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FEBS Lett. 2019 Jun 7. doi: 10.1002/1873-3468.13474. [Epub ahead of print]

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

Author information

1
Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA.
2
Department of Chemistry, Yale University, New Haven, CT, USA.

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.

KEYWORDS:

Cryptosporidium hominis ; X-ray crystallography; chiral recognition; enzyme stereospecificity; inhibitor selectivity; thymidylate synthase

PMID:
31172516
DOI:
10.1002/1873-3468.13474

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