Using Peptide Mimics to Study the Biosynthesis of the Side-Ring System of Nosiheptide

Bo Wang, Joseph W. LaMattina, Edward D. Badding, Lauren K. Gadsby, Tyler L. Grove, Squire J. Booker

Research output: Chapter in Book/Report/Conference proceedingChapter

4 Scopus citations

Abstract

Thiopeptide natural products have gained interest recently for their diverse pharmacological properties, including antibacterial, antifungal, anticancer, and antimalarial activities. Due to their inherent poor solubility and uptake, there is interest in developing new thiopeptides that mimic these unique structures, but which exhibit better pharmacokinetic properties. One strategy is to exploit the biosynthetic pathways using a chemoenzymatic approach to make analogs. However, a complete understanding of thiopeptide biosynthesis is not available, especially for those molecules that contain a large number of modifications to the thiopeptide core. This gap in knowledge and the lack of a facile method for generating a variety of thiopeptide intermediates makes studying particular enzymatic steps difficult. We developed a method to produce thiopeptide mimics based on established synthetic procedures to study the reaction catalyzed by NosN, the class C radical S-adenosylmethionine methylase involved in carbon transfer to C4 of 3-methylindolic acid and completion of the side-ring system in nosiheptide. Herein, we detail strategies for overproducing and isolating NosN, as well as procedures for synthesizing substrate mimics to study the formation of the side-ring system of nosiheptide.

Original languageEnglish (US)
Title of host publicationMethods in Enzymology
EditorsVahe Bandarian
PublisherAcademic Press Inc.
Pages241-268
Number of pages28
ISBN (Print)9780128127940
DOIs
StatePublished - 2018

Publication series

NameMethods in Enzymology
Volume606
ISSN (Print)0076-6879
ISSN (Electronic)1557-7988

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology

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    Wang, B., LaMattina, J. W., Badding, E. D., Gadsby, L. K., Grove, T. L., & Booker, S. J. (2018). Using Peptide Mimics to Study the Biosynthesis of the Side-Ring System of Nosiheptide. In V. Bandarian (Ed.), Methods in Enzymology (pp. 241-268). (Methods in Enzymology; Vol. 606). Academic Press Inc.. https://doi.org/10.1016/bs.mie.2018.06.005