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.
Highlights
Tuberculosis, caused by the bacillus Mycobacterium tuberculosis, is the greatest cause of death by a single infectious agent, surpassing deaths caused by HIV/AIDS1
The majority of amino acid intracellular pool sizes vary only modestly when M. tuberculosis is grown in media containing sole nitrogen sources different to NH4Cl (Fig. 2a, b)
An increase in intracellular pool size is observed for Gly, Ala, Val, Ile, Met, Pro, Phe, Tyr, Trp, Ser, Thr, Arg, and His when M. tuberculosis was cultured with the cognate amino acid as sole nitrogen source
Summary
Tuberculosis, caused by the bacillus Mycobacterium tuberculosis, is the greatest cause of death by a single infectious agent, surpassing deaths caused by HIV/AIDS1. In 201314 two key studies unveiled an important aspect of host-relevant nitrogen metabolism in M. tuberculosis, namely that host amino acids such as L-aspartate (Asp) and L-asparagine (Asn) were shown to be important sources of nitrogen during infection[17,18]. These findings open a new avenue in host-M. tuberculosis relevant metabolism, revealing the use of organic nitrogen sources by M. tuberculosis during infection. We describe our studies aimed at exploring core nitrogen metabolic network of M. tuberculosis (Fig. 1), using amino acids as nitrogen sources
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