The high-resolution crystal structure of periplasmic Haemophilus influenzae NAD nucleotidase reveals a novel enzymatic function of human CD73 related to NAD metabolism
Abstract
Haemophilus influenzae is a major pathogen of the respiratory tract in humans that has developed the capability to exploit host NAD(P) for its nicotinamide dinucleotide requirement. This strategy is organized around a periplasmic enzyme termed NadN (NAD nucleotidase), which plays a central role by degrading NAD into adenosine and NR (nicotinamide riboside), the latter being subsequently internalized by a specific permease. We performed a biochemical and structural investigation on H. influenzae NadN which determined that the enzyme is a Zn2+-dependent 5′-nucleotidase also endowed with NAD(P) pyrophosphatase activity. A 1.3 Å resolution structural analysis revealed a remarkable conformational change that occurs during catalysis between the open and closed forms of the enzyme. NadN showed a broad substrate specificity, recognizing either mono- or di-nucleotide nicotinamides and different adenosine phosphates with a maximal activity on 5′-adenosine monophosphate. Sequence and structural analysis of H. influenzae NadN led us to discover that human CD73 is capable of processing both NAD and NMN, therefore disclosing a possible novel function of human CD73 in systemic NAD metabolism. Our data may prove to be useful for inhibitor design and disclosed unanticipated fascinating evolutionary relationships.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Several studies have suggested that NMN is not directly absorbed by cells but is extracellularly converted to NR by CD73 and then absorbed as NR.
“However, several studies have suggested that NMN is not directly absorbed by cells but is extracellularly converted to NR by CD73, also known as 5′-nucleotidase ecto (NT5E), and then absorbed as the form of NR (29–31).”
From Nicotinamide riboside and nicotinamide mononucleotide facilitate NAD <sup>+</sup> synthesis via enterohepatic circulation (2025) · cites this paper as [30]
Cites
PROCHECK: a program to check the stereochemical quality of protein structures
Laskowski, R. A., MacArthur, M. W., Moss, D. S., & Thornton, J. M. (1993) · Journal of Applied Crystallography · doi:10.1107/s0021889892009944 · Cited by 24,581 · see citing works
<i>PHENIX</i> : a comprehensive Python-based system for macromolecular structure solution
Adams, P. D., Afonine, P. V., Bunkóczi, G., Chen, V. B., Davis, I. W., Echols, N., Headd, J. J., Hung, L.-W., Kapral, G. J., Grosse-Kunstleve, R. W., et al. (2010) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444909052925 · Cited by 23,716 · see citing works
<i>Phaser</i> crystallographic software
McCoy, A. J., Grosse-Kunstleve, R. W., Adams, P. D., Winn, M. D., Storoni, L. C., & Read, R. J. (2007) · Journal of Applied Crystallography · doi:10.1107/s0021889807021206 · Cited by 20,612 · see citing works
The CCP4 suite: programs for protein crystallography
Number Collaborative Computational Project (1994) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444994003112 · Cited by 17,299 · see citing works
Jones, T. A., Zou, J.-Y., Cowan, S. W., & Kjeldgaard, M. (1991) · Acta Crystallographica Section A Foundations of Crystallography · doi:10.1107/s0108767390010224 · Cited by 12,650 · see citing works
PHENIX: a comprehensive Python-based system for macromolecular structure solution
Adams, P. D., Afonine, P. V., Bunkòczi, G., Chen, V. B., Davis, I., Echols, N., Headd, J. J., Hung, L., Kapral, G. J., Grosse‐Kunstleve, R. W., et al. (2012) · International Tables for Crystallography · doi:10.1107/97809553602060000865 · Cited by 7,334 · see citing works
Whole-Genome Random Sequencing and Assembly of Haemophilus influenzae Rd
Fleischmann, R. D., Adams, M. D., White, O. R., Clayton, R. A., Kirkness, E. F., Kerlavage, A. R., Bult, C. J., Tomb, J.-F., Dougherty, B. A., Merrick, J. M., et al. (1995) · Science · doi:10.1126/science.7542800 · Cited by 5,641 · see citing works
Automated protein model building combined with iterative structure refinement.
