Crystal structure analyses of S-adenosyl-L-homosysteine hydrolase from Plasmodium falciparum complexed with inhibitors

School of Pharmaceutical Sciences, Showa University* Department of Biomolecular Science, Faculty of Engineering, Gifu University**
â—‹Nobutada Tanaka* Yoshio Kusakabe* Aoki Ken-ichi* Masayuki Nakanishi** Yukio Kitade** Kazuo T Nakamura*

The human malaria parasite Plasmodium falciparum is responsible for the death of more than a million people each year. The emergence of strains of malarial parasite resistant to conventional drug therapy has stimulated searches for antimalarials with novel modes of action. S-Adenosyl-L-homocysteine hydrolase (SAHH) is a regulator of biological methylations. Plasmodium falciparum SAHH (PfSAHH) inhibitors are expected to provide a new type of chemotherapeutic agent against malaria. Despite the pressing need to develop selective PfSAHH inhibitors, only the mammalian SAHH structures were available. We have determined the crystal structure of PfSAHH complexed with the reaction product adenosine (Ado) [Tanaka et al., J. Mol. Biol. 343, 1007-1017 (2004)]. Knowledge of the structure of the Ado complex in combination with a structural comparison with Homo sapience SAHH (HsSAHH) revealed that a single substitution between the PfSAHH (Cys59) and HsSAHH (Thr60) accounts for the differential interactions with nucleoside inhibitors.
Recent studies suggest that introduction of a fluorine atom at the 2-position of a carbocyclic adenine nucleoside derivative improves the selectivity index between HsSAHH and PfSAHH inhibition. To obtain an insight into structural basis for selective inhibition of SAHHs by the inhibitors, structural analyses of PfSAHH complexed with the selective inhibitors are essential.
Here we present the crystal structure analysis of PfSAHH complexed with a selective inhibitor, 2-fluoronoraristeromycin (Tanaka et al., in preparation).