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Pyruvate Kinase Regulates the Pentose-Phosphate Pathway in Response to Hypoxia in Mycobacterium tuberculosis.
Zhong, Wenhe; Guo, Jingjing; Cui, Liang; Chionh, Yok Hian; Li, Kuohan; El Sahili, Abbas; Cai, Qixu; Yuan, Meng; Michels, Paul A M; Fothergill-Gilmore, Linda A; Walkinshaw, Malcolm D; Mu, Yuguang; Lescar, Julien; Dedon, Peter C.
Afiliación
  • Zhong W; Antimicrobial Resistance Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology, 1 CREATE Way, 138602, Singapore; NTU Institute of Structural Biology, Nanyang Technological University, 636921, Singapore.
  • Guo J; Singapore Centre for Environmental Sciences Engineering (SCELSE), Nanyang Technological University, 60 Nanyang Drive, 637551, Singapore; College of Life Sciences, Nanjing Agricultural University, Nanjing 210095, China.
  • Cui L; Antimicrobial Resistance Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology, 1 CREATE Way, 138602, Singapore.
  • Chionh YH; Antimicrobial Resistance Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology, 1 CREATE Way, 138602, Singapore.
  • Li K; NTU Institute of Structural Biology, Nanyang Technological University, 636921, Singapore; Lee Kong Chian School of Medicine, Nanyang Technological University, 59 Nanyang Drive, 636921, Singapore; School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, 637551, Singapore.
  • El Sahili A; NTU Institute of Structural Biology, Nanyang Technological University, 636921, Singapore; School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, 637551, Singapore.
  • Cai Q; Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
  • Yuan M; Institute of Quantitative Biology, Biochemistry and Biotechnology, University of Edinburgh, King's Buildings, Edinburgh EH9 3BF, UK.
  • Michels PAM; Institute of Quantitative Biology, Biochemistry and Biotechnology, University of Edinburgh, King's Buildings, Edinburgh EH9 3BF, UK.
  • Fothergill-Gilmore LA; Institute of Quantitative Biology, Biochemistry and Biotechnology, University of Edinburgh, King's Buildings, Edinburgh EH9 3BF, UK.
  • Walkinshaw MD; Institute of Quantitative Biology, Biochemistry and Biotechnology, University of Edinburgh, King's Buildings, Edinburgh EH9 3BF, UK.
  • Mu Y; School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, 637551, Singapore. Electronic address: ygmu@ntu.edu.sg.
  • Lescar J; NTU Institute of Structural Biology, Nanyang Technological University, 636921, Singapore; School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, 637551, Singapore. Electronic address: julien@ntu.edu.sg.
  • Dedon PC; Antimicrobial Resistance Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology, 1 CREATE Way, 138602, Singapore; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: pcdedon@mit.edu.
J Mol Biol ; 431(19): 3690-3705, 2019 09 06.
Article en En | MEDLINE | ID: mdl-31381898
In response to the stress of infection, Mycobacterium tuberculosis (Mtb) reprograms its metabolism to accommodate nutrient and energetic demands in a changing environment. Pyruvate kinase (PYK) is an essential glycolytic enzyme in the phosphoenolpyruvate-pyruvate-oxaloacetate node that is a central switch point for carbon flux distribution. Here we show that the competitive binding of pentose monophosphate inhibitors or the activator glucose 6-phosphate (G6P) to MtbPYK tightly regulates the metabolic flux. Intriguingly, pentose monophosphates were found to share the same binding site with G6P. The determination of a crystal structure of MtbPYK with bound ribose 5-phosphate (R5P), combined with biochemical analyses and molecular dynamic simulations, revealed that the allosteric inhibitor pentose monophosphate increases PYK structural dynamics, weakens the structural network communication, and impairs substrate binding. G6P, on the other hand, primes and activates the tetramer by decreasing protein flexibility and strengthening allosteric coupling. Therefore, we propose that MtbPYK uses these differences in conformational dynamics to up- and down-regulate enzymic activity. Importantly, metabolome profiling in mycobacteria reveals a significant increase in the levels of pentose monophosphate during hypoxia, which provides insights into how PYK uses dynamics of the tetramer as a competitive allosteric mechanism to retard glycolysis and facilitate metabolic reprogramming toward the pentose-phosphate pathway for achieving redox balance and an anticipatory metabolic response in Mtb.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Vía de Pentosa Fosfato / Piruvato Quinasa / Hipoxia / Mycobacterium tuberculosis Idioma: En Revista: J Mol Biol Año: 2019 Tipo del documento: Article País de afiliación: Singapur Pais de publicación: Países Bajos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Vía de Pentosa Fosfato / Piruvato Quinasa / Hipoxia / Mycobacterium tuberculosis Idioma: En Revista: J Mol Biol Año: 2019 Tipo del documento: Article País de afiliación: Singapur Pais de publicación: Países Bajos