Perrakis, A., Morris, R. J., & Lamzin, V. S. (1999) · Nature Structural Biology · doi:10.1038/8263 · Cited by 2,423 · see citing works
Hansen, H. M., Hurwitz, W. N., & Madow, W. G. (1953) · Wiley eBooks · Cited by 1,614 · see citing works
The integration of macromolecular diffraction data
Leslie, A. G. W. (2005) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444905039107 · Cited by 1,341 · see citing works
NAD+ metabolism in health and disease
Belenky, P. A., Bogan, K. L., & Brenner, C. (2006) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2006.11.006 · Cited by 983 · see citing works
Nampt/PBEF/Visfatin Regulates Insulin Secretion in β Cells as a Systemic NAD Biosynthetic Enzyme
Revollo, J. R., Körner, A., Mills, K. F., Satoh, A., Wang, T., Garten, A., Dasgupta, B., Sasaki, Y., Wolberger, C., Townsend, R. R., et al. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.09.003 · Cited by 911 · see citing works
5′-Nucleotidase: molecular structure and functional aspects
Zimmermann, H. (1992) · Biochemical Journal · doi:10.1042/bj2850345 · Cited by 880 · see citing works
Bogan, K. L., & Brenner, C. (2008) · Annual Review of Nutrition · doi:10.1146/annurev.nutr.28.061807.155443 · Cited by 707 · see citing works
Integration of macromolecular diffraction data
Leslie, A. G. W. (2006) · International Tables for Crystallography · doi:10.1107/97809553602060000675 · Cited by 703 · see citing works
Connexin 43 hemichannels mediate Ca2+‐regulated transmembrane NAD+ fluxes in intact cells
Bruzzone, S., Guida, L., Zocchi, E., Franco, L., & FLORA, A. D. (2000) · The FASEB Journal · doi:10.1096/fj.00-0566fje · Cited by 464 · see citing works
Self-citationAssessment of phase accuracy by cross validation: the free R value. Methods and applications
Brünger, A. T. (1993) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444992007352 · Cited by 454 · see citing works
Integration of macromolecular diffraction data
Leslie, A. G. W. (1999) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s090744499900846x · Cited by 409 · see citing works
Ecto‐enzyme and signaling functions of lymphocyte CD 7 3
Resta, R., Yamashita, Y., & Thompson, L. F. (1998) · Immunological Reviews · doi:10.1111/j.1600-065x.1998.tb01574.x · Cited by 332 · see citing works
Pathways and Subcellular Compartmentation of NAD Biosynthesis in Human Cells
Nikiforov, A., Dölle, C., Niere, M., & Ziegler, M. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.213298 · Cited by 326 · see citing works
The pathogenicity of Haemophilus influenzae
Turk, D. C. (1984) · Journal of Medical Microbiology · doi:10.1099/00222615-18-1-1 · Cited by 323 · see citing works
Autocrine and Paracrine Calcium Signaling by the CD38/NAD+/Cyclic ADP‐Ribose System
FLORA, A. D., Zocchi, E., Guida, L., Franco, L., & Bruzzone, S. (2004) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1322.021 · Cited by 235 · see citing works
Self-citationβ-Nicotinamide adenine dinucleotide is an inhibitory neurotransmitter in visceral smooth muscle
Mutafova–Yambolieva, V. N., Hwang, S. J., Hao, X., Chen, H., Zhu, M. X., Wood, J. D., Ward, S. M., & Sanders, K. M. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0705510104 · Cited by 173 · see citing works
Nicotinamide Riboside Kinase Structures Reveal New Pathways to NAD+
Tempel, W., Rabeh, W. M., Bogan, K. L., Belenky, P. A., Wójcik, M., Seidle, H. F., Nedyalkova, L., Yang, T., Sauve, A. A., Park, H.-W., et al. (2007) · PLoS Biology · doi:10.1371/journal.pbio.0050263 · Cited by 163 · see citing works
Sträter, N., & Knöfel, T. (1999) · Nature Structural Biology · doi:10.1038/8253 · Cited by 118 · see citing works
Yang, T., Chan, N. Y., & Sauve, A. A. (2007) · Journal of Medicinal Chemistry · doi:10.1021/jm701001c · Cited by 113 · see citing works
Bruzzone, S., Franco, L., Guida, L., Zocchi, E., Contini, P., Bisso, A., Usai, C., & FLORA, A. D. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m107308200 · Cited by 110 · see citing works
Self-citationImai, S. (2011) · FEBS Letters · doi:10.1016/j.febslet.2011.04.060 · Cited by 104 · see citing works
Knöfel, T., & Sträter, N. (2001) · Journal of Molecular Biology · doi:10.1006/jmbi.2001.4656 · Cited by 102 · see citing works
HEMIN BIOSYNTHESIS IN HAEMOPHILUS
White, D. C. S., & Granick, S. (1963) · Journal of Bacteriology · doi:10.1128/jb.85.4.842-850.1963 · Cited by 97 · see citing works
Nicotinamide Riboside and Nicotinic Acid Riboside Salvage in Fungi and Mammals
Belenky, P., Christensen, K. C., Gazzaniga, F., Pletnev, A. A., & Brenner, C. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m807976200 · Cited by 95 · see citing works
Evans, N. M., Smith, D. D., & Wicken, A. J. (1974) · Journal of Medical Microbiology · doi:10.1099/00222615-7-3-359 · Cited by 95 · see citing works
Imai, S. (2010) · Pharmacological Research · doi:10.1016/j.phrs.2010.01.006 · Cited by 89 · see citing works
