Flexible nitrogen utilisation by the metabolic generalist pathogen Mycobacterium tuberculosis

Abstract

Bacterial metabolism is fundamental to survival and pathogenesis. We explore how Mycobacterium tuberculosis utilises amino acids as nitrogen sources, using a combination of bacterial physiology and stable isotope tracing coupled to mass spectrometry metabolomics methods. Our results define core properties of the nitrogen metabolic network from M. tuberculosis, such as: (i) the lack of homeostatic control of certain amino acid pool sizes; (ii) similar rates of utilisation of different amino acids as sole nitrogen sources; (iii) improved nitrogen utilisation from amino acids compared to ammonium; and (iv) co-metabolism of nitrogen sources. Finally, we discover that alanine dehydrogenase is involved in ammonium assimilation in M. tuberculosis, in addition to its essential role in alanine utilisation as a nitrogen source. This study represents the first in-depth analysis of nitrogen source utilisation by M. tuberculosis and reveals a flexible metabolic network with characteristics that are likely a product of evolution in the human host.

Aspartate aminotransferase Rv3722c governs aspartate-dependent nitrogen metabolism in Mycobacterium tuberculosis

“…Aminotransferases are, therefore, indispensable for the liberation and distribution of nitrogen from amino acids. The aminotransferases involved in nitrogen distribution and their essentiality in Mtb, however, remain largely uncharacterized 43 .…”

N-Pyrazinoyl Substituted Amino Acids as Potential Antimycobacterial Agents—the Synthesis and Biological Evaluation of Enantiomers

“…Mtb as any other bacterium is dependent on nitrogen uptake to synthesize vital biomolecules. However, Mtb has been found to prefer proteinogenic aa as the source of nitrogen over ammonium chloride when cultured in vitro [67,68]. Therefore, if the appropriate mechanisms and enzymes involved in these metabolic pathways were identified, the use of aa derived prodrugs could 'trick' Mtb to cleave off the aa and at the same time release the active form of the drug inside the cell.…”

Non-coding RNAs control metabolic state in mycobacteria

“…The ability of mycobacteria to sense oxygen and oxidative stress and the sensors involved in these has been the subject of study for decades (48) (49). However, recent studies highlight the metabolic flexibility of these bacteria, evident in their ability to utilize nitrogen and sulfur for growth and survival (50). Nitrogen metabolism is relevant for growth and virulence of pathogenic mycobacteria like Mtb in oxygen-starved niches such as the lung granulomas.…”