MECHANISMS AND INACTIVATION OF HEMOPROTEINS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者的研究机构。 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、血红素加氧酶和氧传感器的研究。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。这些研究还包括分析血红素蛋白中发生的自催化分子内修饰。这些调查预计将作出实质性贡献，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. 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. 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, heme oxygenases, and oxygen sensors. 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. The studies also include analysis of the autocatalytic intramolecular modifications that occur in hemoproteins. These investigations 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.