Kurnasov, O. V., Polanuyer, B. M., Ananta, S., Sloutsky, R., Tam, A., Gerdes, S., & Osterman, A. L. (2002) · Journal of Bacteriology · doi:10.1128/jb.184.24.6906-6917.2002 · Cited by 87 · see citing works
Structure of Human NMN Adenylyltransferase
Garavaglia, S., D’Angelo, I., Emanuelli, M., Carnevali, F., Pierella, F., Magni, G., & Rizzi, M. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m111589200 · Cited by 85 · see citing works
Self-citationGreen, B. A., Farley, J. E., Quinn-Dey, T., Deich, R. A., & Zlotnick, G. W. (1991) · Infection and Immunity · doi:10.1128/iai.59.9.3191-3198.1991 · Cited by 80 · see citing works
Smyth, L. M., Bobáľová, J., Mendoza, M. G., Lew, C., & Mutafova–Yambolieva, V. N. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m407266200 · Cited by 77 · see citing works
Kemmer, G., Reilly, T. J., Schmidt-Brauns, J., Zlotnick, G. W., Green, B. A., Fiske, M. J., Herbert, M., Kraiß, A., Schlör, S., Smith, A. L., et al. (2001) · Journal of Bacteriology · doi:10.1128/jb.183.13.3974-3981.2001 · Cited by 73 · see citing works
Haemophilus influenzae Disease and Immunization in Developing Countries
Funkhouser, A. W., Steinhoff, M. C., & Ward, J. I. (1991) · Clinical Infectious Diseases · doi:10.1093/clinids/13.supplement_6.s542 · Cited by 69 · see citing works
Structural role of disulfide bridges in the cyclic ADP‐ribose related bifunctional ectoenzyme CD38
Guida, L., Franco, L., Zocchi, E., & FLORA, A. D. (1995) · FEBS Letters · doi:10.1016/0014-5793(95)00715-l · Cited by 65 · see citing works
NADP and NAD utilization in Haemophilus influenzae
Reidl, J., Schlör, S., Kraiß, A., Schmidt-Brauns, J., Kemmer, G., & Soleva, E. (2000) · Molecular Microbiology · doi:10.1046/j.1365-2958.2000.01829.x · Cited by 63 · see citing works
5′‐Nucleotidase from the electric ray electric lobe
Volknandt, W., VOGEL, M., Pevsner, J., MISUME, Y., Ikehara, Y., & Zimmermann, H. (1991) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1991.tb16443.x · Cited by 55 · see citing works
Crystal Structure of Haemophilus influenzae NadR Protein
Singh, S. K., Kurnasov, O. V., Chen, B., Robinson, H. H., Grishin, N. V., Osterman, A. L., & Zhang, H. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m204368200 · Cited by 50 · see citing works
Zocchi, E., Guida, L., Franco, L., Silvestro, L., Guerrini, M., Benatti, U., & FLORA, A. D. (1993) · Biochemical Journal · doi:10.1042/bj2950121 · Cited by 33 · see citing works
Significance of V-Factor Dependency in the Taxonomy of Haemophilus Species and Related Organisms
Niven, D. F., & O'Reilly, T. (1990) · International Journal of Systematic Bacteriology · doi:10.1099/00207713-40-1-1 · Cited by 32 · see citing works
Andersen, C., Maier, E., Kemmer, G., Blaß, J., Hilpert, A.-K., Benz, R., & Reidl, J. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m213087200 · Cited by 30 · see citing works
Kahn, D. W., & Anderson, B. M. (1986) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)38487-9 · Cited by 28 · see citing works
Is a NAD pyrophosphatase activity necessary for type b multiplication in the blood stream?
Schmidt-Brauns, J. (2001) · International Journal of Medical Microbiology · doi:10.1078/1438-4221-00122 · Cited by 27 · see citing works
Nicotinamide Ribosyl Uptake Mutants in Haemophilus influenzae
Herbert, M., Sauer, E., Smethurst, G. J., Kraiβ, A., Hilpert, A.-K., & Reidl, J. (2003) · Infection and Immunity · doi:10.1128/iai.71.9.5398-5401.2003 · Cited by 24 · see citing works
Zagursky, R. J., Ooi, P., Jones, K. F., Fiske, M. J., Smith, R. P., & Green, B. A. (2000) · Infection and Immunity · doi:10.1128/iai.68.5.2525-2534.2000 · Cited by 21 · see citing works
Goodgal, S. H., & Mitchell, M. A. (1998) · Springer eBooks · doi:10.1007/978-1-4615-6369-3_61 · Cited by 16 · see citing works
Singh, H., Schuermann, J. P., Reilly, T. J., Calcutt, M. J., & Tanner, J. J. (2010) · Journal of Molecular Biology · doi:10.1016/j.jmb.2010.09.065 · Cited by 14 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
NAD <sup>+</sup> in aging, metabolism, and neurodegeneration
Verdin, E. (2015) · Science · doi:10.1126/science.aac4854 · Cited by 1,319 · see citing works
NAD(H) and NADP(H) Redox Couples and Cellular Energy Metabolism
Xiao, W., Wang, R., Handy, D. E., & Loscalzo, J. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7216 · Cited by 1,074 · see citing works
Cellular function and molecular structure of ecto-nucleotidases
Zimmermann, H., Zebisch, M., & Sträter, N. (2012) · Purinergic Signalling · doi:10.1007/s11302-012-9309-4 · Cited by 985 · see citing works
Slowing ageing by design: the rise of NAD+ and sirtuin-activating compounds
Bonkowski, M. S., & Sinclair, D. A. (2016) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2016.93 · Cited by 834 · see citing works
Physiological and pathophysiological roles of NAMPT and NAD metabolism.
