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Modeling the sequence-structure-function relationships of ThDP-dependent enzymes

ThDP 依赖性酶的序列-结构-功能关系建模

基本信息

批准号：
172090439
负责人：
Professor Dr. Jürgen Pleiss
金额：
--
依托单位：
Abteilung für Technische Biochemie
依托单位国家：
德国
项目类别：
Research Units
财政年份：
2010
资助国家：
德国
起止时间：
2009-12-31 至 2016-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/172090439?language=en
关键词：
Modeling sequence structure function relationships

项目摘要

While the reaction mechanisms of thiamine diphosphate (ThDP)-dependent enzymes have been investigated for years, a comprehensive model allowing for the prediction of the catalytic activity, specificity, and selectivity of difterent enzymes is not yet available. Their highly diverse substrate specificity and catalytic activity is reflected in the high diversity in sequence and structure of the difterent families of ThDP-dependent enzymes. During the course of evolution, shuftling, rearrangement, and fusion of domains, mutations, and gene duplications have led to an enormous diversity of ThDP-dependent enzymes. However, all ThDP-dependent enzymes contain at least two domains, the pyrophosphate-binding (PP) and the pyrimidine-binding (PYR) domain, which have a similar structure and are essential for binding and activating ThDP. Recently, we established the ThDP-dependent Enzymes Engineering Database (TEED) as a tool for a systematic comparison of ThDP-dependent enzymes. In cooperation with our research partners, this database will be used to create structure models, to model the binding of substrates, to interpret biochemical data, and to re-design selected enzymes for changed specificity, chemo-, regio- and stereoselectivity. Combining a comprehensive sequence and structure comparison analysis with molecular modeling of substrate recognition by the difterent enzymes will lead to a mechanistic understanding of how biochemical properties are encoded in the sequence and structure of ThDP-dependent enzymes.

虽然硫胺素二磷酸（ThDP）依赖性酶的反应机制已被研究多年，一个全面的模型，允许预测的催化活性，特异性和选择性的不同的酶还没有。它们高度多样的底物特异性和催化活性反映在ThDP依赖性酶的不同家族的序列和结构的高度多样性中。在进化过程中，结构域的穿梭、重排和融合、突变和基因复制导致了ThDP依赖性酶的巨大多样性。然而，所有ThDP依赖性酶都含有至少两个结构域，焦磷酸结合（PP）和嘧啶结合（PYR）结构域，它们具有相似的结构，并且对于结合和激活ThDP是必需的。最近，我们建立了ThDP依赖性酶工程数据库（TEED）作为系统比较ThDP依赖性酶的工具。与我们的研究伙伴合作，该数据库将用于创建结构模型，模拟底物的结合，解释生化数据，并重新设计选定的酶，以改变特异性，化学，区域和立体选择性。将全面的序列和结构比较分析与不同酶的底物识别的分子建模相结合，将导致对ThDP依赖性酶的序列和结构中如何编码生化特性的机械理解。