MECHANISMS AND INACTIVATION OF HEMOPROTEINS

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 这是一个一般性的调查机制的催化血红素蛋白和血红素蛋白的结构和活性之间的关系。本研究包括但不限于细胞色素P450、辣根过氧化物酶、乳过氧化物酶、肌红蛋白、髓过氧化物酶、DUOX酶和血红素加氧酶的研究。研究这些蛋白质的一个关键因素是分析产物结构、立体化学和同位素取代。蛋白质加合物的研究也很重要。除产品研究外，还大量使用基于机制的抑制剂和其他不可逆抑制剂来表征蛋白质活性位点。这些不可逆抑制剂使血红素基团或蛋白质烷基化。质谱法是必不可少的血红素加合物的结构的鉴定，并因此使用基于机制的抑制剂作为结构探针。通过与蛋白质骨架反应的试剂修饰的蛋白质残基的鉴定也被追求作为用于分析活性位点结构和机制的附加工具。这些调查，在过去，预计将作出重大贡献，我们的理解血红素蛋白的机制，潜在有用的血红素蛋白抑制剂的发展和我们的一般理解蛋白质的结构和功能。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. This is a general investigation of the mechanisms of catalytic hemoproteins and of the relationships between hemoprotein structure and activity. This investigation includes, but is not limited to, studies of the cytochromes P450, horseradish peroxidase, lactoperoxidase, myoglobin, myeloperoxidase, DUOX enzymes, and heme oxygenases. A key element in the study of these proteins is the analysis of product structure, stereochemistry and isotopic substitution. The investigation of protein adducts is also important. In addition to product studies, heavy use is made of mechanism-based and other irreversible inhibitors to characterize the protein active sites. These irreversible inhibitors alkylate either the heme group or the protein. Mass spectrometry is essential for identification of the structures of the heme adducts, and consequently for the use of mechanism-based inhibitors as structural probes. The identification of protein residues that are modified by agents that react with the protein skeleton is also pursued as an additional tool for analysis of the active site structure and mechanism. These investigations, as in the past, are expected to make substantial contributions to our understanding of hemoprotein mechanisms, to the development of potentially useful hemoprotein inhibitors and to our general understanding of protein structure and function.