Drug resistance to therapeutic antibiotics poses a challenge to the identification of novel targets and drugs for the treatment of infectious diseases. Infections caused by Enterococcus faecalis are a major health problem. Thymidylate synthase (TS) from E. faecalis is a potential target for antibacterial therapy. We have determined the X-ray crystallographic structure of the E. faecalis thymidylate synthase (EfTS), obtained as a native binary complex composed of EfTS and 5-formyltetrahydrofolate (5-FTHF). The structure provide evidence that EfTS is a half-the-sites reactive enzyme as 5-FTHF is bound to two of the four independent subunits present in the crystal asymmetric unit. 5-FTHF is a metabolite of the one-carbon transfer reaction catalysed by 5-formyltetrahydrofolate cycloligase. Kinetic studies show that 5-FTHF is a weak inhibitor of EfTS, suggesting that the EfTS-5-FTHF complex may function as a source of folates and/or may regulate one-carbon metabolism. The structure represents the first example of endogenous 5-FTHF bound to a protein involved in folate metabolism.

The structure of Enterococcus faecalis thymidylate synthase provides clues about folate bacterial metabolism / C., Pozzi; Ferrari, Stefania; D., Cortesi; Luciani, Rosaria; R. M., Stroud; A., Catalano; Costi, Maria Paola; S., Mangani. - In: ACTA CRYSTALLOGRAPHICA. SECTION D. - ISSN 1399-0047. - STAMPA. - 68:(2012), pp. 1232-1241. [10.1107/S0907444912026236]

The structure of Enterococcus faecalis thymidylate synthase provides clues about folate bacterial metabolism

FERRARI, Stefania;LUCIANI, Rosaria;COSTI, Maria Paola;
2012-01-01

Abstract

Drug resistance to therapeutic antibiotics poses a challenge to the identification of novel targets and drugs for the treatment of infectious diseases. Infections caused by Enterococcus faecalis are a major health problem. Thymidylate synthase (TS) from E. faecalis is a potential target for antibacterial therapy. We have determined the X-ray crystallographic structure of the E. faecalis thymidylate synthase (EfTS), obtained as a native binary complex composed of EfTS and 5-formyltetrahydrofolate (5-FTHF). The structure provide evidence that EfTS is a half-the-sites reactive enzyme as 5-FTHF is bound to two of the four independent subunits present in the crystal asymmetric unit. 5-FTHF is a metabolite of the one-carbon transfer reaction catalysed by 5-formyltetrahydrofolate cycloligase. Kinetic studies show that 5-FTHF is a weak inhibitor of EfTS, suggesting that the EfTS-5-FTHF complex may function as a source of folates and/or may regulate one-carbon metabolism. The structure represents the first example of endogenous 5-FTHF bound to a protein involved in folate metabolism.
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The structure of Enterococcus faecalis thymidylate synthase provides clues about folate bacterial metabolism / C., Pozzi; Ferrari, Stefania; D., Cortesi; Luciani, Rosaria; R. M., Stroud; A., Catalano; Costi, Maria Paola; S., Mangani. - In: ACTA CRYSTALLOGRAPHICA. SECTION D. - ISSN 1399-0047. - STAMPA. - 68:(2012), pp. 1232-1241. [10.1107/S0907444912026236]
C., Pozzi; Ferrari, Stefania; D., Cortesi; Luciani, Rosaria; R. M., Stroud; A., Catalano; Costi, Maria Paola; S., Mangani
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/747309
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