Garten, A., Schuster, S., Penke, M., Gorski, T., de Giorgis, T., & Kiess, W. (2015) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2015.117 · Cited by 708 · see citing works
The adenosine pathway in immuno-oncology
Allard, B., Allard, D., Buisseret, L., & Stagg, J. (2020) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-020-0382-2 · Cited by 601 · see citing works
NAD+ metabolism, stemness, the immune response, and cancer
Navas, L. E., & Carnero, A. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00354-w · Cited by 529 · see citing works
Evolving concepts in NAD+ metabolism
Chini, C. C. S., Zeidler, J. D., Kashyap, S., Warner, G. M., & Chini, E. N. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.04.003 · Cited by 294 · see citing works
Horenstein, A. L., Chillemi, A., Zaccarello, G., Bruzzone, S., Quarona, V., Zito, A., Serra, S., & Malavasi, F. (2013) · OncoImmunology · doi:10.4161/onci.26246 · Cited by 278 · see citing works
Self-citationA rise in NAD precursor nicotinamide mononucleotide (NMN) after injury promotes axon degeneration
Di Stefano, M., Nascimento-Ferreira, I., Orsomando, G., Mori, V, Gilley, J., Brown, R., Janeckova, L., Vargas, M. E., Worrell, L. A., Loreto, A., et al. (2015) · Cell Death & Differentiation · doi:10.1038/cdd.2014.164 · Cited by 246 · see citing works
NAD+ homeostasis in human health and disease
Perez, R. Z., Wanders, R. J. A., van Karnebeek, C., & Houtkooper, R. H. (2021) · EMBO Molecular Medicine · doi:10.15252/emmm.202113943 · Cited by 238 · see citing works
Modulating NAD+ metabolism, from bench to bedside
Katsyuba, E., & Auwerx, J. H. (2017) · The EMBO Journal · doi:10.15252/embj.201797135 · Cited by 224 · see citing works
The human NAD metabolome: Functions, metabolism and compartmentalization
Nikiforov, A. A., Kulikova, V., & Ziegler, M. (2015) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.3109/10409238.2015.1028612 · Cited by 214 · see citing works
Knapp, K., Zebisch, M., Pippel, J., El‐Tayeb, A., Müller, C. E., & Sträter, N. (2012) · Structure · doi:10.1016/j.str.2012.10.001 · Cited by 211 · see citing works
NAMPT and NAPRT: Two Metabolic Enzymes With Key Roles in Inflammation
Audrito, V., Messana, V. G., & Deaglio, S. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.00358 · Cited by 209 · see citing works
TARGETED, LCMS-BASED METABOLOMICS FOR QUANTITATIVE MEASUREMENT OF NAD + METABOLITES
Trammell, S. A. J., & Brenner, C. (2013) · Computational and Structural Biotechnology Journal · doi:10.5936/csbj.201301012 · Cited by 193 · see citing works
Zhao, Z. Y., Xie, X. J., Li, W. H., Liu, J., Chen, Z., Zhang, B., Li, T., Li, S. L., Lu, J. G., Zhang, L., et al. (2019) · iScience · doi:10.1016/j.isci.2019.05.001 · Cited by 179 · see citing works
Grozio, A., Sociali, G., Sturla, L., Caffa, I., Soncini, D., Salis, A., Raffaelli, N., De Flora, A., Nencioni, A., & Bruzzone, S. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.470435 · Cited by 158 · see citing works
“The products ADPR and NAM were analyzed and quantified by analytical phosphate HPLC (40).”
