Different ways to transport ammonia in human and Mycobacterium tuberculosis NAD+ synthetases

Watchalee Chuenchor, Tzanko I. Doukov, Kai-Ti Chang, Melissa Resto, Chang-Soo Yun and Barbara Gerratana ()
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Watchalee Chuenchor: University of Maryland
Tzanko I. Doukov: Stanford Synchrotron Radiation Lightsource
Kai-Ti Chang: University of Maryland
Melissa Resto: University of Maryland
Chang-Soo Yun: Korea Research Institute of Chemical Technology
Barbara Gerratana: University of Maryland

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: Abstract NAD+ synthetase is an essential enzyme of de novo and recycling pathways of NAD+ biosynthesis in Mycobacterium tuberculosis but not in humans. This bifunctional enzyme couples the NAD+ synthetase and glutaminase activities through an ammonia tunnel but free ammonia is also a substrate. Here we show that the Homo sapiens NAD+ synthetase (hsNadE) lacks substrate specificity for glutamine over ammonia and displays a modest activation of the glutaminase domain compared to tbNadE. We report the crystal structures of hsNadE and NAD+ synthetase from M. tuberculosis (tbNadE) with synthetase intermediate analogues. Based on the observed exclusive arrangements of the domains and of the intra- or inter-subunit tunnels we propose a model for the inter-domain communication mechanism for the regulation of glutamine-dependent activity and NH3 transport. The structural and mechanistic comparison herein reported between hsNadE and tbNadE provides also a starting point for future efforts in the development of anti-TB drugs.

Date: 2020
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DOI: 10.1038/s41467-019-13845-4

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