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Science 29 October 2004:
Vol. 306. no. 5697, pp. 872 - 876
DOI: 10.1126/science.1101030
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Reports

A Molecular Switch and Proton Wire Synchronize the Active Sites in Thiamine Enzymes

René A. W. Frank, Christopher M. Titman, J. Venkatesh Pratap, Ben F. Luisi,* Richard N. Perham*

Thiamine diphosphate (ThDP) is used as a cofactor in many key metabolic enzymes. We present evidence that the ThDPs in the two active sites of the E1 (EC 1.2.4.1) component of the pyruvate dehydrogenase complex communicate over a distance of 20 angstroms by reversibly shuttling a proton through an acidic tunnel in the protein. This "proton wire" permits the co-factors to serve reciprocally as general acid/base in catalysis and to switch the conformation of crucial active-site peptide loops. This synchronizes the progression of chemical events and can account for the oligomeric organization, conformational asymmetry, and "ping-pong" kinetic properties of E1 and other thiamine-dependent enzymes.

Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, UK.

* To whom correspondence should be addressed. E-mail: r.n.perham{at}bioc.cam.ac.uk or ben{at}cryst.bioc.cam.ac.uk

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