XAFS STUDIES OF BIOINORGANIC SYSTEMS

生物无机系统的 XAFS 研究

• 批准号: 7597959
• 负责人: PETER A LAY
• 金额: $ 0.02万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7597959
• 关键词: Adverse effects; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Binding; Biological Process; Cell Death; Complex; Computer Retrieval of Information on Scientific Projects Database; Drug Formulations; Electron Transport Complex III; Freezing; Funding; Gastric Juice; Grant; Growth; Heme; Hemeproteins; Hydrogen Peroxide; Institution; Investigation; Ions; Lead; Levodopa; Malignant Neoplasms; Melanins; Melanoma Cell; Metabolic Biotransformation; Metal Ion Binding; Metalloproteins; Metals; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Research; Research Personnel; Resources; Roentgen Rays; Role; Simulate; Solutions; Source; Structure; System; Thinking; Toxin; United States National Institutes of Health; base; cell killing; chromium hexavalent ion; diabetic; dietary supplements; lead ion; melanoma; prevent; small molecule

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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 硬 X 射线 XAS 研究将针对金属蛋白、金属药物、与金属诱发的癌症相关的基因毒性物质以及其他生物无机系统进行。将进行血红素蛋白研究，其中 Fe K 边缘研究将集中于小分子与血红素的结合，以了解影响这种结合是否用作生物功能开关或运输（或储存）小分子的因素。 K 边缘 Cr XAS 研究将用于确定与 Cr 诱发癌症相关的反应性 Cr(VI)、Cr(V) 和 Cr(IV) 物质的冷冻溶液的结构。许多这些物质的反应性太强而无法结晶，只能在溶液中瞬态产生。同样，Cr(III) 复合物被用作膳食补充剂和潜在的抗糖尿病药，但其活性物质的特征却很少。 XAFS 将用于表征生物分子中间体，这些生物分子被认为与此类膳食补充剂的生物转化相关。金属离子与黑色素的结合是黑色素瘤细胞阻止金属离子导致细胞死亡的重要途径，因为黑色素瘤细胞内含有较高浓度的H2O2，它与金属离子反应产生毒素，杀死细胞，从而阻止黑色素瘤的生长。因此，我们正在使用 K 边缘 XAFS 研究金属离子与黑色素的结合及其在左旋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铜、镍和锌抗炎药物的结构，以了解复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。