BackgroundMethodInfluentialSelf-citationCd73: An Emerging Checkpoint for Cancer Immunotherapy
Chen, S., Wainwright, D. A., Wu, J. D., Wan, Y., Matei, D. E., Zhang, Y., & Zhang, B. (2019) · Immunotherapy · doi:10.2217/imt-2018-0200 · Cited by 145 · see citing works
NAD+ salvage pathway in cancer metabolism and therapy
Kennedy, B. E., Sharif, T., Martell, E., Dai, C., Kim, Y., Lee, P. W. K., & Gujar, S. A. (2016) · Pharmacological Research · doi:10.1016/j.phrs.2016.10.027 · Cited by 144 · see citing works
Igarashi, M., Nakagawa-Nagahama, Y., Miura, M., Kashiwabara, K., Yaku, K., Sawada, M., Sekine, R., Fukamizu, Y., Sato, T., Sakurai, T., et al. (2022) · npj Aging · doi:10.1038/s41514-022-00084-z · Cited by 125 · see citing works
Regulation and Function of Extracellular Nicotinamide Phosphoribosyltransferase/Visfatin
Carbone, F., Liberale, L., Bonaventura, A., Vecchié, A., Casula, M., Cea, M., Monacelli, F., Caffa, I., Bruzzone, S., Montecucco, F., et al. (2017) · Comprehensive physiology · doi:10.1002/cphy.c160029 · Cited by 107 · see citing works
Self-citationExtracellular NAD+ enhances PARP-dependent DNA repair capacity independently of CD73 activity
Wilk, A. M., Hayat, F., Cunningham, R., Li, J., Garavaglia, S., Zamani, L., Ferraris, D. M., Sýkora, P., Andrews, J., Clark, J., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-57506-9 · Cited by 88 · see citing works
Self-citationMateuszuk, Ł., Campagna, R., Kutryb-Zając, B., Kuś, K., Słominska, E. M., Smolenski, R. T., & Chlopicki, S. (2020) · Biochemical Pharmacology · doi:10.1016/j.bcp.2020.114019 · Cited by 81 · see citing works
Crystal Structure of a Soluble Form of Human CD73 with Ecto‐5′‐Nucleotidase Activity
Heuts, D. P. H. M., Weissenborn, M. J., Olkhov, R. V., Shaw, A. M., Gummadova, J., Levy, C., & Scrutton, N. S. (2012) · ChemBioChem · doi:10.1002/cbic.201200426 · Cited by 82 · see citing works
Subcellular compartmentalization of NAD+ and its role in cancer: A sereNADe of metabolic melodies
Zhu, Y., Liu, J., Park, J., Rai, P., & Zhai, R. G. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2019.04.002 · Cited by 82 · see citing works
Targeting the adenosine pathway for cancer immunotherapy
Hammami, A., Allard, D., Allard, B., & Stagg, J. (2019) · Seminars in Immunology · doi:10.1016/j.smim.2019.101304 · Cited by 81 · see citing works
The purinergic neurotransmitter revisited: A single substance or multiple players?
Mutafova–Yambolieva, V. N., & Durnin, L. (2014) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2014.05.012 · Cited by 75 · see citing works
Reduced nicotinamide mononucleotide is a new and potent NAD + precursor in mammalian cells and mice
Perez, R. Z., Tammaro, A., Schomakers, B. V., Scantlebery, A. M. L., Denis, S. W., Elfrink, H. L., Giroud‐Gerbetant, J., Cantó, C., López‐Leonardo, C., McIntyre, R. L., et al. (2021) · The FASEB Journal · doi:10.1096/fj.202001826r · Cited by 75 · see citing works
Diverse therapeutic efficacies and more diverse mechanisms of nicotinamide
Song, S. B., Park, J., Chung, G. J., Lee, I. H., & Hwang, E. S. (2019) · Metabolomics · doi:10.1007/s11306-019-1604-4 · Cited by 72 · see citing works
Ruggieri, S., Orsomando, G., Sorci, L., & Raffaelli, N. (2015) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2015.02.021 · Cited by 71 · see citing works
Antitumor effect of combined NAMPT and CD73 inhibition in an ovarian cancer model
Sociali, G., Raffaghello, L., Magnone, M., Zamporlini, F., Emionite, L., Sturla, L., Bianchi, G., Vigliarolo, T., Nahimana, A., Nencioni, A., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.6502 · Cited by 70 · see citing works
Self-citationKato, M., & Lin, S.-J. (2014) · DNA repair · doi:10.1016/j.dnarep.2014.07.009 · Cited by 68 · see citing works
Magnone, M., Bauer, I., Poggi, A. D., Mannino, E., Sturla, L., Brini, M., Zocchi, E., FLORA, A. D., Nencioni, A., & Bruzzone, S. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.324269 · Cited by 66 · see citing works
Self-citationRegulation of SIRT2-dependent α-tubulin deacetylation by cellular NAD levels
Skoge, R. H., Dölle, C., & Ziegler, M. (2014) · DNA repair · doi:10.1016/j.dnarep.2014.04.011 · Cited by 65 · see citing works
Sayers, S. R., Beavil, R. L., Fine, N. H. F., Huang, G. C., Choudhary, P., Pacholarz, K. J., Barran, P. E., Butterworth, S., Mills, C. E., Cruickshank, J. K., et al. (2019) · Diabetologia · doi:10.1007/s00125-019-05029-y · Cited by 64 · see citing works
Cellular Compartmentation and the Redox/Nonredox Functions of NAD +
