Title of Oral/Poster Presentation

Understanding Substrate Promiscuity in Two Non-Ribosomal Peptide Synthetase Systems

Presenter Information

Kyle MayFollow

Class

Article

Department

Chemistry and Biochemistry

Faculty Mentor

Joanie Hevel

Presentation Type

Oral Presentation

Abstract

In nature, many bacteria and other microorganisms express large protein complexes referred to as Non-Ribosomal Peptide Synthetases (NRPS) which are responsible for the synthesis of natural product peptides. These synthetases have a modular, assembly line-like structural arrangement, and often produce important biologically relevant products, such as antibiotics, siderophores, pesticides, toxins, and many others. Due to the increasing problem of antibiotic resistance in many harmful pathogens, researchers would like to utilize these systems for their potential use in the engineering of novel, designer drugs and other compounds. Beauveria bassiana, a naturally occurring soil fungus, utilizes two such NRPS systems, termed BSLS and BEAS, which produce the natural products bassianolide and beauvericin, respectively. These compounds are responsible for the insecticidal properties of Beauveria bassiana, and beauvericin in particular is also currently under investigation for its antitumor properties. These two complexes possess a high level of similarity in primary sequence and modular arrangement, yet produce two very distinct products, the mechanism for which is still unknown. Both of these NRPSs also possess a unique methyltransferase domain insertion within the second adenylation domain. We find that the substrate specificity of these methyltransferases can be altered when expressed as an isolated protein as compared to being inserted within the full complex, suggesting that the protein environment can influence the exact type of natural product formed. Thus, we are interested in understanding the properties and dynamics within these two systems which are responsible for natural product determination. Understanding the dynamics of these systems may allow us to utilize this unique chemistry for the purpose of designing novel drugs and other compounds.

Start Date

4-9-2015 12:00 PM

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Apr 9th, 12:00 PM

Understanding Substrate Promiscuity in Two Non-Ribosomal Peptide Synthetase Systems

In nature, many bacteria and other microorganisms express large protein complexes referred to as Non-Ribosomal Peptide Synthetases (NRPS) which are responsible for the synthesis of natural product peptides. These synthetases have a modular, assembly line-like structural arrangement, and often produce important biologically relevant products, such as antibiotics, siderophores, pesticides, toxins, and many others. Due to the increasing problem of antibiotic resistance in many harmful pathogens, researchers would like to utilize these systems for their potential use in the engineering of novel, designer drugs and other compounds. Beauveria bassiana, a naturally occurring soil fungus, utilizes two such NRPS systems, termed BSLS and BEAS, which produce the natural products bassianolide and beauvericin, respectively. These compounds are responsible for the insecticidal properties of Beauveria bassiana, and beauvericin in particular is also currently under investigation for its antitumor properties. These two complexes possess a high level of similarity in primary sequence and modular arrangement, yet produce two very distinct products, the mechanism for which is still unknown. Both of these NRPSs also possess a unique methyltransferase domain insertion within the second adenylation domain. We find that the substrate specificity of these methyltransferases can be altered when expressed as an isolated protein as compared to being inserted within the full complex, suggesting that the protein environment can influence the exact type of natural product formed. Thus, we are interested in understanding the properties and dynamics within these two systems which are responsible for natural product determination. Understanding the dynamics of these systems may allow us to utilize this unique chemistry for the purpose of designing novel drugs and other compounds.