Nitrogen Metabolism in Mycobacterial Systems

Nitrogen metabolism in mycobacterial species encompasses the uptake, assimilation and utilisation of diverse nitrogen sources—from inorganic ammonium and nitrate to organic amino acids—and underpins bacterial growth, persistence and pathogenesis. Central to this process are enzymes such as glutamine synthetase and glutamate dehydrogenase, which channel ammonium into amino acid pools, and specialised transporters and reductases that enable nitrate and asparagine utilisation. Regulation is orchestrated by global transcription factors that sense nitrogen availability and reprogramme gene expression, while post-translational mechanisms fine-tune enzyme activities via oligomeric transitions or feedback inhibition. In the host environment, adaptive modulation of nitrogen pathways supports survival under acid stress, hypoxia and nutrient limitation within macrophage phagosomes and granulomas. These metabolic adaptations contribute to dormancy, immune evasion and the emergence of drug resistance. Deciphering the enzymes, regulators and metabolic fluxes that govern nitrogen homeostasis thus reveals vulnerabilities for novel antimycobacterial strategies and host-directed therapies, with broad implications for tuberculosis control and drug discovery worldwide.

Research from Nature Portfolio

A glutamine metabolism antagonist was shown to exert both direct antibacterial effects against Mycobacterium tuberculosis and beneficial immunomodulatory actions in infected hosts. Treatment with the inhibitor reduced pulmonary bacterial load, accelerated T-cell recruitment and increased nitric oxide production by macrophages, while diminishing immunosuppressive myeloid populations. These findings highlight host-directed modulation of glutamine pathways as a dual strategy to enhance pathogen clearance and ameliorate lung pathology.

Structural and biophysical analysis of the mycobacterial phosphoserine phosphatase SerB2 revealed a dynamic morpheein equilibrium in which the enzyme interconverts between dimeric, trimeric and tetrameric assemblies of distinct catalytic competence. Binding of l-serine shifts this oligomeric distribution, providing mechanistic insight into allosteric regulation and laying the groundwork for selective inhibitor design targeting the conformational landscape of SerB2.

Nitrogen Metabolism in Mycobacterial Systems publication trend

The graph below shows the total number of articles in nitrogen metabolism in mycobacterial systems across all publications each year (not limited to Nature Index journals).

Technical terms

Glutamine synthetase: ATP-dependent enzyme catalysing the incorporation of ammonium into glutamate to form glutamine, a central nitrogen donor in biosynthetic pathways.

Morpheein equilibrium: A regulatory mechanism in which a protein interconverts between distinct oligomeric assemblies, each with different activity levels.

Transposon sequencing (Tn-seq): A high-throughput method combining random insertion mutagenesis with deep sequencing to identify genes essential for fitness under defined conditions.

Allosteric regulation: Modulation of an enzyme’s activity through binding of an effector molecule at a site distinct from the catalytic centre, inducing conformational changes.

References

1. Glutamine metabolism inhibition has dual immunomodulatory and antibacterial activities against Mycobacterium tuberculosis. Nature Communications (2023).
2. A morpheein equilibrium regulates catalysis in phosphoserine phosphatase SerB2 from Mycobacterium tuberculosis. Communications Biology (2023).
3. Transposon sequencing reveals metabolic pathways essential for Mycobacterium tuberculosis infection. PLOS Pathogens (2024).
4. Nitrogen metabolism in mycobacteria: the key genes and targeted antimicrobials. Frontiers in Microbiology (2023).
5. Amino Acid Biosynthesis Inhibitors in Tuberculosis Drug Discovery. Pharmaceutics (2024).