Kulkarni, C. A., & Brookes, P. S. (2019) · Antioxidants and Redox Signaling · doi:10.1089/ars.2018.7722 · Cited by 64 · see citing works
CD73, Tumor Plasticity and Immune Evasion in Solid Cancers
Yang, H., Yao, F., Davis, P. F., Tan, S. T., & Hall, S. R. R. (2021) · Cancers · doi:10.3390/cancers13020177 · Cited by 64 · see citing works
Extracellular NAD+: a danger signal hindering regulatory T cells
Adriouch, S., Haag, F., Boyer, O., Séman, M., & Koch‐Nolte, F. (2012) · Microbes and Infection · doi:10.1016/j.micinf.2012.05.011 · Cited by 65 · see citing works
Diversification of NAD biological role : the importance of location
Stefano, M. D., & Conforti, L. (2013) · FEBS Journal · doi:10.1111/febs.12433 · Cited by 61 · see citing works
Poly(ADP-Ribose) Polymerases in Host-Pathogen Interactions, Inflammation, and Immunity
Brady, P. N., Goel, A., & Johnson, M. A. (2019) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.00038-18 · Cited by 58 · see citing works
CD38 in the age of COVID-19: a medical perspective
Horenstein, A., Faini, A., & Malavasi, F. (2021) · Physiological Reviews · doi:10.1152/physrev.00046.2020 · Cited by 53 · see citing works
New strategies to maximize therapeutic opportunities for NAMPT inhibitors in oncology
Roulston, A., & Shore, G. C. (2015) · Molecular & Cellular Oncology · doi:10.1080/23723556.2015.1052180 · Cited by 54 · see citing works
Rissiek, B., Haag, F., Boyer, O., Koch‐Nolte, F., & Adriouch, S. (2014) · Current topics in microbiology and immunology · doi:10.1007/82_2014_420 · Cited by 53 · see citing works
Peri, L. E., Sanders, K. M., & Mutafova–Yambolieva, V. N. (2013) · Neurogastroenterology & Motility · doi:10.1111/nmo.12174 · Cited by 52 · see citing works
Enzymology of extracellular NAD metabolism
Gasparrini, M., Sorci, L., & Raffaelli, N. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-020-03742-1 · Cited by 51 · see citing works
Takeda, T.-A., Miyazaki, S., Kobayashi, M., Nishino, K., Gotō, T., Matsunaga, M., Ooi, M., Shirakawa, H., Tani, F., Kawamura, T., et al. (2018) · Communications Biology · doi:10.1038/s42003-018-0118-3 · Cited by 51 · see citing works
Targeting CD73 and downstream adenosine receptor signaling in triple-negative breast cancer
Allard, B., Turcotte, M., & Stagg, J. (2014) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2014.915315 · Cited by 48 · see citing works
Nicotinamide Phosphoribosyltransferase as a Key Molecule of the Aging/Senescence Process
Khaidizar, F. D., Bessho, Y., & Nakahata, Y. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22073709 · Cited by 48 · see citing works
Zheng, L., Khemlani, A. H. J., Lorenz, N., Loh, J. M. S., Langley, R. J., & Proft, T. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.677443 · Cited by 43 · see citing works
Yaku, K., Palikhe, S., Iqbal, T., Hayat, F., Watanabe, Y., Fujisaka, S., Izumi, H., Yoshida, T., Karim, M., Uchida, H., et al. (2025) · Science Advances · doi:10.1126/sciadv.adr1538 · Cited by 40 · see citing works
Zakataeva, N. P. (2021) · Applied Microbiology and Biotechnology · doi:10.1007/s00253-021-11547-w · Cited by 40 · see citing works
CD39 and CD73: biological functions, diseases and therapy
Shen, J., Liao, B., Gong, L., Li, S., Zhao, J., Yang, H., Gong, Y., & Li, Y. (2025) · Molecular Biomedicine · doi:10.1186/s43556-025-00345-9 · Cited by 40 · see citing works
Degradation of Extracellular NAD+ Intermediates in Cultures of Human HEK293 Cells
Kulikova, V., Shabalin, K. A., Nerinovski, K., Yakimov, A., Svetlova, M., Solovjeva, L., Kropotov, A., Khodorkovskiy, M., Migaud, M. E., Ziegler, M., et al. (2019) · Metabolites · doi:10.3390/metabo9120293 · Cited by 36 · see citing works
The Extracellular NADome Modulates Immune Responses
Audrito, V., Messana, V. G., Brandimarte, L., & Deaglio, S. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.704779 · Cited by 34 · see citing works
The function of nicotinamide phosphoribosyl transferase (NAMPT) and its role in diseases
Peng, A., Li, J., Xing, J., Yao, Y., Niu, X., & Zhang, K. (2024) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2024.1480617 · Cited by 32 · see citing works
CD73; a key ectonucleotidase in the development of breast cancer: Recent advances and perspectives
Soleimani, A., Taghizadeh, E., Shahsavari, S., Amini, Y., Rashidpour, H., Azadian, E., Jafari, A., Parizadeh, M. R., Mashayekhi, K., Soukhtanloo, M., et al. (2019) · Journal of Cellular Physiology · doi:10.1002/jcp.28187 · Cited by 30 · see citing works
The therapeutic potential of targeting CD73 and CD73-derived adenosine in melanoma
