Raman Studies of Mammalian Cytochromes P450

描述(由申请人提供)： 该研究计划的总体长期目标是在分子水平上深入了解各种血红素蛋白所显示的令人印象深刻的功能多样性。这些物质在人体生理学和一般生物学过程中至关重要。在促进许多重要的生化过程，包括氧储存和运输，电子转移，消除活性过氧化物，激素的合成和清除积累的环境毒素的过程中，血红素位点固有的多样性的化学反应受到与相关多肽的分子内相互作用的有效调节，并进一步受到与其他蛋白质或小调节分子的分子间相互作用的控制。为了充分理解结构与功能的相关关系，不仅要获得反应中稳定的终态的结构信息，而且要获得短暂的反应中间体的结构信息。这项研究计划使用强大的共振拉曼技术和时间分辨共振拉曼技术应用于天然和战略性操作的血红素蛋白，以揭示调节血红素基团反应性的分子基础。在这里提出的研究中要研究的具体系统是参与人体生理学的细胞色素P450酶的两个重要亚类。一类是类固醇生成P450，催化关键内源性物质的化学转化，形成必需的类固醇激素。另一个亚类代谢包括药物和环境污染物在内的外源物质，为消除它们做好准备。 公共卫生相关性： 血红素蛋白是对许多生化过程的正常运作至关重要的分子，这些生化过程对人类生理和其他形式的生命至关重要。血红素蛋白研究人员面临的主要任务是能够洞察发生关键化学反应的蛋白质活性部位的结构，这种洞察有望在设计某些疾病的治疗方法时非常有用。这项工作中使用的共振拉曼技术是获取这一关键信息的最有力的方法之一。

DESCRIPTION (provided by applicant): The general long term goals of the research program are to gain a molecular level insight into the impressive range of functional diversity displayed by various heme proteins. These substances are of critical importance in human physiology and general biology processes. In facilitating many crucial biochemical processes, including oxygen storage and transport, electron transfer, elimination of reactive peroxides, synthesis of hormones and elimination of accumulated environmental toxins, the inherently diverse chemical reactivity of the heme sites are effectively regulated by intramolecular interactions with the associated polypeptides and controlled further by intermolecular interactions with other proteins or small regulatory molecules. In order to fully understand the pertinent relationship of structure to function, it is important to acquire structural information for not only the stable terminal states in a reaction, but also for the fleeting reaction intermediates. This research program uses powerful resonance Raman and time-resolved resonance Raman techniques applied to native and strategically manipulated heme proteins to reveal the molecular basis for modulation of heme group reactivity. The specific systems to be studied in the research being proposed here are two important sub-classes of cytochrome P450 enzymes involved in human physiology. One class, the steroidogenic P450s catalyze the chemical conversions of critical endogenous substances to form essential steroid hormones. The other subclass metabolizes exogenous substances including pharmaceuticals and environmental pollutants, preparing them for elimination. PUBLIC HEALTH RELEVANCE: Heme proteins are molecules that are of prime importance for proper functioning of many biochemical processes important to human physiology and other forms of life. The main task facing heme protein researchers is to be able to gain insight into the structure of the protein active site, where the key chemical reactions occur, such insight being expected to be very useful in designing treatments for some diseases. The resonance Raman technique being used in this work is one of the most powerful methods to acquire this critical information.