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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Watchalee Chuenchor & Tzanko I. Doukov & Kai-Ti Chang & Melissa Resto & Chang-Soo Yun & Barbara Gerratana, 2020. "Different ways to transport ammonia in human and Mycobacterium tuberculosis NAD+ synthetases," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-019-13845-4
    DOI: 10.1038/s41467-019-13845-4
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