XAFS STUDIES OF BIOINORGANIC SYSTEMS

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。将对金属蛋白、金属基药物、与金属诱发癌症相关的遗传毒性物种以及其他生物无机系统进行硬X射线XAS研究。将进行血红素蛋白质研究，其中Fe K边缘研究将集中在小分子与血红素的结合上，以了解影响这种结合是否用作生物功能中的开关或运输（或储存）小分子的因素。K-edge Cr XAS研究将用于确定与Cr诱导的癌症相关的反应性Cr（VI）、Cr（V）和Cr（IV）物质的冷冻溶液的结构。这些物质中的许多反应性太强而不能结晶，只能在溶液中作为瞬态产生。类似地，Cr（III）络合物被用作膳食补充剂和潜在的抗糖尿病药物，但活性物质的特征很差。XAFS将被用来表征被认为与这种膳食补充剂的生物转化相关的生物分子的中间体。金属离子与黑色素的结合是黑色素瘤细胞防止金属离子导致细胞死亡的重要方式，因为黑色素瘤细胞含有相对高的细胞内浓度的H2 O2，其与金属离子反应以产生将杀死细胞并因此防止黑色素瘤生长的毒素。因此，我们利用K-edge XAFS研究了金属离子与黑色素的结合及其在L-多巴形成黑色素中的作用。最后，我们正在研究药物制剂和人工胃液中Cu，Ni和Zn抗炎药物的结构，以了解络合物的结构如何影响其功效和副作用。通过了解它们在不同制剂中的稳定性和结构以及它们在模拟胃液中的生物转化，我们将优化药物制剂并更好地了解这些药物的药理学。

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. Hard X-ray XAS studies will be conducted on metalloproteins, metal-based drugs, genotoxic species of relevance to metal-induced cancers, and other bioinorganic systems. Heme protein studies will be conducted, in which Fe K-edge investigations will be focused on the binding of small molecules to the heme, in order to understand the factors that influence whether such binding is used as a switch in a biological function, or to transport (or store) the small molecule. K-edge Cr XAS studies will be used to determine the structures of frozen solutions of reactive Cr(VI), Cr(V) and Cr(IV) species of relevance to Cr-induced cancers. Many of these species are too reactive to be crystallized and can only be generated as transients in solution. Similarly, Cr(III) complexes are used as dietary supplements and potential anti-diabetics, but the active species are poorly characterized. XAFS will be used to characterize intermediates with biomolecules that are thought to be relevant to the biotransformations of such dietary supplements. The binding of metal ions to melanin is an important way in which melanoma cells prevent metal ions from leading to cell death, because melanoma cells contain relatively high intracellular concentration of H2O2 that reacts with metal ions to lead to toxins that would kill the cells and hence prevent the growth of melanomas. Hence are investigating the binding of metals ions to melanin and their roles in forming melanin from L-dopa using K-edge XAFS. Finally, we are investigating the structures of Cu, Ni and Zn anti-inflammatory drugs in pharmaceutical preparations and artificial gastric juices in order to understand how the structure of the complexes affects their efficacy and side-effects. By understanding their stabilities and structures in different formulations and their biotransformations in simulated gastric juices, we will optimize pharmaceutical formulations and gain a better understanding of the pharmacology of these drugs.