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.

X-ray crystal structures of Enterococcus faecalis thymidylate synthase with folate binding site inhibitors / Catalano, Alessia; Luciani, Rosaria; Carocci, Alessia; Cortesi, Debora; Pozzi, Cecilia; Borsari, Chiara; Ferrari, Stefania; Mangani, Stefano. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - STAMPA. - 123:(2016), pp. 649-664. [10.1016/j.ejmech.2016.07.066]

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

LUCIANI, Rosaria;CORTESI, DEBORA;BORSARI, CHIARA;FERRARI, Stefania;
2016-01-01

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.
123
649
664
X-ray crystal structures of Enterococcus faecalis thymidylate synthase with folate binding site inhibitors / Catalano, Alessia; Luciani, Rosaria; Carocci, Alessia; Cortesi, Debora; Pozzi, Cecilia; Borsari, Chiara; Ferrari, Stefania; Mangani, Stefano. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - STAMPA. - 123:(2016), pp. 649-664. [10.1016/j.ejmech.2016.07.066]
Catalano, Alessia; Luciani, Rosaria; Carocci, Alessia; Cortesi, Debora; Pozzi, Cecilia; Borsari, Chiara; Ferrari, Stefania; Mangani, Stefano
File in questo prodotto:
File Dimensione Formato  
38_EJMC_2016_123_649_efts.pdf

non disponibili

Descrizione: Articolo
Tipologia: Versione pubblicata dall'editore
Dimensione 2.2 MB
Formato Adobe PDF
2.2 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
Catalano-Mangani_EJMC_sf-2016-07-24.pdf

Open access

Tipologia: Versione dell'autore revisionata e accettata per la pubblicazione
Dimensione 1.99 MB
Formato Adobe PDF
1.99 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

Licenza Creative Commons
I metadati presenti in IRIS UNIMORE sono rilasciati con licenza Creative Commons CC0 1.0 Universal, mentre i file delle pubblicazioni sono rilasciati con licenza Attribuzione 4.0 Internazionale (CC BY 4.0), salvo diversa indicazione.
In caso di violazione di copyright, contattare Supporto Iris

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1116221
Citazioni
  • ???jsp.display-item.citation.pmc??? 7
  • Scopus 14
  • ???jsp.display-item.citation.isi??? 14
social impact