FOR 1296: Diversity of Asymmetric Thiamine Catalysis

硫胺素二磷酸（ThDP）依赖酶催化广泛的反应，许多仍有待发现，特别是如果非生理的。研究单位的中心目标是通过对不对称硫胺素催化多样性的基本理解，确定并引入新的酶催化转化实践。特别是，它应该被定义，哪些条件是必不可少的酶，使一个辅因子催化许多不同的反应。这里特别令人感兴趣的是thdp依赖性酶在不对称合成手性产物产生药学上感兴趣的化合物时的碳化潜力。C-C键形成反应需要酶内特定的环境，有明确的供体或受体分子，需要适当定位。通过对属于不同thdp依赖性酶家族的12种特异性酶的序列、结构和功能的分析，将有助于鉴定和调节结构-功能关系。通过这种方式，可以定义和实现诸如改进的底物特异性和立体选择性等优越参数。随后，新的生物催化剂的定向设计可以为新的不对称合成铺平道路，这目前还不可行。深入了解thdp依赖性酶的结构-功能关系对于非酶催化和理论考虑也具有重要意义。可以开发仿生有机催化的新策略来模仿在自然界中进化以催化广泛反应的辅因子ThDP。稳定酶中的中间体或在底物活化中起作用的一般参数可以影响优化的杂唑催化剂的发展。同样，n -杂环碳烯（NHC）催化的新反应向酶促反应的潜在转移也被设想。所选的thdp依赖性酶将在生化、机械、动力学和立体化学方面进行深入的表征。由于thdp依赖性酶类的异质性和较低的序列相似性，本部分将由中央生物信息学和结构分析来补充。

Thiamine diphosphate (ThDP)-dependent enzymes catalyse a broad range of reactions, many still to be discovered, especially if non-physiological. The central aim of the Research Unit is to identify and introduce into practice new enzyme-catalysed transformations through a fundamental understanding of the diversity of asymmetric thiamine catalysis. In particular, it should be defined, which conditions are essential within the enzyme to enable one cofactor to catalyse many diverse reactions. Of particular interest here is the carboligating potential of ThDP-dependent enzymes for the asymmetric synthesis of chiral products yielding pharmaceutically interesting compounds. C-C bond forming reactions require a particular environment within the enzyme with well-defined donor or acceptor molecules that need to be positioned appropriately. The analysis of sequence, structure and function of twelve specifically chosen enzymes, belonging to different families of ThDP-dependent enzymes, will allow the identification and modulation of the structure-function relationships. In this manner, superior parameters such as improved substrate specificity and stereoselectivity can be defined and implemented. Subsequently, the directed design of new biocatalysts could pave the way for new asymmetric syntheses, which are currently not yet feasible. A thorough understanding of the structure-function relationship of ThDP-dependent enzymes is also significant for non-enzymatic catalysis and for theoretical considerations. New strategies in biomimetic organocatalysis could be developed to mimick the cofactor ThDP that has evolved in nature to catalyse a broad range of reactions. General parameters that stabilise intermediates in the enzyme or play a role in the activation of substrates can influence the development of optimised heterazolium catalysts. Likewise, potential transfer of N-heterocyclic carbene (NHC)-catalysed new reactions to enzymatic reactions is envisioned. The selected ThDP-dependent enzymes will be characterised in depth under biochemical, mechanistic, kinetic and stereochemical aspects. Due to the heterogeneity of the class of ThDP-dependent enzymes and due to the low sequence similarity this part will be complemented by central bioinformatic and structural analysis.