A molecular switch and proton wire synchronize the active sites in thiamine enzymes |
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Authors: | Frank René A W Titman Christopher M Pratap J Venkatesh Luisi Ben F Perham Richard N |
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Institution: | Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, UK. |
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Abstract: | 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. |
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