Allosteric pyruvate kinase-based “logic gate” synergistically senses energy and sugar levels in Mycobacterium tuberculosis
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...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
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Nature Publishing Group
2018
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| Online Access: | http://hdl.handle.net/1721.1/113572 https://orcid.org/0000-0003-0011-3067 |
| _version_ | 1811091435281186816 |
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| author | Zhong, Wenhe Cui, Liang Goh, Boon Chong Cai, Qixu Ho, Peiying Chionh, Yok Hian Yuan, Meng Sahili, Abbas El Fothergill-Gilmore, Linda A. Walkinshaw, Malcolm D. Lescar, Julien Dedon, Peter C |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Zhong, Wenhe Cui, Liang Goh, Boon Chong Cai, Qixu Ho, Peiying Chionh, Yok Hian Yuan, Meng Sahili, Abbas El Fothergill-Gilmore, Linda A. Walkinshaw, Malcolm D. Lescar, Julien Dedon, Peter C |
| author_sort | Zhong, Wenhe |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T15:02:22Z |
| format | Article |
| id | mit-1721.1/113572 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T15:02:22Z |
| publishDate | 2018 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | mit-1721.1/1135722022-10-02T00:10:42Z Allosteric pyruvate kinase-based “logic gate” synergistically senses energy and sugar levels in Mycobacterium tuberculosis Zhong, Wenhe Cui, Liang Goh, Boon Chong Cai, Qixu Ho, Peiying Chionh, Yok Hian Yuan, Meng Sahili, Abbas El Fothergill-Gilmore, Linda A. Walkinshaw, Malcolm D. Lescar, Julien Dedon, Peter C Massachusetts Institute of Technology. Department of Biological Engineering Dedon, Peter C 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. 2018-02-12T16:00:47Z 2018-02-12T16:00:47Z 2017-12 2017-07 2018-02-02T19:40:33Z Article http://purl.org/eprint/type/JournalArticle 2041-1723 http://hdl.handle.net/1721.1/113572 Zhong, Wenhe et al. “Allosteric Pyruvate Kinase-Based ‘logic Gate’ Synergistically Senses Energy and Sugar Levels in Mycobacterium Tuberculosis.” Nature Communications 8, 1 (December 2017): 1986 © 2017 The Author(s) https://orcid.org/0000-0003-0011-3067 http://dx.doi.org/10.1038/s41467-017-02086-y Nature Communications Creative Commons Attribution 4.0 International License https://creativecommons.org/licenses/by/4.0/ application/pdf Nature Publishing Group Nature Communications |
| spellingShingle | Zhong, Wenhe Cui, Liang Goh, Boon Chong Cai, Qixu Ho, Peiying Chionh, Yok Hian Yuan, Meng Sahili, Abbas El Fothergill-Gilmore, Linda A. Walkinshaw, Malcolm D. Lescar, Julien Dedon, Peter C Allosteric pyruvate kinase-based “logic gate” synergistically senses energy and sugar levels in Mycobacterium tuberculosis |
| title | Allosteric pyruvate kinase-based “logic gate” synergistically senses energy and sugar levels in Mycobacterium tuberculosis |
| title_full | Allosteric pyruvate kinase-based “logic gate” synergistically senses energy and sugar levels in Mycobacterium tuberculosis |
| title_fullStr | Allosteric pyruvate kinase-based “logic gate” synergistically senses energy and sugar levels in Mycobacterium tuberculosis |
| title_full_unstemmed | Allosteric pyruvate kinase-based “logic gate” synergistically senses energy and sugar levels in Mycobacterium tuberculosis |
| title_short | Allosteric pyruvate kinase-based “logic gate” synergistically senses energy and sugar levels in Mycobacterium tuberculosis |
| title_sort | allosteric pyruvate kinase based logic gate synergistically senses energy and sugar levels in mycobacterium tuberculosis |
| url | http://hdl.handle.net/1721.1/113572 https://orcid.org/0000-0003-0011-3067 |
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