Tuberculosis (TB), is a major global pathogen caused by Mycobacterium tuberculosis (Mtb). TB is a major global pathogen: it is estimated that one-third of the world’s population are latently infected with Mtb, and that over 1.8 million people die from TB each year, more than HIV and malaria. Despite the global threat of TB there are limited studies to investigate the nutrient requirements and subsequent metabolism of these nutrients for this pathogenic organism. Therefore, new targets and drugs are urgently needed. Here we report the structures of the Mtb N-acetylglucosamine-6-phosphate deacetylase (NagA), an enzyme that is predicted to be essential in Mtb and responsible for the deacetylation of N-acetylglucosamine-6-phosphate (NAcGlcN6P) to glucosamine-6-phosphate (GlcN6P) - the key enzymatic step to generate essential amino-sugar precursors required for Mtb cell wall biosynthesis and influence recycling of Mtb cell wall peptidoglycan fragments. The structures reveal a two-subdomain architecture encompassing a (β/α)8 barrel that encloses the active-site and a small β-barrel domain and Fe2+ and Zn2+ present in its active-site. The structure is dimeric, with the active-site formed at the dimer interface and the structure of the NagA complex has enabled the mode of NAcGlcN6P substrate binding to be determined. Kinetic studies reveal a distinct preference for NAcGlcN6P over epimeric sugar derivatives and site-directed mutagenesis indicate the importance of conserved residues in the active site which underpin selective substrate recognition and catalysis. Our studies establish the mechanistic basis of substrate recognition for this important enzyme, providing a framework for exciting new opportunities for inhibitor design.

Structural and functional analysis of the N-acetylglucosamine-6-phosphate deacetylase (NagA) from Mycobacterium tuberculosis

255th National Meeting (2018)

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