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从分子水平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。在促进许多关键的生物化学过程中，包括氧储存和运输、电子转移、消除反应性过氧化物、合成激素和消除积累的环境毒素，血红素位点的固有多样性化学反应性通过与相关多肽的分子内相互作用有效地调节，并通过与其他蛋白质或小调节分子的分子间相互作用进一步控制。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终态的结构信息，而且要获得短暂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和时间分辨共振拉曼技术应用于本地和战略操纵血红素蛋白，以揭示血红素基团的反应性调制的分子基础。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酶的两个重要子类。一类是类固醇生成P450，催化关键内源性物质的化学转化以形成必需的类固醇激素。另一个亚类代谢外源性物质，包括药物和环境污染物，为消除它们做好准备。 公共卫生相关性： 血红素蛋白是对人类生理学和其他生命形式重要的许多生化过程的正常运作至关重要的分子。血红素蛋白研究人员面临的主要任务是能够深入了解蛋白质活性位点的结构，在那里发生关键的化学反应，这种洞察力有望在设计治疗某些疾病方面非常有用。在这项工作中使用的共振拉曼技术是获得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.