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

Czyzyk, Daniel J.; Valhondo, Margarita; Jorgensen, William L.; Anderson, Karen S.

doi:10.1002/1873-3468.13474

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

Journal Article · Tue Jun 18 00:00:00 EDT 2019 · FEBS Letters

DOI:https://doi.org/10.1002/1873-3468.13474· OSTI ID:1557325

Czyzyk, Daniel J. ^[1]; Valhondo, Margarita ^[1]; Jorgensen, William L. ^[1]; Anderson, Karen S. ^[1]

Yale Univ., New Haven, CT (United States)

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 finally discuss a possible mechanism for enzyme stereospecificity and inhibitor selectivity.

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Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE; National Institutes of Health (NIH)

Grant/Contract Number:: 5T32AI007404-23; AI083146; GM32136

OSTI ID:: 1557325

Journal Information:: FEBS Letters, Vol. 593, Issue 15; ISSN 0014-5793

Publisher:: Federation of European Biochemical SocietiesCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 1 work

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
chiral recognition
Cryptosporidium hominis
enzyme stereospecificity
inhibitor selectivity
thymidylate synthase
x-ray crystallography

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

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