Elucidating the molecular programming of a nonlinear non-ribosomal peptide synthetase responsible for fungal siderophore biosynthesis

Matthew Jenner (), Yang Hai (), Hong H. Nguyen, Munro Passmore, Will Skyrud, Junyong Kim, Neil K. Garg, Wenjun Zhang, Rachel R. Ogorzalek Loo and Yi Tang
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Matthew Jenner: University of Warwick
Yang Hai: University of California
Hong H. Nguyen: University of California
Munro Passmore: University of Warwick
Will Skyrud: University of California
Junyong Kim: University of California
Neil K. Garg: University of California
Wenjun Zhang: University of California
Rachel R. Ogorzalek Loo: University of California
Yi Tang: University of California

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract Siderophores belonging to the ferrichrome family are essential for the viability of fungal species and play a key role for virulence of numerous pathogenic fungi. Despite their biological significance, our understanding of how these iron-chelating cyclic hexapeptides are assembled by non-ribosomal peptide synthetase (NRPS) enzymes remains poorly understood, primarily due to the nonlinearity exhibited by the domain architecture. Herein, we report the biochemical characterization of the SidC NRPS, responsible for construction of the intracellular siderophore ferricrocin. In vitro reconstitution of purified SidC reveals its ability to produce ferricrocin and its structural variant, ferrichrome. Application of intact protein mass spectrometry uncovers several non-canonical events during peptidyl siderophore biosynthesis, including inter-modular loading of amino acid substrates and an adenylation domain capable of poly-amide bond formation. This work expands the scope of NRPS programming, allows biosynthetic assignment of ferrichrome NRPSs, and sets the stage for reprogramming towards novel hydroxamate scaffolds.

Date: 2023
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DOI: 10.1038/s41467-023-38484-8

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