Current Science

Open Access Open Access  Restricted Access Subscription Access

Nucleotide metabolism pathway: the achilles’ heel for bacterial pathogens


Affiliations
1 National Institute of Immunology, New Delhi 110 067, India; Present address: Department of Zoology, Magadh Mahila College, Patna University, Patna 800 001, India
2 National Institute of Immunology, New Delhi 110 067, India; Present address: Institute of Molecular Medicine, Jamia Hamdard, New Delhi 110 062, India
 

Pathogens exploit their host to extract nutrients for their survival. They occupy a diverse range of host niches during infection which offer variable nutrients accessibility. To cause a successful infection a pathogen must be able to acquire these nutrients from the host as well as be able to synthesize the nutrients on its own, if required. Nucleotides are the essential metabolite for a pathogen and also affect the pathophysiology of infection. This article focuses on the role of nucleotide metabolism of pathogens during infection in a host. Nucleotide metabolism and disease pathogenesis are closely related in various pathogens. Nucleotides, purines and pyrimidines, are biosynthesized by the de novo and salvage pathways. Whether the pathogen will employ the de novo or salvage pathway during infection is dependent on various factors, like availability of nucleotides, energy condition and presence of enzymes of the particular pathway. Understanding the nucleotide metabolism of a pathogen within its host will provide a key insight into the host– pathogen interaction and will also aid in the development of novel therapeutic strategies.

Keywords

Drug target, host niches, nucleotide biosynthesis, pathogens, virulence
User
Notifications
Font Size

  • Jensen, K. F., Dandanell, G., Hove-Jensen, B. and WillemoEs, M., Nucleotides, nucleosides, and nucleobases. EcoSal. Plus, 2008, 3.

  • Hopp, A. K., Gruter, P. and Hottiger, M. O., Regulation of glucose metabolism by NAD(+) and ADP-ribosylation. Cells, 2019, 8.

  • Zimmer, B. M., Barycki, J. J. and Simpson, M. A., Integration of sugar metabolism and proteoglycan synthesis by UDP-glucose dehydrogenase. J. Histochem. Cytochem., 2020, 22155420947500.

  • Gomelsky, M., Camp, c-di-GMP, c-di-AMP and now cGMP: bacteria use them all! Mol. Microbiol., 2011, 79, 562–565.

  • Turnbough Jr, C. L. and Switzer, R. L., Regulation of pyrimidine biosynthetic gene expression in bacteria: repression without repressors. Microbiol. Mol. Biol. Rev., 2008, 72, 266–300.

  • Samant, S., Lee, H., Ghassemi, M., Chen, J., Cook, J. L., Mankin, A. S. and Neyfakh, A. A., Nucleotide biosynthesis is critical for growth of bacteria in human blood. PLOS Pathog., 2008, 4, e37.

  • Connolly, J., Boldock, E., Prince, L. R., Renshaw, S. A., Whyte, M. K. and Foster, S. J., Identification of Staphylococcus aureus factors required for pathogenicity and growth in human blood. Infect. Immunol., 2017, 85.

  • Mei, J. M., Nourbakhsh, F., Ford, C. W. and Holden, D. W., Identification of Staphylococcus aureus virulence genes in a murine model of bacteraemia using signature-tagged mutagenesis. Mol. Microbiol., 1997, 26, 399–407.

  • Lan, L., Cheng, A., Dunman, P. M., Missiakas, D. and He, C., Golden pigment production and virulence gene expression are affected by metabolisms in Staphylococcus aureus. J. Bacteriol., 2010, 192, 3068–3077.

  • Li, L. et al., Role of purine biosynthesis in persistent methicillinresistant Staphylococcus aureus infection. J. Infect. Dis., 2018, 218, 1367–1377.

  • Kofoed, E. M. et al., De novo guanine biosynthesis but not the rioswitch-regulated purine salvage pathway is required for Staphylococcus aureus infection in vivo. J. Bacteriol., 2016, 198, 2001– 2015.

  • Kriegeskorte, A. et al., Inactivation of thya in Staphylococcus aureus attenuates virulence and has a strong impact on metabolism and virulence gene expression. MBiol., 2014, 5, e01447–e01414.

  • Jenkins, A., Cote, C., Twenhafel, N., Merkel, T., Bozue, J. and Welkos, S., Role of purine biosynthesis in Bacillus anthracis pathogenesis and virulence. Infect. Immunol., 2011, 79, 153–166.

  • McFarland, W. C. and Stocker, B. A., Effect of different purine auxotrophic mutations on mouse-virulence of a VI-positive strain of Salmonella dublin and of two strains of Salmonella typhimurium. Microb. Pathog., 1987, 3, 129–141.

  • Jelsbak, L., Mortensen, M. I. B., Kilstrup, M. and Olsen, J. E., The in vitro redundant enzymes purN and purT are both essential for systemic infection of mice in Salmonella enterica serovar typhimurium. Infect. Immunol., 2016, 84, 2076–2085.

  • Yang, H. J., Bogomolnaya, L., McClelland, M. and AndrewsPolymenis, H., De novo pyrimidine synthesis is necessary for intestinal colonization of Salmonella Typhimurium in chicks. PLOS ONE, 2017, 12, e0183751.

