A Key Metabolic Protein in Active Mycobacterium tuberculosis: Insights into Carbon, Nitrogen, and Sulfur Metabolism.

Mycobacterium tuberculosis (Mtb) employs a highly adaptable network of metabolic pathways that are pivotal for its survival and pathogenesis within the host during both exponential growth and persistent infection phases. Central carbon metabolism in Mtb exhibits remarkable flexibility, enabling the bacterium to utilize diverse carbon sources efficiently. In the absence of glucose, Mtb preferentially metabolizes fatty acids as primary carbon substrates. This metabolic shift is supported by the glyoxylate shunt and methyl citrate cycle, which replenish tricarboxylic acid (TCA) cycle intermediates essential for energy production and biosynthesis. Key enzymes such as isocitrate lyase (icl) and methylcitrate lyase (mcl) facilitate the catabolism of fatty acids and maintain TCA cycle functionality, thereby sustaining bacterial growth under nutrient-limited conditions. Further enhancing metabolic adaptability, Mtb modulates central carbon metabolism through lysine acetylation, a posttranslational modification that regulates enzyme activity, particularly within fatty acid metabolic pathways. This regulatory mechanism allows Mtb to fine-tune its metabolic responses and optimize carbon utilization in response to fluctuating environmental nutrient availability.Nitrogen metabolism in Mtb is equally versatile, characterized by the capacity to utilize a variety of nitrogen sources. Amino acids such as glutamine, glutamate, aspartate, and asparagine serve as superior nitrogen donors compared to inorganic ammonium (NH₄