著者

中西 雅之

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.127, no.6, pp.977-982, 2007 (Released:2007-06-01)

参考文献数

25

被引用文献数

10 12

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S-Adenosyl-L-homocysteine (SAH) hydrolase catalyzes breakdown of SAH, which arises after S-adenosylmethionine-dependent methylation, into adenosine and homocysteine. The enzyme activity is required for both metabolic pathway of sulfur-containing amino acids and a variety of biological methylations. Because of the essential roles of SAH hydrolase for living cells, inhibitors of SAH hydrolase are expected to be antimicrobial drugs, especially for viruses and malaria parasite. Our research focused on the development of new antimalarials based on the SAH hydrolase inhibition. Malaria parasite employs SAH hydrolase of itself for coping with the toxicity of SAH, so that the target offers opportunities for chemotherapy if structural differences are exploited between the parasite and human enzymes. In vitro screens of nucleoside analogs resulted in moderate but selective inhibition for recombinant SAH hydrolase of malaria parasite, Plasmodium falciparum, by 2-position substituted adenosine analogs. Similar selectivity was observed in the growth inhibition assay of cultured cells. Following crystal structure analysis of the parasite SAH hydrolase discovered an additional space, which is located near the 2-position of the adenine-ring, in the substrate binding pocket. Mutagenic analysis of the amino acid residue forming the additional space confirmed that the inhibition selectivity is due to the difference of only one amino acid residue, between Cys59 in P. falciparum and Thr60 in human. For developing antimalarial drugs, it might be suitable to select target from pathways that are present in the parasite but absent from humans; nevertheless, even if the target was common in parasite and host, slight structural difference such as single amino acid variation is likely to be available for improving inhibitor selectivity.

著者

田中 信忠 梅田 知伸 日下部 吉男 中西 雅之 北出 幸夫 中村 和郎

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.133, no.5, pp.527-537, 2013 (Released:2013-05-01)

参考文献数

30

被引用文献数

4 4

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The human malaria parasite Plasmodium falciparum is responsible for the death of more than a million people each year. The emergence of strains of this malaria parasite resistant to conventional drug therapy has stimulated the search for antimalarial compounds with novel modes of action. Here the structure-function relationship studies for two Plasmodium proteins are presented. One example is the structural studies for S-adenosyl-L-homocysteine hydrolase from Plasmodium falciparum (PfSAHH) and the other example is those for 1-deoxy-D-xylulose reductoisomerase from Plasmodium falciparum (PfDXR). In the former study, the clue for design of species specific PfSAHH inhibitors was obtained by the structural comparison of the active site of PfSAHH with that of human SAHH (HsSAHH). Our study revealed that the inhibitor selectivity depends on the difference of only one amino acid residue in the active site; Cys59 in PfSAHH vs. Thr60 in HsSAHH. In the latter study, the inhibition of PfDXR enzyme by fosmidomycin has proved to be efficient in the treatment of uncomplicated malaria in recent clinical trials conducted in Gabon and Thailand. Our crystal structure analyses of PfDXR/inhibitor complexes revealed the molecular basis of fosmidomycin's action in P. falciparum. We expect that the structure-function relationship studies on Plasmodium proteins are useful for developing the more effective antimalarial compounds.