tailieunhanh - Báo cáo khoa học: Thiamin diphosphate in biological chemistry: analogues of thiamin diphosphate in studies of enzymes and riboswitches

The role of thiamin diphosphate (ThDP) as a cofactor for enzymes has been known for many decades. This minireview covers the progress made in understanding the catalytic mechanism of ThDP-dependent enzymes through the use of ThDP analogues. Many such analogues have been syn-thesized and have provided information on the functional groups necessary for the binding and catalytic activity of the cofactor. | ỊFEBS Journal MINIREVIEW Thiamin diphosphate in biological chemistry analogues of thiamin diphosphate in studies of enzymes and riboswitches Kwasi Agyei-Owusu and Finian J. Leeper Department of Chemistry University of Cambridge UK Keywords acetohydroxyacid synthase enzyme crystal structure enzyme inhibition pyruvate decarboxylase pyruvate dehydrogenase reaction mechanism riboswitch thiamin pyrophosphate thiamine diphosphate transketolase Correspondence F. J. Leeper Department of Chemistry University of Cambridge Lensfield Road Cambridge CB2 1EW UK Fax 44 1223 336362 Tel 44 1223 336403 E-mail FJL1@ Website http staff Received 9 October 2008 revised 9 March 2009 accepted 12 March 2009 The role of thiamin diphosphate ThDP as a cofactor for enzymes has been known for many decades. This minireview covers the progress made in understanding the catalytic mechanism of ThDP-dependent enzymes through the use of ThDP analogues. Many such analogues have been synthesized and have provided information on the functional groups necessary for the binding and catalytic activity of the cofactor. Through these studies the important role of hydrophobic interactions in stabilizing reaction intermediates in the catalytic cycle has been recognized. Stable analogues of intermediates in the ThDP-catalysed reaction mechanism have also been synthesized and crystallographic studies using these analogues have allowed enzyme structures to be solved that represent snapshots of the reaction in progress. As well as providing mechanistic information about ThDP-depen-dent enzymes many analogues are potent inhibitors of these enzymes. The potential of these compounds as therapeutic targets and as important herbicidal agents is discussed. More recently the way that ThDP regulates the genes for its own biosynthesis through the action of riboswitches has been discovered. This opens a new branch of thiamin research with the potential to provide new therapeutic targets in

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