Soleimani, A., Farshchi, H. K., Mirzavi, F., Zamani, P., Ghaderi, A., Amini, Y., Khorrami, S., Mashayekhi, K., & Jaafari, M. R. (2020) · Biochimie · doi:10.1016/j.biochi.2020.06.001 · Cited by 28 · see citing works
Regulation of Cancer and Cancer-Related Genes via NAD +
Sharif, T., Martell, E., Dai, C., Ghassemi-Rad, M. S., Kennedy, B. E., Lee, P. W. K., & Gujar, S. A. (2018) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7478 · Cited by 25 · see citing works
Fliegert, R., Heeren, J., Koch‐Nolte, F., Nikolaev, V. O., Lohr, C., Meier, C., & Guse, A. H. (2019) · Biochemical Society Transactions · doi:10.1042/bst20180419 · Cited by 25 · see citing works
Deka, R. K., Brautigam, C. A., Liu, W. Z., Tomchick, D. R., & Norgard, M. V. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.449975 · Cited by 25 · see citing works
Nedeljković, N. (2019) · Pharmacological Research · doi:10.1016/j.phrs.2019.04.007 · Cited by 25 · see citing works
Ng, P. S. K., Day, C. J., Atack, J. M., Hartley‐Tassell, L. E., Winter, L. E., Marshanski, T., Padler‐Karavani, V., Varki, A. P., Barenkamp, S. J., Apicella, M. A., et al. (2019) · mBio · doi:10.1128/mbio.00422-19 · Cited by 24 · see citing works
The CD73 immune checkpoint promotes tumor cell metabolic fitness
Allard, D., Cousineau, I., Ma, E. H., Allard, B., Barèche, Y., Fleury, H., & Stagg, J. (2023) · eLife · doi:10.7554/elife.84508 · Cited by 24 · see citing works
Scaletti, E. R., Huschmann, F. U., Müeller, U., Weiss, M. S., & Sträter, N. (2021) · Purinergic Signalling · doi:10.1007/s11302-021-09802-w · Cited by 22 · see citing works
Biological characterization of sheep kidney-derived mesenchymal stem cells
Ji, M., Bai, C., Li, L., Fan, Y., Ma, C., Li, X., & Guan, W. (2016) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2016.3902 · Cited by 21 · see citing works
Cortés-García, J. D., López-López, C., Cortez-Espinosa, N., García-Hernández, M. H., Guzmán‐Flores, J. M., Layseca‐Espinosa, E., Portales‐Cervantes, L., & Portales‐Pérez, D. P. (2015) · Immunobiology · doi:10.1016/j.imbio.2015.07.018 · Cited by 20 · see citing works
Regulation and Function of Extracellular Nicotinamide Phosphoribosyltransferase/Visfatin
Carbone, F., Liberale, L., Bonaventura, A., Vecchié, A., Casula, M., Cea, M., Monacelli, F., Caffa, I., Bruzzone, S., Montecucco, F., et al. (2017) · Comprehensive physiology · doi:10.1002/j.2040-4603.2017.tb00757.x · Cited by 18 · see citing works
Self-citationZhan, J., Huang, L., Niu, L., Lu, W., Sun, C., Liu, S., Ding, Z., & Li, E. (2024) · Cell Communication and Signaling · doi:10.1186/s12964-024-01755-y · Cited by 17 · see citing works
NAD+ metabolism in peripheral neuropathic pain
Dai, Y., Lin, J., Ren, J., Zhu, B., Wu, C., & Yu, L. (2022) · Neurochemistry International · doi:10.1016/j.neuint.2022.105435 · Cited by 15 · see citing works
Nicastro, G. G., Burroughs, A. M., Iyer, L. M., & Aravind, L. (2023) · Nucleic Acids Research · doi:10.1093/nar/gkad879 · Cited by 14 · see citing works
Park, J. S., & Perl, A. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241310749 · Cited by 14 · see citing works
Metalation and Maturation of Zinc Ectoenzymes: A Perspective
Kambe, T. (2019) · Biochemistry · doi:10.1021/acs.biochem.9b00924 · Cited by 14 · see citing works
Damschroder, D., Perez, R. Z., Richardson, K., Vaz, F. M., Houtkooper, R. H., & Wessells, R. J. (2022) · Disease Models & Mechanisms · doi:10.1242/dmm.049279 · Cited by 13 · see citing works
Jabłońska, P., Kutryb-Zając, B. A., Mierzejewska, P., Jasztal, A., Bocian, B., Lango, R., Rogowski, J. A., Chłopicki, S., Smolenski, R. T., & Slominska, E. M. (2021) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.15912 · Cited by 11 · see citing works
Biological Functions and Therapeutic Potential of NAD+ Metabolism in Gynecological Cancers
Myong, S., Nguyen, A. Q., & Challa, S. (2024) · Cancers · doi:10.3390/cancers16173085 · Cited by 10 · see citing works
Ectonucleotidases in Solid Organ and Allogeneic Hematopoietic Cell Transplantation
Chernogorova, P., & Zeiser, R. (2012) · BioMed Research International · doi:10.1155/2012/208204 · Cited by 8 · see citing works
Cortés-García, J. D., Briones-Espinoza, M., Vega‐Cárdenas, M., Ruiz-Rodríguez, V. M., Méndez‐Mancilla, A., Gómez-Otero, A., Morales, J. M. V., García-Hernández, M. H., & Portales‐Pérez, D. P. (2018) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2018.04.020 · Cited by 8 · see citing works
The Role of NAD+ and NAD+-Boosting Therapies in Inflammatory Response by IL-13
