Abstract:

<p>Thymidylate synthase (TS), found in all organisms, is an essential enzyme responsible for the de&nbsp;novo synthesis of deoxythymidine monophosphate. The TS active sites of the protozoal parasite Cryptosporidium&nbsp;hominis and human are relatively conserved. Evaluation of antifolate compound 1 and its R-enantiomer 2 against both enzymes reveals divergent inhibitor selectivity and enzyme stereospecificity. To establish how C.&nbsp;hominis and human TS (ChTS and hTS) selectively discriminate 1 and 2, respectively, we determined crystal structures of ChTS complexed with 2 and hTS complexed with 1 or 2. Coupled with the previously determined structure of ChTS complexed with 1, we discuss a possible mechanism for enzyme stereospecificity and inhibitor selectivity.</p>