Date of Award

1-1-2017

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

College/School/Department

Department of Chemistry

Content Description

1 online resource (ii, xxxvi, 173 pages)

Dissertation/Thesis Chair

John T Welch

Committee Members

Alan Chen, Daniele Fabris, Alexander Shekhtman, Kathleen A McDonough

Keywords

NAD+, Nicotinamide, NMR, Pyrazinamide, SIRT6, Site Directed Mutagenesis, Sirtuins, Nuclear magnetic resonance spectroscopy

Subject Categories

Biochemistry | Chemistry

Abstract

The allosteric regulation of SIRT6 by nicotinamide (NAM), along with the growing evidence of this enzyme's key role in the immune response, prompted the mechanistic study of SIRT6 inhibition by pyrazinamide (PZA) and analogs. In our current study, PZA, an analog of NAM, was revealed to have a modest modulatory effect on SIRT6, an enzyme that regulates the NF-κB signaling pathway at the transcriptional level (a relevant pathway to inflammation). Similarly, the analogs of PZA, 5-Cl PZA, 5-MeO PZA, and POA exhibited a modulatory effect against SIRT6 in our in vitro studies, enabling identification of a potential new target for PZA and PZA analogs. These findings lead to the proposal of a new mechanism of action for PZA, a mechanism in which PZA may act as an in vivo immune modulator rather than as an antimicrobial agent. These results could lead to a rationalization of how modulation of the host inflammatory response influences tuberculosis infection.

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