Structure and Substrate Sequestration in the Pyoluteorin Type II Peptidyl Carrier Protein PltL

Journal of the American Chemical Society
Matt J JaremkoMichael D Burkart

Abstract

Type II nonribosomal peptide synthetases (NRPS) generate exotic amino acid derivatives that, combined with additional pathways, form many bioactive natural products. One family of type II NRPSs produce pyrrole moieties, which commonly arise from proline oxidation while tethered to a conserved, type II peptidyl carrier protein (PCP), as exemplified by PltL in the biosynthesis of pyoluteorin. We sought to understand the structural role of pyrrole PCPs in substrate and protein interactions through the study of pyrrole analogs tethered to PltL. Solution-phase NMR structural analysis revealed key interactions in residues of helix II and III with a bound pyrrole moiety. Conservation of these residues among PCPs in other pyrrole containing pathways suggests a conserved mechanism for formation, modification, and incorporation of pyrrole moieties. Further NOE analysis provided a unique pyrrole binding motif, offering accurate substrate positioning within the cleft between helices II and III. The overall structure resembles other PCPs but contains a unique conformation for helix III. This provides evidence of sequestration by the PCP of aromatic pyrrole substrates, illustrating the importance of substrate protection and regulation in typ...Continue Reading

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Citations

Feb 14, 2016·Fungal Genetics and Biology : FG & B·Simon BoeckerRoderich D Süssmuth
Mar 24, 2016·Proceedings of the National Academy of Sciences of the United States of America·Abrahim El GamalBradley S Moore
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Dec 12, 2020·RSC Chemical Biology·Joshua C CorpuzMichael D Burkart
May 15, 2021·Journal of the American Chemical Society·Dongqi YiVinayak Agarwal

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