Abstract
The bacterial ecto-5′-nucleotidases (5′-NTs) are metalloenzymes that hydrolyze 5′-nucleoside-monophosphates (NMPs) to generate nucleosides and phosphate. These metallophosphoesterases are found in the periplasmic space and cytoplasm or are connected to the bacterial outer membrane. Membrane-bound and periplasmic 5′-NTs break down extracellular nucleotides for microbe feeding requirements, whereas cytosolic 5′-NTs control the bacterial ribo- and deoxyribonucleoside monophosphates and nucleotides levels. Both membrane-associated and periplasmic 5′-NTs have been linked to enhanced microbial virulence and pathogenicity for various pathogenic microorganisms, including Staphylococcus aureus, Vibrio cholerae, Streptococcus agalactiae, Pseudomonas aeruginosa, and Legionella pneumophila. Although these enzymes are considered as potential targets for developing inhibitors with pharmacological action as antibacterials, few drug design studies have been described in the literature. At the moment, only protein-based products, natural polyphenolic compounds, and 1-amino-4-ar(alk)ylamino-2-sulfoanthraquinones with low-micromolar IC50 values were described as bacterial 5′-NT inhibitors. Thus, this chapter may serve as a warning for the scientific community to find inhibitors of bacterial 5-NTs, which may represent a potential solution to the troublesome issue of antibiotic resistance to presently used anti-infective agents.
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References
Illes P, Xu GY, Tang Y (2020) Purinergic signaling in the central nervous system in health and disease. Neurosci Bull 36:1239–1241
Nocentini A, Capasso C, Supuran CT (2021) Small-molecule CD73 inhibitors for the immunotherapy of cancer: a patent and literature review (2017-present). Expert Opin Ther Pat 31:867–876
Camici M, Garcia-Gil M, Tozzi MG (2018) The inside story of adenosine. Int J Mol Sci 19
Cekic C, Linden J (2016) Purinergic regulation of the immune system. Nat Rev Immunol 16:177–192
Knöfel T, Sträter N (1999) X-ray structure of the Escherichia coli periplasmic 5′-nucleotidase containing a dimetal catalytic site. Nat Struct Biol 6:448–453
Knofel T, Strater N (2001) Mechanism of hydrolysis of phosphate esters by the dimetal center of 5'-nucleotidase based on crystal structures. J Mol Biol 309:239–254
Santos CA, Saraiva AM, Toledo MA, Beloti LL, Crucello A, Favaro MT, Horta MA, Santiago AS, Mendes JS, Souza AA, Souza AP (2013) Initial biochemical and functional characterization of a 5′-nucleotidase from Xylella fastidiosa related to the human cytosolic 5′-nucleotidase I. Microb Pathog 59-60:1–6
Tamao Y, Noguchi K, Sakai-Tomita Y, Hama H, Shimamoto T, Kanazawa H, Tsuda M, Tsuchiya T (1991) Sequence analysis of nutA gene encoding membrane-bound Cl(−)-dependent 5′-nucleotidase of vibrio parahaemolyticus. J Biochem 109:24–29
Burns DM, Beacham IR (1986) Nucleotide sequence and transcriptional analysis of the E. coli ushA gene, encoding periplasmic UDP-sugar hydrolase (5′-nucleotidase): regulation of the ushA gene, and the signal sequence of its encoded protein product. Nucleic Acids Res 14:4325–4342
Terakawa A, Natsume A, Okada A, Nishihata S, Kuse J, Tanaka K, Takenaka S, Ishikawa S, Yoshida K (2016) Bacillus subtilis 5'-nucleotidases with various functions and substrate specificities. BMC Microbiol 16
Zakataeva NP (2021) Microbial 5'-nucleotidases: their characteristics, roles in cellular metabolism, and possible practical applications. Appl Microbiol Biotechnol 105:7661–7681
Proudfoot M, Kuznetsova E, Brown G, Rao NN, Kitagawa M, Mori H, Savchenko A, Yakunin AF (2004) General enzymatic screens identify three new nucleotidases in Escherichia coli – biochemical characterization of SurE, YfbR, and YjjG. J Biol Chem 279:54687–54694
Botero S, Chiaroni-Clarke R, Simon SM (2019) Escherichia coli as a platform for the study of phosphoinositide biology. Sci Adv:5
Reaves ML, Young BD, Hosios AM, Xu YF, Rabinowitz JD (2013) Pyrimidine homeostasis is accomplished by directed overflow metabolism. Nature 500:237
Kates M (1980) Citation classic – bacterial lipids. Life Sci 12-12
Pinchuk GE, Ammons C, Culley DE, Li SMW, McLean JS, Romine MF, Nealson KH, Fredrickson JK, Beliaev AS (2008) Utilization of DNA as a sole source of phosphorus, carbon, and energy by Shewanella spp.: ecological and physiological implications for dissimilatory metal reduction. Appl Environ Microbiol 74:1198–1208
Kakehi M, Usuda Y, Tabira Y, Sugimoto S (2007) Complete deficiency of 5'-nucleotidase activity in Escherichia coli leads to loss of growth on purine nucleotides but not of their excretion. J Mol Microbiol Biotechnol 13:96–104
