Central role of pyruvate kinase in carbon co-catabolism of mycobacterium tuberculosis

Tahel Noy, Olivia Vergnolle, Travis E. Hartman, Kyu Y. Rhee, William R. Jacobs, Michael Berney, John S. Blanchard

Research output: Contribution to journalArticlepeer-review

34 Scopus citations


Mycobacterium tuberculosis (Mtb) displays a high degree of metabolic plasticity to adapt to challenging host environments. Genetic evidence suggests that Mtb relies mainly on fatty acid catabolism in the host. However, Mtb also maintains a functional glycolytic pathway and its role in the cellular metabolism of Mtb has yet to be understood. Pyruvate kinase catalyzes the last and rate-limiting step in glycolysis and the Mtb genome harbors one putative pyruvate kinase (pykA, Rv1617). Here we show that pykA encodes an active pyruvate kinase that is allosterically activated by glucose 6-phosphate (Glc-6-P) and adenosine monophosphate (AMP). Deletion of pykA prevents Mtb growth in the presence of fermentable carbon sources and has a cidal effect in the presence of glucose that correlates with elevated levels of the toxic catabolite methylglyoxal. Growth attenuation was also observed in media containing a combination of short chain fatty acids and glucose and surprisingly, in media containing odd and even chain fatty acids alone. Untargeted high sensitivity metabolomics revealed that inactivation of pyruvate kinase leads to accumulation of phosphoenolpyruvate (P-enolpyruvate), citrate, and aconitate, which was consistent with allosteric inhibition of isocitrate dehydrogenase by P-enolpyruvate. This metabolic block could be relieved by addition of the α-ketoglutarate precursor glutamate. Taken together, our study identifies an essential role of pyruvate kinase in preventing metabolic block during carbon co-catabolism in Mtb.

Original languageEnglish (US)
Pages (from-to)7060-7069
Number of pages10
JournalJournal of Biological Chemistry
Issue number13
StatePublished - Mar 25 2016

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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