halogenases[6] and glycosyltransferases.[7]
In the past few years our group has developed ‘chain termination’ probes for the investigation of polyketide biosynthesis: nonhydrolysable small molecule mimics of malonate building blocks recruited in polyketide formation were devised to interfere in the key decarboxylative Claisen condensation step leading to polyketide chain assembly, thereby ‘capturing’ transient biosynthetic intermediates for characterisation.[23,24,25,26]
Summary
Chemical probes were devised and evaluated for the capture of biosynthetic intermediates involved in the bio-assembly of the nonribosomal peptide echinomycin. In the past few years our group has developed ‘chain termination’ probes for the investigation of polyketide biosynthesis: nonhydrolysable small molecule mimics of malonate building blocks recruited in polyketide formation were devised to interfere in the key decarboxylative Claisen condensation step leading to polyketide chain assembly, thereby ‘capturing’ transient biosynthetic intermediates for characterisation.[23,24,25,26] These tools have proved successful for intermediate isolation and characterisation of intermediate species from modular23b,24,26 and iterative PKS enzymes,23a,25 gathering in vitro and in vivo key information on the timing and the mechanism of catalytic events otherwise inaccessible, and unveiling novel opportunities for natural product diversification.24c
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