  • Vogel-Scheel, J., Alpert, C., Engst, W., Loh, G. and Blaut, M., Requirement of purine and pyrimidine synthesis for colonization of the mouse intestine by Escherichia coli. Appl. Environ. Microbiol., 2010, 76, 5181–5187.

  • Drazek, E. S., Houng, H. S., Crawford, R. M., Hadfield, T. L., Hoover, D. L. and Warren, R. L., Deletion of purE attenuates Brucella melitensis 16 m for growth in human monocyte-derived macrophages. Infect. Immun., 1995, 63, 3297–3301.

  • Truong, Q. L., Cho, Y., Barate, A. K., Kim, S., Watarai, M. and Hahn, T. W., Mutation of purD and purF genes further attenuates Brucella abortus strain rb51. Microb. Pathog., 2015, 79, 1–7.

  • Alcantara, R. B., Read, R. D., Valderas, M. W., Brown, T. D. and Roop, R. M., Intact purine biosynthesis pathways are required for wild-type virulence of Brucella abortus 2308 in the balb/c mouse model. Infect. Immunol., 2004, 72, 4911–4917.

  • Thach, T. T., Luong, T. T., Lee, S. and Rhee, D. K., Adenylate kinase from Streptococcus pneumoniae is essential for growth through its catalytic activity. FEBS Open Biol., 2014, 4, 672–682.

  • Markaryan, A., Zaborina, O., Punj, V. and Chakrabarty, A. M., Adenylate kinase as a virulence factor of Pseudomonas aeruginosa. J. Bacteriol., 2001, 183, 3345–3352.

  • Munier-Lehmann, H., Chenal-Francisque, V., Ionescu, M., Chrisova, P., Foulon, J., Carniel, E. and Barzu, O., Relationship between bacterial virulence and nucleotide metabolism: a mutation in the adenylate kinase gene renders Versinia pestis avirulent. Biochem. J., 2003, 373, 515–522.

  • Yu, H., Rao, X. and Zhang, K., Nucleoside diphosphate kinase (NDK): a pleiotropic effector manipulating bacterial virulence and adaptive responses. Microbiol. Res., 2017, 205, 125–134.

  • Morrow, C. A. et al., De novo GTP biosynthesis is critical for virulence of the fungal pathogen Cryptococcus neoformans. PLOS Pathog., 2012, 8, e1002957.

  • Chitty, J. L. et al., Gmp synthase is required for virulence factor production and infection by Cryptococcus neoformans. J. Biol. Chem., 2017, 292, 3049–3059.

  • Blundell, R. D. et al., Disruption of de novo adenosine triphosphate (ATP) biosynthesis abolishes virulence in Cryptococcus neoformans. ACS Infect. Dis., 2016, 2, 651–663.

  • Chitty, J. L. et al., Cryptococcus neoformans ADS lyase is an enzyme essential for virulence whose crystal structure reveals features exploitable in antifungal drug design. J. Biol. Chem., 2017, 292, 11829–11839.

  • Fox, B. A. and Bzik, D. J., De novo pyrimidine biosynthesis is required for virulence of Toxoplasma gondii. Nature, 2002, 415, 926–929.

  • Li, Q., Leija, C., Rijo-Ferreira, F., Chen, J., Cestari, I., Stuart, K., Tu, B. P. and Phillips, M. A., Gmp synthase is essential for viability and infectivity of Trypanosoma brucei despite a redundant purine salvage pathway. Mol. Microbiol., 2015, 97, 1006–1020.


Abstract Views: 318

PDF Views: 117




  • Nucleotide metabolism pathway: the achilles’ heel for bacterial pathogens

Abstract Views: 318  |  PDF Views: 117

Authors

Sujata Kumari
National Institute of Immunology, New Delhi 110 067, India; Present address: Department of Zoology, Magadh Mahila College, Patna University, Patna 800 001, India
Prajna Tripathi
National Institute of Immunology, New Delhi 110 067, India; Present address: Institute of Molecular Medicine, Jamia Hamdard, New Delhi 110 062, India

Abstract


Pathogens exploit their host to extract nutrients for their survival. They occupy a diverse range of host niches during infection which offer variable nutrients accessibility. To cause a successful infection a pathogen must be able to acquire these nutrients from the host as well as be able to synthesize the nutrients on its own, if required. Nucleotides are the essential metabolite for a pathogen and also affect the pathophysiology of infection. This article focuses on the role of nucleotide metabolism of pathogens during infection in a host. Nucleotide metabolism and disease pathogenesis are closely related in various pathogens. Nucleotides, purines and pyrimidines, are biosynthesized by the de novo and salvage pathways. Whether the pathogen will employ the de novo or salvage pathway during infection is dependent on various factors, like availability of nucleotides, energy condition and presence of enzymes of the particular pathway. Understanding the nucleotide metabolism of a pathogen within its host will provide a key insight into the host– pathogen interaction and will also aid in the development of novel therapeutic strategies.

Keywords


Drug target, host niches, nucleotide biosynthesis, pathogens, virulence

References





DOI: https://doi.org/10.18520/cs%2Fv120%2Fi9%2F1458-1463