RUI: Magnetic Circular Dichroism of Dicobalt(II) Enzymes and Complexes

该研究奖授予CHE学部无机、生物无机和金属有机化学项目以及分子和细胞生物科学部，支持Middlebury学院的James Larrabee教授使用磁性圆二色谱对金属水解酶进行基础研究。研究中的四种酶是蛋氨酸氨基肽酶、甘油磷酸二酯酶和磷酸三酯酶；这些酶都具有由羧酸盐和水(或氢氧化物)配体桥联的两个金属离子的共同活性中心结构基序。这些酶是以钴(II)的形式进行研究的。这种方法提供了一个特别强的磁性圆二色信号，用于监测当抑制剂与酶结合时金属环境的变化。这些变化被用来深入了解酶的机制，由于酶活性部位的结构相似，预计这些机制将是相似的。米德尔伯里学院的这项研究是由本科生研究助理作为合作者进行的。这种类型的研究经验鼓励本科生追求科学事业，并通过进入研究生院继续他们的科学教育。该研究奖共资助9名本科生研究助理。了解酶的功能通常对科学很重要；然而，更好地了解这四种酶对社会有潜在的好处。蛋氨酸氨基肽酶已被确定为抗血管生成药物的靶酶；因此，抑制剂是治疗实体瘤癌症、动脉硬化和类风湿性关节炎的候选药物。金属β-内酰胺酶降解β-内酰胺类抗生素，这一过程是细菌对β-内酰胺类药物产生耐药性的主要原因。这些酯酶能降解多种有机磷，在有机磷农药污染的生物修复和有机磷神经毒剂的解毒方面具有潜在的应用前景。

This research award in the Inorganic, Bioinorganic, and Organometallic Chemistry program of the CHE division and in the Molecular and Cellular Biosciences Division supports work by Professor James Larrabee at Middlebury College to carry out fundamental studies on metallohydrolase enzymes using magnetic circular dichroism spectroscopy. Four enzymes that are in the study are methionine aminopeptidase metallo beta-lactamase, glycerophosphodiesterase, and phosphotriesterase; these enzymes all share the common active site structural motif of two metal ions bridged by carboxylate and water (or hydroxide) ligands. These enzymes are studied in the cobalt(II) form. This approach provides an especially strong magnetic circular dichroism signal that is used to monitor changes in the metal environment as inhibitors are bound to the enzymes. These changes are used to gain insight into the enzyme mechanisms, which are expected to be similar because of the structural similarities of the enzyme active sites.This research study at Middlebury College is conducted by undergraduate research assistants as collaborators. This type of research experience encourages undergraduates to pursue careers in science and to further their science education by attending graduate school. This research award is supporting a total of nine undergraduate research assistants. Understanding how enzymes function is generally important to science; however, a better understanding of these four enzymes has potential benefit to society. Methionine aminopeptidase has been identified as the target enzyme of anti-angiogenesis drugs; therefore, inhibitors are drug candidates to treat solid tumor cancers, arterial sclerosis, and rheumatoid arthritis. Metallo beta-lactamase hydrolyzes beta-lactams, a process which is the major cause of bacterial resistance to beta-lactam therapy. The esterases hydrolyze a number of organophosphates and have potential in bioremediation of organophosphate pesticide contamination and detoxification of organophosphate nerve agents.