An unexpected discovery could lead to new antibiotics, claim researchers in the US.

Amnon Kohen, at the University of Iowa, and colleagues were investigating the mechanism of the enzyme FDTS (flavin dependent thymidylate synthase). FDTS - found in pathogenic bacteria and parasites - catalyses the conversion of dUMP, a derivative of the nucleoside uridine, to its thymidine analogue, dTMP, used in DNA formation. Kohen found that the substrate dUMP activates an initial stage in the enzyme's catalytic cycle: the reduction of the cofactor FAD.

 

In the absence of dUMP, the FAD reduction step was delayed - a lag phase. Further experiments showed that dUMP concentration affected how long this lag phase lasted, implying that dUMP assists FAD reduction. Kohen suggests that to do this dUMP makes the enzyme change shape.

According to Ursula Liebl at the École Polytechnique in France, this 'represents the first thermodynamic evidence for earlier proposals that dUMP binding causes conformational changes in FDTS.'

Kohen suggests that the lag phase phenomenon could be a feature of other biological systems, hidden by the experimental conditions used.

Hannu Myllykallio of the Université Paris-Sud in France said that Kohen's research 'provides interesting hints towards the rational design of new antimicrobial compounds.' Kohen aims to extend the work to study FDTS from pathogenic bacteria.

Rachel Warfield