title: E1 of α-ketoglutarate dehydrogenase defends Mycobacterium tuberculosis against glutamate anaplerosis and nitroxidative stress.
abstract: Enzymes of central carbon metabolism (CCM) in Mycobacterium tuberculosis (Mtb) make an important contribution to the pathogen's virulence. Evidence is emerging that some of these enzymes are not simply playing the metabolic roles for which they are annotated, but can protect the pathogen via additional functions. Here, we found that deficiency of 2-hydroxy-3-oxoadipate synthase (HOAS), the E1 component of the α-ketoglutarate (α-KG) dehydrogenase complex (KDHC), did not lead to general metabolic perturbation or growth impairment of Mtb, but only to the specific inability to cope with glutamate anaplerosis and nitroxidative stress. In the former role, HOAS acts to prevent accumulation of aldehydes, including growth-inhibitory succinate semialdehyde (SSA). In the latter role, HOAS can participate in an alternative four-component peroxidase system, HOAS/dihydrolipoyl acetyl transferase (DlaT)/alkylhydroperoxide reductase colorless subunit gene (ahpC)-neighboring subunit (AhpD)/AhpC, using α-KG as a previously undescribed source of electrons for reductase action. Thus, instead of a canonical role in CCM, the E1 component of Mtb's KDHC serves key roles in situational defense that contribute to its requirement for virulence in the host. We also show that pyruvate decarboxylase (AceE), the E1 component of pyruvate dehydrogenase (PDHC), can participate in AceE/DlaT/AhpD/AhpC, using pyruvate as a source of electrons for reductase action. Identification of these systems leads us to suggest that Mtb can recruit components of its CCM for reactive nitrogen defense using central carbon metabolites.
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10065;
authors.forename: Christina
authors.initials: C
authors.lastname: Maksymiuk
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10065;
authors.forename: Anand
authors.initials: A
authors.lastname: Balakrishnan
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10065;
authors.forename: Ruslana
authors.initials: R
authors.lastname: Bryk
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, NY 10065.
authors.forename: Kyu Y
authors.initials: KY
authors.lastname: Rhee
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10065; cnathan@med.cornell.edu.
authors.forename: Carl F
authors.initials: CF
authors.lastname: Nathan
mesh_terms: D000818:Animals; D018698:Glutamic Acid / Q000378:metabolism*; D007655:Ketoglutarate Dehydrogenase Complex / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000378:metabolism*; D015538:Nitrosation; D018384:Oxidative Stress
chemical_list: D018698:Glutamic Acid; D007655:Ketoglutarate Dehydrogenase Complex
keywords: Mycobacterium tuberculosis; hydroxyoxoadipate synthase; peroxidase; peroxynitrite reductase; α-ketoglutarate dehydrogenase