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.