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Allosteric pyruvate kinase-based "logic gate" synergistically senses energy and sugar levels in Mycobacterium tuberculosis.

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Zhong W, Cui L, Goh BC, Cai Q, Ho P, Chionh YH, Yuan M, Sahili AE, Fothergill-Gilmore LA, Walkinshaw MD, Lescar J, Dedon PC
OpenAccess logo Nat Commun 8 1986 (2017)
Related entries: 5wrp, 5ws9, 5wsa, 5wsb, 5wsc

Cited: 27 times
EuropePMC logo PMID: 29215013

Abstract

Pyruvate kinase (PYK) is an essential glycolytic enzyme that controls glycolytic flux and is critical for ATP production in all organisms, with tight regulation by multiple metabolites. Yet the allosteric mechanisms governing PYK activity in bacterial pathogens are poorly understood. Here we report biochemical, structural and metabolomic evidence that Mycobacterium tuberculosis (Mtb) PYK uses AMP and glucose-6-phosphate (G6P) as synergistic allosteric activators that function as a molecular "OR logic gate" to tightly regulate energy and glucose metabolism. G6P was found to bind to a previously unknown site adjacent to the canonical site for AMP. Kinetic data and structural network analysis further show that AMP and G6P work synergistically as allosteric activators. Importantly, metabolome profiling in the Mtb surrogate, Mycobacterium bovis BCG, reveals significant changes in AMP and G6P levels during nutrient deprivation, which provides insights into how a PYK OR gate would function during the stress of Mtb infection.

Articles - 5ws8 mentioned but not cited (1)

  1. Allosteric pyruvate kinase-based "logic gate" synergistically senses energy and sugar levels in Mycobacterium tuberculosis. Zhong W, Cui L, Goh BC, Cai Q, Ho P, Chionh YH, Yuan M, Sahili AE, Fothergill-Gilmore LA, Walkinshaw MD, Lescar J, Dedon PC. Nat Commun 8 1986 (2017)


Reviews citing this publication (5)

  1. Metabolic principles of persistence and pathogenicity in Mycobacterium tuberculosis. Ehrt S, Schnappinger D, Rhee KY. Nat Rev Microbiol 16 496-507 (2018)
  2. An overview of structure, function, and regulation of pyruvate kinases. Schormann N, Hayden KL, Lee P, Banerjee S, Chattopadhyay D. Protein Sci 28 1771-1784 (2019)
  3. Integrated Computational Approaches and Tools forAllosteric Drug Discovery. Sheik Amamuddy O, Veldman W, Manyumwa C, Khairallah A, Agajanian S, Oluyemi O, Verkhivker G, Tastan Bishop O. Int J Mol Sci 21 E847 (2020)
  4. Beyond mitochondria: Alternative energy-producing pathways from all strata of life. Auger C, Vinaik R, Appanna VD, Jeschke MG. Metabolism 118 154733 (2021)
  5. All DACs in a Row: Domain Architectures of Bacterial and Archaeal Diadenylate Cyclases. Galperin MY. J Bacteriol 205 e0002323 (2023)

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