Cholesterol Catabolism by Mycobacterium tuberculosis Requires Transcriptional and Metabolic Adaptations

Methylcitrate cycle defines the bactericidal essentiality of isocitrate lyase for survival of Mycobacterium tuberculosis on fatty acids

“…We further found that VB 12 could also augment the growth-promoting effects of dextrose and/or aspartate on ICL-deficient Mtb metabolizing acetate, as reported by its ability to reduce and/or eliminate the lag phase of growth observed in Fig. 2A, and support growth on propionate concentrations up to fivefold higher (0.05%) than those achievable in the absence of VB 12 (Fig. 2 D-F), respectively.…”

“…S3B and S5 A and B). Consistent with the specific role of VB 12 as a cofactor for the terminal enzyme of the methlymalonyl-CoA pathway, methylmalonyl-CoA mutase (which catalyzes the interconversion of methylmalonyl-CoA and succinyl-CoA), we discovered that ICLdeficient Mtb cultured on propionate accumulated a second CoA species matching that of methylmalonyl-CoA, whose accumulation is predicted to arise from the carboxylation of excess propionyl-CoA by propionyl-CoA carboxylase (the first enzyme of the methylmalonyl-CoA pathway), and whose abundance decreased in response to VB 12 . Levels of acetyl-CoA, in contrast, were unchanged (Fig.…”

“…Defects in propionate metabolism have been associated with a broad range of secondary effects arising from the accumulation of propionyl-CoA and/or propionate-derived metabolites. These secondary effects include the inhibition of enzymes involved in branched chain amino acid turnover, and those of the pyruvate dehydrogenase complex and electron transport chain and, ultimately, result in a cellular acidosis (9)(10)(11)(12). Membrane potential and cytosolic pH homeostasis are essential for the survival of all cells and potentially more so for those residing in acidic niches, including the phagosomes of immune-activated macrophages (13,14).…”

“…Lack of MCL activity converts Mtb's methylcitrate cycle into a "dead end" pathway that sequesters tricarboxylic acid (TCA) cycle intermediates into methylcitrate cycle intermediates, depletes gluconeogenic precursors, and results in defects of membrane potential and intrabacterial pH. Activation of an alternative vitamin B 12 -dependent pathway of propionate metabolism led to selective corrections of TCA cycle activity, membrane potential, and intrabacterial pH that specifically restored survival, but not growth, of ICL-deficient Mtb metabolizing acetate or propionate. These results thus resolve the biochemical basis of essentiality for Mtb's ICLs and survival on fatty acids.…”

E1 of α-ketoglutarate dehydrogenase defends Mycobacterium tuberculosis against glutamate anaplerosis and nitroxidative stress

“…Thus, elevation of SSA could reflect the joint impact of two effects of HOAS deficiency: increased activity of the GABA shunt and inhibition of SSADH activity by increased glyoxylate. The toxic potential of SSA illustrates the principle that intermediary metabolism produces not just molecules that sustain life but life-threatening molecules as well, as shown for Mtb, which also accumulates branched chain α-ketoacids, propionate, maltose 1-phosphate, or glycerol phosphate when the relevant metabolic pathways are disrupted by chemical or genetic means (5,8,(43)(44)(45)(46)(47).…”