Thammavongsa V, Kern JW, Missiakas DM, Schneewind O (2009) Staphylococcus aureus synthesizes adenosine to escape host immune responses. J Exp Med 206:2417–2427
Punj V, Zaborina O, Dhiman N, Falzari K, Bagdasarian M, Chakrabarty AM (2000) Phagocytic cell killing mediated by secreted cytotoxic factors of vibrio cholerae. Infect Immun 68:4930–4937
Firon A, Dinis M, Raynal B, Poyart C, Trieu-Cuot P, Kaminski PA (2014) Extracellular nucleotide catabolism by the group B streptococcus ectonucleotidase NudP increases bacterial survival in blood. J Biol Chem 289:5479–5489
Zaborina O, Dhiman N, Ling Chen M, Kostal J, Holder IA, Chakrabarty AM (2000) Secreted products of a nonmucoid Pseudomonas aeruginosa strain induce two modes of macrophage killing: external-ATP-dependent, P2Z-receptor-mediated necrosis and ATP-independent, caspase-mediated apoptosis. Microbiology (Reading) 146(Pt 10):2521–2530
Alves-Pereira I, Canales J, Cabezas A, Cordero PM, Costas MJ, Cameselle JC (2008) CDP-alcohol hydrolase, a very efficient activity of the 5'-nucleotidase/UDP-sugar hydrolase encoded by the ushA gene of yersinia intermedia and Escherichia coli. J Bacteriol 190:6153–6161
Melnikov A, Zaborina O, Dhiman N, Prabhakar BS, Chakrabarty AM, Hendrickson W (2000) Clinical and environmental isolates of Burkholderia cepacia exhibit differential cytotoxicity towards macrophages and mast cells. Mol Microbiol 36:1481–1493
Zaborina O, Misra N, Kostal J, Kamath S, Kapatral V, El-Idrissi ME, Prabhakar BS, Chakrabarty AM (1999) P2Z-independent and P2Z receptor-mediated macrophage killing by Pseudomonas aeruginosa isolated from cystic fibrosis patients. Infect Immun 67:5231–5242
Mansfield J, Genin S, Magori S, Citovsky V, Sriariyanum M, Ronald P, Dow M, Verdier V, Beer SV, Machado MA, Toth I, Salmond G, Foster GD (2012) Top 10 plant pathogenic bacteria in molecular plant pathology. Mol Plant Pathol 13:614–629
Zheng LS, Khemlani A, Lorenz N, Loh JMS, Langley RJ, Proft T (2015) Streptococcal 5'-Nucleotidase A (S5nA), a novel streptococcus pyogenes virulence factor that facilitates immune evasion. J Biol Chem 290:31126–31137
Dangel ML, Dettmann JC, Hasselbarth S, Krogull M, Schakat M, Kreikemeyer B, Fiedler T (2019) The 5'-nucleotidase S5nA is dispensable for evasion of phagocytosis and biofilm formation in streptococcus pyogenes. PloS One:14
Begun J, Sifri CD, Goldman S, Calderwood SB, Ausubel FM (2005) Staphylococcus aureus virulence factors identified by using a high-throughput Caenorhabditis elegans-killing model. Infect Immun 73:872–877
Zimmermann H (1992) 5'-Nucleotidase – molecular-structure and functional-aspects. Biochem J 285:345–365
Iwamoto M, Matsuo T, Uchino K, Tonosaki Y, Fukuchi A (1988) New 5′-nucleotidase inhibitors, NPF-86IA, NPF-86IB, NPF-86IIA, and NPF-86IIB from Areca catechu; Part II anti-tumor effects. Planta Med 54(5):422–425
Uchino K, Matsuo T, Iwamoto M, Tonosaki Y, Fukuchi A (1988) New 5′-nucleotidase inhibitors, NPF-86IA, NPF-86IB, NPF-86IIA, and NPF-86IIB from Areca catechu; part I isolation and biological properties. Planta Med 54(5):419–422
Toukairin T, Uchino K, Iwamoto M, Murakami S, Tatebayashi T, Ogawara H, Tonosaki Y (1991) New polyphenolic 5′-nucleotidase inhibitors isolated from the wine grape “Koshu” and their biological effects. Chem Pharm Bull(Tokyo) 39(6):1480–1483
Sansom FM, Riedmaier P, Newton HJ, Dunstone MA, Müller CE, Stephan H, Byres E, Beddoe T, Rossjohn J, Cowan PJ, d'Apice AJ, Robson SC, Hartland EL (2008) Enzymatic properties of an ecto-nucleoside triphosphate diphosphohydrolase from legionella pneumophila: substrate specificity and requirement for virulence. J Biol Chem 283(19):12909–12918
Fiene A, Baqi Y, Malik EM, Newton P, Li W, Lee SY, Hartland EL, Müller CE (2016) Inhibitors for the bacterial ectonucleotidase Lp1NTPDase from Legionella pneumophila. Bioorg Med Chem 24(18):4363–4371
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Original research of our team is funded by the MIUR (Italian Ministry for University and Research) projects FISR2019_04819 (BacCAD) and by Ente Cassa di Risparmio di Firenze (ECRF), grant CRF2020.1395.
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Nocentini, A., Capasso, C., Supuran, C.T. (2023). Bacterial Ectonucleotidases: Underexplored Antibacterial Drug Targets. In: Colotta, V., Supuran, C.T. (eds) Purinergic Receptors and their Modulators. Topics in Medicinal Chemistry, vol 41. Springer, Cham. https://doi.org/10.1007/7355_2023_159
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DOI: https://doi.org/10.1007/7355_2023_159
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