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Understanding the structural basis of species selective, stereospecific inhibition for Cryptosporidium and human thymidylate synthase
Author(s) -
Czyzyk Daniel J.,
Valhondo Margarita,
Jorgensen William L.,
Anderson Karen S.
Publication year - 2019
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1002/1873-3468.13474
Subject(s) - thymidylate synthase , chemistry , stereospecificity , enzyme , stereochemistry , enantiomer , biochemistry , biology , fluorouracil , genetics , chemotherapy , catalysis
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 ( Ch TS and hTS) selectively discriminate 1 and 2 , respectively, we determined crystal structures of Ch TS complexed with 2 and hTS complexed with 1 or 2 . Coupled with the previously determined structure of Ch TS complexed with 1 , we discuss a possible mechanism for enzyme stereospecificity and inhibitor selectivity.