[S-adenosyl-L-homocysteine hydrolase as an attractive target for antimicrobial drugs].
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.
Nakanishi
Masayuki
M
Department of Biomolecular Science, Faculty of Engineering, Gifu University, Japan. mnakanis@cc.matsuyama-u.ac.jp
D043383:Adenosylhomocysteinase / Q000037:antagonists & inhibitors* / Q000502:physiology; D000818:Animals; D000962:Antimalarials; D000998:Antiviral Agents; D015195:Drug Design; D004791:Enzyme Inhibitors; D006801:Humans; D010963:Plasmodium falciparum / Q000201:enzymology; D012435:S-Adenosylhomocysteine / Q000378:metabolism
D000962:Antimalarials; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D012435:S-Adenosylhomocysteine; D043383:Adenosylhomocysteinase