Structural and metabolic specificity of methylthiocoformycin for malarial adenosine deaminases

Meng Chiao Ho, María B. Cassera, Dennis C. Madrid, Li-Min Ting, Peter C. Tyler, Kami Kim, Steven C. Almo, Vern L. Schramm

Research output: Contribution to journalArticlepeer-review

26 Scopus citations


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., Fröhlich, 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°. 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.

Original languageEnglish (US)
Pages (from-to)9618-9626
Number of pages9
Issue number40
StatePublished - 2009

ASJC Scopus subject areas

  • Biochemistry


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