Allosteric regulation of pyruvate kinase from Mycobacterium tuberculosis by metabolites

0501819 - ÚOCHB 2020 RIV NL eng J - Journal Article
Snášel, Jan - Pichová, Iva
Allosteric regulation of pyruvate kinase from Mycobacterium tuberculosis by metabolites.
Biochimica Et Biophysica Acta-Proteins and Proteomics. Roč. 1867, č. 2 (2019), s. 125-139. ISSN 1570-9639. E-ISSN 1878-1454
R&D Projects: GA MŠMT LO1302
Institutional support: RVO:61388963
Keywords : pyruvate kinase * Mycobacterium tuberculosis * allosteric regulation * metabolites * ions * metabolism
OECD category: Biochemistry and molecular biology
Impact factor: 2.371, year: 2019
Method of publishing: Limited access
https://www.sciencedirect.com/science/article/abs/pii/S1570963918302000?via%3Dihub

Mycobacterium tuberculosis (Mtb) causes both acute tuberculosis and latent, symptom-free infection that affects roughly one-third of the world's population. It is a globally important pathogen that poses multiple dangers. Mtb reprograms its metabolism in response to the host niche, and this adaptation contributes to its pathogenicity. Knowledge of the metabolic regulation mechanisms in Mtb is still limited. Pyruvate kinase, involved in the late stage of glycolysis, helps link various metabolic routes together. Here, we demonstrate that Mtb pyruvate kinase (Mtb PYK) predominantly catalyzes the reaction leading to the production of pyruvate, but its activity is influenced by multiple metabolites from closely interlinked pathways that act as allosteric regulators (activators and inhibitors). We identified allosteric activators and inhibitors of Mtb PYK originating from glycolysis, citrate cycle, nucleotide/nucleoside inter-conversion related pathways that had not been described so far. Enzyme was found to be activated by fructose-1,6-bisphosphate, ribose-5-phosphate, adenine, adenosine, hypoxanthine, inosine, L-2-phosphoglycerate, L-aspartate, glycerol-2-phosphate, glycerol-3-phosphate. On the other hand thiamine pyrophosphate, glyceraldehyde-3-phosphate and L-malate were identified as inhibitors of Mtb PYK. The detailed kinetic analysis indicated a morpheein model of Mtb PYK allosteric control which is strictly dependent on Mg2+ and substantially increased by the co-presence of Mg2+ and K+.
Permanent Link: http://hdl.handle.net/11104/0296398