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

Wenhe Zhong, Liang Cui, Boon Chong Goh, Qixu Cai, Peiying Ho, Yok Hian Chionh, Meng Yuan, Abbas El Sahili, Linda A. Fothergill-Gilmore, Malcolm D. Walkinshaw, Julien Lescar () and Peter C. Dedon ()
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Wenhe Zhong: Singapore-MIT Alliance for Research and Technology
Liang Cui: Singapore-MIT Alliance for Research and Technology
Boon Chong Goh: Singapore-MIT Alliance for Research and Technology
Qixu Cai: Hong Kong University of Science and Technology
Peiying Ho: Singapore-MIT Alliance for Research and Technology
Yok Hian Chionh: Singapore-MIT Alliance for Research and Technology
Meng Yuan: University of Edinburgh
Abbas El Sahili: Nanyang Technological University
Linda A. Fothergill-Gilmore: University of Edinburgh
Malcolm D. Walkinshaw: University of Edinburgh
Julien Lescar: Nanyang Technological University
Peter C. Dedon: Singapore-MIT Alliance for Research and Technology

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-02086-y

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