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The anaplerotic node is essential for the intracellular survival of.

The anaplerotic node is essential for the intracellular survival of.
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Basu P, Sanhu N, Bhatt A, Singh A, Balhana R, Gobe I, Crowhurst NA, Mendum TA, Gao L, Ward JL, Beale M, McFadden J, Beste DJ,


Basu P, Sanhu N, Bhatt A, Singh A, Balhana R, Gobe I, Crowhurst NA, Mendum TA, Gao L, Ward JL, Beale M, McFadden J, Beste DJ, (click to view)

Basu P, Sanhu N, Bhatt A, Singh A, Balhana R, Gobe I, Crowhurst NA, Mendum TA, Gao L, Ward JL, Beale M, McFadden J, Beste DJ,

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The Journal of biological chemistry 2018 02 23() pii jbc.RA118.001839
Abstract

Enzymes at the PEP-pyruvate-oxaloacetate or anaplerotic (ANA) node control the metabolic flux to glycolysis, gluconeogenesis and anaplerosis. Here we use genetic, biochemical andC isotopomer analysis to characterize the role of the enzymes at the ANA node during the intracellular survival of the world’s most successful bacterial pathogen,(). 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  We show that in addition to PCK, intracellularrequires 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 COthrough the ANA node is essential for intracellular survival and thatpossesses three enzymes (PCA, PCK and MEZ) capable of fulfilling this function. In addition to providing a back-up role in anaplerosis we show that MEZ also has a role in lipid biosynthesis.  MEZ knock out strains have an altered cell wall and were deficient in the initial entry into macrophages. This work reveals the ANA node as a focal point for controlling the intracellular replication ofwhich goes beyond canonical gluconeogenesis and represents a promising target for designing novel anti-TB drugs.

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