3 years ago

Functional Characterization of a Condensation Domain That Links Nonribosomal Peptide and Pteridine Biosynthetic Machineries in Photorhabdus luminescens

Functional Characterization of a Condensation Domain
That Links Nonribosomal Peptide and Pteridine Biosynthetic Machineries
in Photorhabdus luminescens
Jason M. Crawford, Corey E. Perez, Hyun Bong Park
Nonribosomal peptide synthetases (NRPSs) produce a wide variety of biologically important small molecules. NRPSs can interface with other enzymes to form hybrid biosynthetic systems that expand the structural and functional diversity of their products. The pepteridines are metabolites encoded by an unprecedented pteridine–NRPS-type hybrid biosynthetic gene cluster in Photorhabdus luminescens, but how the distinct enzymatic systems interface to produce these molecules has not been examined at the biochemical level. By an unknown mechanism, the genetic locus can also affect the regulation of other enzymes involved in autoinducer and secondary metabolite biosynthesis. Here, through in vitro protein biochemical assays, we demonstrate that an atypical NRPS condensation (C) domain present in the pathway condenses acyl units derived from α-keto acids onto a free 5,6,7,8-tetrahydropterin core, producing the tertiary cis-amide-containing pepteridines. Solution studies of the chemically synthesized molecules led to the same amide regiochemistries that were observed in the natural products. The biochemical transformations mediated by the C domain destroy the radical scavenging activity of its redox active tetrahydropterin substrate. Secondary metabolite analyses revealed that the pepteridine locus affects select metabolic pathways associated with quorum sensing, antibiosis, and symbiosis. Taken together, the results suggest that the pathway likely regulates cellular redox and specialized metabolic pathways through engagement with the citric acid cycle.

Publisher URL: http://dx.doi.org/10.1021/acs.biochem.7b00863

DOI: 10.1021/acs.biochem.7b00863

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