Understanding the structural basis of species selective, stereospecific inhibition for Cryptosporidium and human thymidylate synthase

Abstract

Thymidylate synthase (TS), found in all organisms, is an essential enzyme responsible for the de novo synthesis of deoxythymidine monophosphate. The TS active sites of the protozoal parasite Cryptosporidium 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. 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.

Chiral evasion and stereospecific antifolate resistance in Staphylococcus aureus

“…The stereochemical configuration of molecules is an important factor to be considered in the context of biological processes, particularly in enzyme-catalyzing reactions since enzyme-substrate systems usually require strict chiral matching [ 27 ]. In the SaDHFR system, not only the NADPH cofactor but also the PLAs can bind in different configurations.…”

Chiral evasion and stereospecific antifolate resistance inStaphylococcus aureus

“…The stereochemical configuration of molecules is an important factor to be considered in the context of biological processes, particularly in enzyme-catalyzing reactions since enzyme-substrate systems usually require strict chiral matching (30). In the SaDHFR system, not only the NADPH cofactor but also the PLAs can bind in different configurations.…”