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Kinetics and crystal structure of human purine nucleoside phosphorylase in complex with 7-methyl-6-thio-guanosine.

Silva RG, Pereira JH, Canduri F, de Azevedo WF, Basso LA, Santos DS
Arch Biochem Biophys 442 49-58 (2005)
Cited: 10 times
EuropePMC logo PMID: 16154528

Abstract

Purine nucleoside phosphorylase (PNP) catalyzes the reversible phosphorolysis of nucleosides and deoxynucleosides, generating ribose 1-phosphate and the purine base, which is an important step of purine catabolism pathway. The lack of such an activity in humans, owing to a genetic disorder, causes T-cell impairment, and drugs that inhibit this enzyme may have the potential of being utilized as modulators of the immunological system to treat leukemia, autoimmune diseases, and rejection in organ transplantation. Here, we describe kinetics and crystal structure of human PNP in complex with 7-methyl-6-thio-guanosine, a synthetic substrate, which is largely used in activity assays. Analysis of the structure identifies different protein conformational changes upon ligand binding, and comparison of kinetic and structural data permits an understanding of the effects of atomic substitution on key positions of the synthetic substrate and their consequences to enzyme binding and catalysis. Such knowledge may be helpful in designing new PNP inhibitors.

Reviews citing this publication (1)

  1. Computational methods for de novo protein design and its applications to the human immunodeficiency virus 1, purine nucleoside phosphorylase, ubiquitin specific protease 7, and histone demethylases. Bellows ML, Floudas CA. Curr Drug Targets 11 264-278 (2010)

Articles citing this publication (9)

  1. Humanized ADEPT comprised of an engineered human purine nucleoside phosphorylase and a tumor targeting peptide for treatment of cancer. Afshar S, Asai T, Morrison SL. Mol Cancer Ther 8 185-193 (2009)
  2. Substrate specificity and kinetic mechanism of purine nucleoside phosphorylase from Mycobacterium tuberculosis. Ducati RG, Santos DS, Basso LA. Arch Biochem Biophys 486 155-164 (2009)
  3. Molecular modeling and dynamics simulations of PNP from Streptococcus agalactiae. Caceres RA, Saraiva Timmers LF, Dias R, Basso LA, Santos DS, de Azevedo WF. Bioorg Med Chem 16 4984-4993 (2008)
  4. Conservation of structure and activity in Plasmodium purine nucleoside phosphorylases. Chaikuad A, Brady RL. BMC Struct Biol 9 42 (2009)
  5. Structural studies of human purine nucleoside phosphorylase: towards a new specific empirical scoring function. Timmers LF, Caceres RA, Vivan AL, Gava LM, Dias R, Ducati RG, Basso LA, Santos DS, de Azevedo WF. Arch Biochem Biophys 479 28-38 (2008)
  6. Functional and Structural Characterization of Purine Nucleoside Phosphorylase from Kluyveromyces lactis and Its Potential Applications in Reducing Purine Content in Food. Mahor D, Priyanka A, Prasad GS, Thakur KG. PLoS One 11 e0164279 (2016)
  7. Molecular modeling, dynamics and docking studies of purine nucleoside phosphorylase from Streptococcus pyogenes. Timmers LF, Caceres RA, Dias R, Basso LA, Santos DS, de Azevedo WF. Biophys Chem 142 7-16 (2009)
  8. Molecular dynamics studies of a hexameric purine nucleoside phosphorylase. Zanchi FB, Caceres RA, Stabeli RG, de Azevedo WF. J Mol Model 16 543-550 (2010)
  9. Molecular modeling and dynamics studies of purine nucleoside phosphorylase from Bacteroides fragilis. Pauli I, Timmers LF, Caceres RA, Basso LA, Santos DS, de Azevedo WF. J Mol Model 15 913-922 (2009)


Related citations provided by authors (1)

  1. Crystal structure of human purine nucleoside phosphorylase at 2.3A resolution.. de Azevedo WF, Canduri F, dos Santos DM, Silva RG, de Oliveira JS, de Carvalho LP, Basso LA, Mendes MA, Palma MS, Santos DS Biochem Biophys Res Commun 308 545-52 (2003)

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