The anaplerotic node is essential for the intracellular survival of Mycobacterium tuberculosis

The Journal of Biological Chemistry
Piyali BasuDany J V Beste

Abstract

Enzymes at the phosphoenolpyruvate (PEP)-pyruvate-oxaloacetate or anaplerotic (ANA) node control the metabolic flux to glycolysis, gluconeogenesis, and anaplerosis. Here we used genetic, biochemical, and 13C isotopomer analysis to characterize the role of the enzymes at the ANA node in intracellular survival of the world's most successful bacterial pathogen, Mycobacterium tuberculosis (Mtb). We show that each of the four ANA enzymes, pyruvate carboxylase (PCA), PEP carboxykinase (PCK), malic enzyme (MEZ), and pyruvate phosphate dikinase (PPDK), performs a unique and essential metabolic function during the intracellular survival of Mtb. We show that in addition to PCK, intracellular Mtb requires PPDK as an alternative gateway into gluconeogenesis. Propionate and cholesterol detoxification was also identified as an essential function of PPDK revealing an unexpected role for the ANA node in the metabolism of these physiologically important intracellular substrates and highlighting this enzyme as a tuberculosis (TB)-specific drug target. We show that anaplerotic fixation of CO2 through the ANA node is essential for intracellular survival of Mtb and that Mtb possesses three enzymes (PCA, PCK, and MEZ) capable of fulfilling this func...Continue Reading

References

Jun 1, 1985·Journal of General Microbiology·D E MinnikinM Ridell
Jul 22, 2004·European Journal of Biochemistry·Matthias Brock, Wolfgang Buckel
Aug 17, 2005·FEMS Microbiology Reviews·Uwe Sauer, Bernhard J Eikmanns
May 25, 2007·Genome Biology·Dany J V BesteJohnjoe McFadden
Mar 13, 2008·Proceedings of the National Academy of Sciences of the United States of America·Amit K Pandey, Christopher M Sassetti
Oct 17, 2008·Nature Reviews. Microbiology·Julia C van KesselGraham F Hatfull
Jun 23, 2009·Journal of Bacteriology·Jennifer C ChangDavid R Sherman
Apr 9, 2010·The Journal of Biological Chemistry·Anil K OjhaGraham F Hatfull
Apr 23, 2010·Proceedings of the National Academy of Sciences of the United States of America·Arren Bar-EvenRon Milo
May 5, 2010·Proceedings of the National Academy of Sciences of the United States of America·Joeli MarreroSabine Ehrt
May 13, 2011·Trends in Microbiology·Kyu Y RheeCarl Nathan
Sep 20, 2011·Trends in Microbiology·Hugues OuelletPaul R Ortiz de Montellano
Mar 1, 2012·Chemistry & Biology·Jennifer E GriffinChristopher M Sassetti
Jan 12, 2013·The Journal of Biological Chemistry·Wonsik LeeDavid G Russell
Feb 18, 2014·Applied and Environmental Microbiology·Guangfei HaoYong Q Chen
Dec 3, 2014·Seminars in Immunology·Rienk A RienksmaVitor A P Martins dos Santos
Aug 19, 2015·Frontiers in Microbiology·Sebastiaan K SpaansServé W M Kengen
Dec 22, 2016·British Journal of Pharmacology·Areej Abuhammad

❮ Previous
Next ❯

Citations

Jun 17, 2020·PLoS Computational Biology·Víctor A López-AgudeloRigoberto Rios-Estepa
Nov 17, 2019·Progress in Biophysics and Molecular Biology·Kiel HardsGregory M Cook
May 5, 2021·Molecular Systems Biology·Khushboo BorahDany J V Beste
Aug 14, 2021·PloS One·Janine HofmannFiona M Sansom

❮ Previous
Next ❯

Methods Mentioned

BETA
PCA
PCR
FCS

Related Concepts

Related Feeds

ASBMB Publications

The American Society for Biochemistry and Molecular Biology (ASBMB) includes the Journal of Biological Chemistry, Molecular & Cellular Proteomics, and the Journal of Lipid Research. Discover the latest research from ASBMB here.