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Structural and metabolic specificity of methylthiocoformycin for malarial adenosine deaminases.

Ho MC, Cassera MB, Madrid DC, Ting LM, Tyler PC, Kim K, Almo SC, Schramm VL
Biochemistry 48 9618-26 (2009)
Cited: 20 times
EuropePMC logo PMID: 19728741

Abstract

Plasmodium falciparum is a purine auxotroph requiring hypoxanthine as a key metabolic precursor. Erythrocyte adenine nucleotides are the source of the purine precursors, making adenosine deaminase (ADA) a key enzyme in the pathway of hypoxanthine formation. Methylthioadenosine (MTA) is a substrate for most malarial ADAs, but not for human ADA. The catalytic site specificity of malarial ADAs permits methylthiocoformycin (MT-coformycin) to act as a Plasmodium-specific transition state analogue with low affinity for human ADA [Tyler, P. C., Taylor, E. A., Frohlich, R. G. G., and Schramm, V. L. (2007) J. Am. Chem. Soc. 129, 6872-6879]. The structural basis for MTA and MT-coformycin specificity in malarial ADAs is the subject of speculation [Larson, E. T., et al. (2008) J. Mol. Biol. 381, 975-988]. Here, the crystal structure of ADA from Plasmodium vivax (PvADA) in a complex with MT-coformycin reveals an unprecedented binding geometry for 5'-methylthioribosyl groups in the malarial ADAs. Compared to malarial ADA complexes with adenosine or deoxycoformycin, 5'-methylthioribosyl groups are rotated 130 degrees . A hydrogen bonding network between Asp172 and the 3'-hydroxyl of MT-coformycin is essential for recognition of the 5'-methylthioribosyl group. Water occupies the 5'-hydroxyl binding site when MT-coformycin is bound. Mutagenesis of Asp172 destroys the substrate specificity for MTA and MT-coformycin. Kinetic, mutagenic, and structural analyses of PvADA and kinetic analysis of five other Plasmodium ADAs establish the unique structural basis for its specificity for MTA and MT-coformycin. Plasmodium gallinaceum ADA does not use MTA as a substrate, is not inhibited by MT-coformycin, and is missing Asp172. Treatment of P. falciparum cultures with coformycin or MT-coformycin in the presence of MTA is effective in inhibiting parasite growth.

Reviews - 3ewc mentioned but not cited (1)

  1. Enzymatic Transition States and Drug Design. Schramm VL. Chem Rev 118 11194-11258 (2018)

Articles - 3ewc mentioned but not cited (4)

  1. Sampling protein motion and solvent effect during ligand binding. Limongelli V, Marinelli L, Cosconati S, La Motta C, Sartini S, Mugnaini L, Da Settimo F, Novellino E, Parrinello M. Proc Natl Acad Sci U S A 109 1467-1472 (2012)
  2. Cyanuric acid hydrolase: evolutionary innovation by structural concatenation. Peat TS, Balotra S, Wilding M, French NG, Briggs LJ, Panjikar S, Cowieson N, Newman J, Scott C. Mol Microbiol 88 1149-1163 (2013)
  3. Structural and metabolic specificity of methylthiocoformycin for malarial adenosine deaminases. Ho MC, Cassera MB, Madrid DC, Ting LM, Tyler PC, Kim K, Almo SC, Schramm VL. Biochemistry 48 9618-9626 (2009)
  4. Transition Path Sampling Based Calculations of Free Energies for Enzymatic Reactions: The Case of Human Methionine Adenosyl Transferase and Plasmodium vivax Adenosine Deaminase. Balasubramani SG, Schwartz SD. J Phys Chem B 126 5413-5420 (2022)


Reviews citing this publication (3)

  1. Purine and pyrimidine pathways as targets in Plasmodium falciparum. Cassera MB, Zhang Y, Hazleton KZ, Schramm VL. Curr Top Med Chem 11 2103-2115 (2011)
  2. Moonlighting adenosine deaminase: a target protein for drug development. Cortés A, Gracia E, Moreno E, Mallol J, Lluís C, Canela EI, Casadó V. Med Res Rev 35 85-125 (2015)
  3. Transition-state inhibitors of purine salvage and other prospective enzyme targets in malaria. Ducati RG, Namanja-Magliano HA, Schramm VL. Future Med Chem 5 1341-1360 (2013)

Articles citing this publication (12)

  1. Reconstruction and flux-balance analysis of the Plasmodium falciparum metabolic network. Plata G, Hsiao TL, Olszewski KL, Llinás M, Vitkup D. Mol Syst Biol 6 408 (2010)
  2. Novel Plasmodium falciparum metabolic network reconstruction identifies shifts associated with clinical antimalarial resistance. Carey MA, Papin JA, Guler JL. BMC Genomics 18 543 (2017)
  3. Adenine aminohydrolase from Leishmania donovani: unique enzyme in parasite purine metabolism. Boitz JM, Strasser R, Hartman CU, Jardim A, Ullman B. J Biol Chem 287 7626-7639 (2012)
  4. Letter Discovery of a cytokinin deaminase. Goble AM, Fan H, Sali A, Raushel FM. ACS Chem Biol 6 1036-1040 (2011)
  5. Methylthioadenosine deaminase in an alternative quorum sensing pathway in Pseudomonas aeruginosa. Guan R, Ho MC, Fröhlich RF, Tyler PC, Almo SC, Schramm VL. Biochemistry 51 9094-9103 (2012)
  6. Pa0148 from Pseudomonas aeruginosa catalyzes the deamination of adenine. Goble AM, Zhang Z, Sauder JM, Burley SK, Swaminathan S, Raushel FM. Biochemistry 50 6589-6597 (2011)
  7. Development of a target identification approach using native mass spectrometry. Liu M, Van Voorhis WC, Quinn RJ. Sci Rep 11 2387 (2021)
  8. Computed structures of point deletion mutants and their enzymatic activities. Berrondo M, Gray JJ. Proteins 79 2844-2860 (2011)
  9. Deamination of 6-aminodeoxyfutalosine in menaquinone biosynthesis by distantly related enzymes. Goble AM, Toro R, Li X, Ornelas A, Fan H, Eswaramoorthy S, Patskovsky Y, Hillerich B, Seidel R, Sali A, Shoichet BK, Almo SC, Swaminathan S, Tanner ME, Raushel FM. Biochemistry 52 6525-6536 (2013)
  10. Mechanism of growth inhibition of intraerythrocytic stages of Plasmodium falciparum by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR). Bulusu V, Thakur SS, Venkatachala R, Balaram H. Mol Biochem Parasitol 177 1-11 (2011)
  11. A theoretical study on the catalytic mechanism of Mus musculus adenosine deaminase. Wu XH, Zou GL, Quan JM, Wu YD. J Comput Chem 31 2238-2247 (2010)
  12. The adenosine deaminases of Plasmodium vivax and Plasmodium falciparum exhibit surprising differences in ligand specificity. Ivanov A, Matsumura I. J Mol Graph Model 35 43-48 (2012)


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