X-ray crystal structures of Enterococcus faecalis thymidylate synthase with folate binding site inhibitors.

Abstract:

:Infections caused by Enterococcus faecalis (Ef) represent nowadays a relevant health problem. We selected Thymidylate synthase (TS) from this organism as a potential specific target for antibacterial therapy. We have previously demonstrated that species-specific inhibition of the protein can be achieved despite the relatively high structural similarity among bacterial TSs and human TS. We had previously obtained the EfTS crystal structure of the protein in complex with the metabolite 5-formyl-tetrahydrofolate (5-FTHF) suggesting the protein role as metabolite reservoir; however, protein-inhibitors complexes were still missing. In the present work we identified some inhibitors bearing the phthalimidic core from our in-house library and we performed crystallographic screening towards EfTS. We obtained two X-ray crystallographic structures: the first with a weak phthalimidic inhibitor bound in one subunit and 5-hydroxymethylene-6-hydrofolic acid (5-HMHF) in the other subunit; a second X-ray structure complex with methotrexate. The structural information achieved confirm the role of EfTS as an enzyme involved in the folate pool system and provide a structural basis for structure-based drug design.

journal_name

Eur J Med Chem

authors

Catalano A,Luciani R,Carocci A,Cortesi D,Pozzi C,Borsari C,Ferrari S,Mangani S

doi

10.1016/j.ejmech.2016.07.066

subject

Has Abstract

pub_date

2016-11-10 00:00:00

pages

649-664

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(16)30631-6

journal_volume

123

pub_type

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