Agyei-Owusu Kwasi, Leeper Finian J
Department of Chemistry, University of Cambridge, UK.
FEBS J. 2009 Jun;276(11):2905-16. doi: 10.1111/j.1742-4658.2009.07018.x. Epub 2009 Apr 23.
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-dependent 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 the fight against infection.
硫胺素二磷酸（ThDP）作为酶的辅因子的作用已为人所知达数十年之久。这篇小型综述涵盖了通过使用ThDP类似物在理解ThDP依赖性酶催化机制方面取得的进展。许多此类类似物已被合成，并提供了关于辅因子结合和催化活性所需官能团的信息。通过这些研究，人们认识到疏水相互作用在催化循环中稳定反应中间体的重要作用。ThDP催化反应机制中中间体的稳定类似物也已被合成，使用这些类似物的晶体学研究使得能够解析代表反应进行过程中瞬间状态的酶结构。除了提供有关ThDP依赖性酶的机制信息外，许多类似物还是这些酶的有效抑制剂。讨论了这些化合物作为治疗靶点和重要除草剂的潜力。最近，发现了ThDP通过核糖开关的作用调节其自身生物合成基因的方式。这为硫胺素研究开辟了一个新分支，有可能在对抗感染方面提供新的治疗靶点。
