Resonance Raman Studies of Mammalian Heme Proteins

该计划的长期研究目标是在分子水平上了解血红素蛋白的显著功能多样性，这些物质在生物系统中通常是至关重要的，特别是在人类生理学中。在参与和促进许多关键的生化过程，包括氧和电子传递，以及消除内部产生的和环境中积累的毒素的过程中，血红素位点的固有反应性受到与相关多肽的分子间相互作用的有效调节，并进一步受到与其他蛋白质和小调节分子的分子间相互作用的控制。除了更稳定的初始和最终状态外，人们对短暂但功能重要的瞬时或中间状态非常感兴趣。本研究计划的基本策略是将强大的光谱探针，特别是共振拉曼和时间分辨共振拉曼技术应用于天然和战略性操作的蛋白质，以揭示这种调节血红素基团反应性的分子基础。事实上，通常的情况是，这些特定的方法是对这些地点的唯一有效的探测。本提案中要讨论的具体系统是涉及哺乳动物生理学的三类重要的血红素蛋白；细胞色素P450，它将外源物质的转化编目，为消除它们做好准备；鸟苷环化酶，神经递质的最重要的受体分子，NO，它在人类生理中起着关键的调节作用；以及，最后，一组 被称为过氧化物酶的酶在人类抵御入侵微生物方面发挥着关键作用。

The long term research goals of this program are to attain a molecular level understanding of the remarkable functional diversity of heme proteins, substances that are of critical importance in biological systems, in general, and in human physiology in particular. In participating in and facilitating many critical biochemical processes, including oxygen and electron transport, as well as the elimination of internally generated and environmentally accumulated toxins, the inherent reactivity of the heme sites are effectively regulated by intermolecular interactions with the associated polypeptides and further controlled by intermolecular interactions with other proteins and small regulatory molecules. In addition to the more stable initial and final states, a great deal of interest is attached to the fleeting, but functionally important, transient or intermediate states.The essential strategy of this research program is to apply powerful spectroscopic probes, especially resonance Raman and time-resolved resonance Raman techniques, to the native and strategically manipulated proteins in order to reveal the molecular basis for this modulation of heme group reactivity. In fact, it is often the case that these particular methods are uniquely effective probes of these sites. The specific systems to be addressed in the present proposal are three important classes of heme proteins involved in mammalian physiology; cytochromes P450, which catalayze the conversion of xenobiotics, preparing them for elimination; guanylate cyclase, the most important receptor molecule for the neurotransmitter, NO, which serves a crucial regulatory function in human physiology; and, finally, a group of enzymes known as peroxidases that play a critical role in human defence against invading microorganisms.