LAYING THE FOUNDATIONS FOR GENOMIC ENZYMOLOGY

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 机制上不同的酶超家族代表了不同的蛋白质组，其底物，产物甚至整体功能都可以有很大的不同。这种广泛变化的化学反应的发散进化可以通过酶进化的化学约束模型来描述，其中自然界通过保留基本的化学能力（例如部分反应）来重新设计用于各种功能的祖先支架，同时进化底物结合的变化，从而进化整体化学。该更新提案有四个目标，这些目标扩展了先前赠款所取得的进展： 第一章 研究额外的机制不同的酶超家族，以确定如何传递催化是由共同的催化模块在每个约束。我们还将详细介绍每一种新的催化剂是如何产生的，以执行各种功能。我们期望结果揭示在自然界中使用的酶设计的一般原则，并确定适用于每个超家族的功能推断和机械理解的具体规则。这些信息将通过我们的网站提供给科学界。结构-功能连锁数据库（SFLD）。 （二） 识别序列/结构差异，区分亚组/家庭的特点超家族，以实现更精确的功能推断比可以通过预测的超家族共同的功能单独获得。 第三章 调查利用复杂辅因子的超家族，以了解此类超家族与相对较多的超家族有何不同？简单？我们以前研究过的超家族类型。这些研究将首先关注使用FAD辅因子的超家族。 四、 为预测混杂和新的化学反应奠定基础，这些反应可以由本提案中研究的催化模块支持。对接方法将用于鉴定可能结合或可能被超家族成员翻转的小分子。研究结果将被添加到SFLD中，以帮助其他人推断功能，鉴定在结构表征或药物设计中有用的抑制剂，并指导蛋白质工程/设计应用于人类健康。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Mechanistically diverse enzyme superfamilies represent sets of divergent proteins whose substrates, products and even overall functions can be substantially different. Divergent evolution of such broadly varied chemical reactions can be described by the chemistry-constrained model of enzyme evolution, in which nature re-engineers the ancestral scaffold for a variety of functions by conserving a fundamental chemical capability such as a partial reaction, while evolving variations in substrate binding, and therefore overall chemistry. This renewal proposal has four aims, which extend the progress achieved in the previous grant: 1) Investigate additional mechanistically diverse enzyme superfamilies to determine how the delivery of catalysis is constrained by the common catalytic module in each. We will also detail for each how new catalysts have arisen to perform a variety of functions. We expect the results to reveal general principles of enzyme design utilized in nature and identify specific rules applicable for functional inference and mechanistic understanding for each of the superfamilies investigated. This information will be made available to the scientific community via our ?Structure-Function Linkage Database (SFLD)?. 2) Identify sequence/structural differences that discriminate subgroups/families in characterized superfamilies to achieve more precision in functional inference than can be obtained by prediction of the superfamily-common functions alone. 3) Investigate superfamilies that utilize complex co-factors to learn how such superfamilies differ from the relatively more ?simple? types of superfamilies we have previously studied. These studies will focus first on superfamilies that use FAD cofactors. 4) Lay the groundwork for predicting promiscuity and new chemical reactions that could be supported by the catalytic modules studied in this proposal. Docking methodologies will be used to identify small molecules likely to bind or that could be turned over by superfamily members. The results will be added to the SFLD to aid others in inference of function, identification of inhibitors useful in structural characterization or drug design, and to guide protein engineering/design for applications to human health.