Pugel, A. D., Schoenfeld, A. M., Alsaifi, S. Z., Holmes, J. R., & Morrison, B. E. (2024) · Pharmaceuticals · doi:10.3390/ph17020226 · Cited by 7 · see citing works
Skaldin, M., Tuittila, M., Zavialov, A. V., & Zavialov, A. V. (2018) · Molecular Biology and Evolution · doi:10.1093/molbev/msy193 · Cited by 7 · see citing works
Koszałka, P., Kutryb-Zając, B. A., Mierzejewska, P., Tomczyk, M., Wietrzyk, J., Serafin, P. K., Smolenski, R. T., & Slominska, E. M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23105774 · Cited by 5 · see citing works
Crystallization and preliminary X-ray analysis of the open form of human ecto-5′-nucleotidase (CD73)
Knapp, K. M., Zebisch, M., & Sträter, N. (2012) · Acta Crystallographica Section F Structural Biology and Crystallization Communications · doi:10.1107/s1744309112045447 · Cited by 5 · see citing works
Sandhu, P., Kumari, M., Naini, K., & Akhter, Y. (2016) · Current Genetics · doi:10.1007/s00294-016-0664-5 · Cited by 4 · see citing works
Ectonucleotidases in Cancer and Inflammation
Stagg, J., Thompson, L. F., & Dwyer, K. M. (2012) · BioMed Research International · doi:10.1155/2012/951423 · Cited by 4 · see citing works
Transcriptional and Metabolic Investigation in 5′-Nucleotidase Deficient Cancer Cell Lines
Cadassou, O., Forey, P., Machon, C., Petrotto, E., Chettab, K., Tozzi, M. G., Guitton, J., Dumontet, C., Cros‐Perrial, E., & Jordheim, L. P. (2021) · Cells · doi:10.3390/cells10112918 · Cited by 3 · see citing works
Hwang, E. S. (2025) · Elsevier eBooks · doi:10.1016/b978-0-443-18722-3.00011-6 · Cited by 1 · see citing works
Novel NAD+ metabolomic technologies and their applications to Nicotinamide Riboside interventions
Trammell, S. A. J., Wright, M. E., Piper, R. C., Brenner, C., Slusarski, D. C., & Wilson, M. E. (2016) · doi:10.17077/etd.mk206led · Cited by 1 · see citing works
Zamporlini, F. (2016) · Università Politecnica delle Marche (Università Politecnica delle Marche)
Damschroder, D., Perez, R. Z., Houtkooper, R. H., & Wessells, R. J. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.01.06.475267
Rocha-Vieira, T. C., & Meyer-Fernandes, J. R. (2026) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2026.130913
Xie, P., Fan, J., Song, L., Cao, J., Grigorescu, A. A., Wan, Y., Kuzel, T. M., Schiltz, G. E., & Zhang, B. (2026) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6c00746
Aggregatibacter actinomycetemcomitans NadN contributes to neutrophil extracellular trap degradation
Puanglai, Y., Kasorn, A., Matangkasombut, O., Waraho‐Zhmayev, D., Chaturongakul, S., & Loison, F. (2026) · Journal of Oral Microbiology · doi:10.1080/20002297.2026.2694756
- Authors
- Garavaglia, S., Bruzzone, S., Cassani, C., Canella, L., Allegrone, G., Sturla, L., Mannino, E., Millo, E., De Flora, A., & Rizzi, M.
- Affiliations
- Università degli Studi del Piemonte Orientale “Amedeo Avogadro” (IT)
- University of Genoa (IT)
- Dipartimento di Medicina Sperimentale Section of Biochemistry, University of Genova, V.le Benedetto XV, 16132 Genova, Italy
- Corresponding author
- Garavaglia, Silvia
- Cassani, Camilla
- Canella, Laura
- Allegrone, Gianna
- Rizzi, Menico
- ORCID
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2011-12-14
- Volume
- 441
- Issue
- 1
- Pages
- 131-141
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- OpenAlex
- W2012919786
- Cited by
- 94
- References
- 52
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 4 · 2023: 3 · 2022: 5 · 2021: 12 · 2020: 6 · 2019: 14 · 2018: 4 · 2017: 5 · 2016: 6 · 2015: 8 · 2014: 6 · 2013: 6 · 2012: 8
- FWCI
- 2.59
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemical Journal (publishedVersion)
- PubMed (publishedVersion)
- CINECA IRIS Institutial Research Information System (University of Genoa) (submittedVersion)
- Funders
- European Synchrotron Radiation Facility
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Keywords
- Haemophilus influenzae, CD73, NAD+ metabolism, nicotinamide riboside, 5'-nucleotidase, zinc metalloenzyme, enzyme conformational change, substrate specificity, nicotinamide mononucleotide, enzyme inhibitor design, phylogenetic relationships
- MeSH terms
- Adenosine Diphosphate, Amino Acid Sequence, Animals, Bacterial Proteins, Binding Sites, Chlorocebus aethiops, Cloning, Molecular, Crystallization, Haemophilus influenzae, Humans, Models, Molecular, Molecular Sequence Data, NAD, Nicotinamide Mononucleotide, Nucleotidases, Protein Conformation, Pyrophosphatases, Zinc, 5'-Nucleotidase, Gene Expression Regulation, Bacterial, COS Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
