Biosynthesis Guided the Discovery of Proteusin RiPP Natural Products
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Nguyen, Nguyet
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Abstract
The primary focus of this research revolves around proteusins, a group of secondary metabolites categorized as ribosomally synthesized and post-translationally modified peptides. The study delves into the distinctive properties of proteusins and their associated enzymes, particularly emphasizing YcaO cyclodehydratases and flavin-dependent halogenases, which are relatively understudied in this context. A significant milestone in my research was successfully determining the solution-state structure of a proteusin precursor peptide. This structural analysis unveiled a fascinating architecture of the proteusin leader peptide, featuring a well-organized α-helical bundle at the N-terminus and a highly unstructured region at the C-terminus. Regarding YcaO cyclodehydratases, a comprehensive investigation was conducted to examine the activity, substrate preference, and potential applications of two proteusin enzymes (SrpC, MprC) found in the srp and mpr biosynthetic gene clusters, respectively. Additionally, the research highlighted the first instance of peptide bromination by a flavin-dependent halogenase (SrpI) encoded in the srp biosynthetic gene cluster. By identifying the specific region on the precursor peptide interacting with the peptide brominase SrpI and validating it experimentally, a working model was developed using advanced computational modeling techniques and molecular dynamics (MD) simulations. This model sheds light on the intricate interaction between the peptide brominase SrpI and the proteusin precursor peptide, paving the way for potential applications of the halogenase SrpI as a biocatalyst for protein and peptide modification. The motivation behind this investigation lies in the aspiration to expand our understanding of RiPPs and explore their potential applications in various fields. By uncovering novel insights into proteusins and their enzymes, this research contributes to the growing knowledge surrounding RiPPs, and their potential applications in diverse areas such as drug discovery and peptide synthesis.
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2023-07-27
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Dissertation