Borosins: The biosynthesis of ribosomal alpha-N-methylated peptides from fungi and bacteria
2020-05
Loading...
View/Download File
Persistent link to this item
Statistics
View StatisticsJournal Title
Journal ISSN
Volume Title
Title
Borosins: The biosynthesis of ribosomal alpha-N-methylated peptides from fungi and bacteria
Authors
Published Date
2020-05
Publisher
Type
Thesis or Dissertation
Abstract
Natural products are bioactive small molecules synthesized by living organisms. They are often used in medicine and industry as pharmaceuticals, flavors, pigments, and more. α-N-Methylation of the peptide backbone, as seen in the immunosuppressant natural product cyclosporin A, confers desirable pharmacokinetic characteristics such as resistance against proteolytic degradation, enhanced rigidity/target specificity, membrane permeability, and drug oral bioavailability. Until recently, it was thought that this backbone modification was only naturally accessible through non-ribosomal peptide synthesis. Our discovery of the borosin family of peptide natural products challenged that assumption by identifying nematocidal metabolites as α-N-methylated, ribosomally synthesized and posttranslationally modified peptides (RiPPs, a quickly growing class of natural products known for their modular and potentially engineerable biosynthesis). The first borosins we discovered, found primarily in basidiomycete fungi, are signified by a unique autocatalytic mechanism for incorporating α-N-methylations, where the natural product sequence is tethered in a single protein to an iteratively acting autocatalytic methyltransferase. In-depth bioinformatics analysis has since revealed an even more diverse subfamily of putative α-N-methylated peptides that have natural product precursors encoded in trans to the methyltransferase. These so-called “split borosins” are found primarily in bacteria. This thesis describes how borosins fit into the larger field of natural product and RiPP biosynthesis. It includes the discovery of additional domain architectures for the fused and split systems as well as a structural and biochemical analysis of a putative split borosin system in the bacterium Shewanella oneidensis MR-1. We have also begun to investigate the native role the split borosin peptide natural product may play in S. oneidensis MR-1 through the creation of genetic knockouts and in vivo phenotyping experiments.
Keywords
Description
University of Minnesota Ph.D. dissertation. 2020. Major: Biochemistry, Molecular Bio, and Biophysics. Advisor: Michael Freeman. 1 computer file (PDF); 342 pages.
Related to
Replaces
License
Collections
Series/Report Number
Funding information
Isbn identifier
Doi identifier
Previously Published Citation
Suggested citation
Miller, Fredarla. (2020). Borosins: The biosynthesis of ribosomal alpha-N-methylated peptides from fungi and bacteria. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/241439.
Content distributed via the University Digital Conservancy may be subject to additional license and use restrictions applied by the depositor. By using these files, users agree to the Terms of Use. Materials in the UDC may contain content that is disturbing and/or harmful. For more information, please see our statement on harmful content in digital repositories.