The biosynthesis and discovery of lanthipeptides
type: CreativeWork
description: Natural products and their derivatives have been significant resources for the development of therapeutic compounds. They attracted interests from both academia and industry because of their high structural diversity and potential applications. Lanthipeptides are one class of natural products that have provided antibiotics to the food industry and drug candidates for treating human diseases. Lanthipeptides are polypeptides enzymatically decorated with lanthionine rings and sometimes other post-translational modifications, which dramatically elevate their protease-resistances, improved their chemical stabilities, and increased their structural complexity. To add onto the structure knowledge and biosynthetic toolkits for lanthipeptides, I investigated the biosynthesis and discovery of lanthipeptides during my Ph.D training. Duramycin/cinnamycin-type of lanthipeptides interact tightly with phosphatidylethanolamine and several of their members displayed high potential to be drug candidates. Duramycin contains an activity-essential lysinoalanine ring which is installed by a previously unknown hypothetical protein, DurN. In Chapter 2, I described the mechanism of action studies on DurN. I reconstituted the in vitro activity of DurN. Together with Dr. Cogan, we obtained the co-crystal structures of DurN with its product or substrate analog. We demonstrated that DurN catalyzes the lysinoalanine formation through a unique substrate-assisted catalysis mechanism. Enlightened by the biosynthesis of lanthipeptide, I further designed and initiated a proof-of-concept lanthipeptide discovery project based on the predictions for the potential mode of action of natural products, which is described in Chapter 3. I hypothesized that if the gene encoding a small molecule-processing enzyme locates in the biosynthetic gene cluster of a natural product on the bacterial genome, this processing enzyme may function as the immunity protein to prevent producer viability loss during the producti…
abstract: Natural products and their derivatives have been significant resources for the development of therapeutic compounds. They attracted interests from both academia and industry because of their high structural diversity and potential applications. Lanthipeptides are one class of natural products that have provided antibiotics to the food industry and drug candidates for treating human diseases. Lanthipeptides are polypeptides enzymatically decorated with lanthionine rings and sometimes other post-translational modifications, which dramatically elevate their protease-resistances, improved their chemical stabilities, and increased their structural complexity. To add onto the structure knowledge and biosynthetic toolkits for lanthipeptides, I investigated the biosynthesis and discovery of lanthipeptides during my Ph.D training. Duramycin/cinnamycin-type of lanthipeptides interact tightly with phosphatidylethanolamine and several of their members displayed high potential to be drug candidates. Duramycin contains an activity-essential lysinoalanine ring which is installed by a previously unknown hypothetical protein, DurN. In Chapter 2, I described the mechanism of action studies on DurN. I reconstituted the in vitro activity of DurN. Together with Dr. Cogan, we obtained the co-crystal structures of DurN with its product or substrate analog. We demonstrated that DurN catalyzes the lysinoalanine formation through a unique substrate-assisted catalysis mechanism. Enlightened by the biosynthesis of lanthipeptide, I further designed and initiated a proof-of-concept lanthipeptide discovery project based on the predictions for the potential mode of action of natural products, which is described in Chapter 3. I hypothesized that if the gene encoding a small molecule-processing enzyme locates in the biosynthetic gene cluster of a natural product on the bacterial genome, this processing enzyme may function as the immunity protein to prevent producer viability loss during the producti…
author: An, Linna
language: en
keywords: lanthipeptide, biosynthesis, lipid II, duramycin, lysinoalanine, haloduracin.
date published: 2020-03-02T22:15:02Z
date modified: 2026-07-22T22:24:45Z
provider: University of Illinois - Urbana-Champaign
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Illinois at Urbana-Champaign

PropertyValue
property ID: Handle
value: http://hdl.handle.net/2142/106356