Adenylating Enzymes in Mycobacterium tuberculosis as Drug Targets

Benjamin      P. Duckworth; Kathryn      M. Nelson; Courtney      C. Aldrich

Abstract

Adenylation or adenylate-forming enzymes (AEs) are widely found in nature and are responsible for the activation of carboxylic acids to intermediate acyladenylates, which are mixed anhydrides of AMP. In a second reaction, AEs catalyze the transfer of the acyl group of the acyladenylate onto a nucleophilic amino, alcohol, or thiol group of an acceptor molecule leading to amide, ester, and thioester products, respectively. Mycobacterium tuberculosis encodes for more than 60 adenylating enzymes, many of which represent potential drug targets due to their confirmed essentiality or requirement for virulence. Several strategies have been used to develop potent and selective AE inhibitors including highthroughput screening, fragment-based screening, and the rationale design of bisubstrate inhibitors that mimic the acyladenylate. In this review, a comprehensive analysis of the mycobacterial adenylating enzymes will be presented with a focus on the identification of small molecule inhibitors. Specifically, this review will cover the aminoacyl tRNAsynthetases (aaRSs), MenE required for menaquinone synthesis, the FadD family of enzymes including the fatty acyl- AMP ligases (FAAL) and the fatty acyl-CoA ligases (FACLs) involved in lipid metabolism, and the nonribosomal peptide synthetase adenylation enzyme MbtA that is necessary for mycobactin synthesis. Additionally, the enzymes NadE, GuaA, PanC, and MshC involved in the respective synthesis of NAD, guanine, pantothenate, and mycothiol will be discussed as well as BirA that is responsible for biotinylation of the acyl CoA-carboxylases.

Keywords: Adenylation, adenylate-forming, tuberculosis, bisubstrate inhibitor, adenylate-forming enzymes (AEs), nucleophilic amino, small molecule inhibitors, granuloma, acyl CoA-carboxylases, hiacetazone, fatty acyl-CoA ligases (FACLs), Tuberculosis (TB), antiretroviral drugs, multidrug resistant (MDR)