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

Publication Type:

Journal Article

Source:

FEBS Lett, Volume 593, Issue 15, p.2069-2078 (2019)

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>

PDB: 
6OJS, 6OJU, 6OJV
Detector: 
PILATUS
EIGER
Beamline: 
24-ID-C
24-ID-E