Redefining Renalase

重新定义肾酶

• 批准号: 1904277
• 负责人: Graham Moran
• 金额: $ 0.95万
• 依托单位: Loyola University of Chicago
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1904277&HistoricalAwards=false
• 关键词: Redefining; Renalase

Renalase was an enzyme of unknown biological function for almost a decade. While it was described as a new renal hormone secreted into blood by the kidney to consume adrenaline and thereby lower blood pressure and slow the heart rate, no convincing demonstration of this activity was ever made. Based on a recent discovery by the principal investigator, it appears that the true function has nothing to do with blood pressure. Renalase instead appears to be a salvage enzyme that prevents the loss of a molecule at the heart of metabolism in all living organisms. This molecule has a tendency to alter its structure in a way that makes it useless in metabolism. Renalase prevents the accumualtion of the inactive molecules, saving or salvaging them, by turning them back into the correct, active structure. This function for renalase involves unprecedented enzyme chemistry that is likely to be found to be pervasive, utilized by many if not all forms of life. The intent of this award is to establish a foundational understanding of this curious new chemical activity. As new enzyme chemistry, the investigation of renalase will be an excellent platform to teach graduate students about enzymology. Moreover, the principal investigator will integrate the discovery of new examples of this activity into an Introductory Biochemistry Laboratory class such that undergraduates can participate directly in the advancement of this research by making genuine scientific discoveries in the laboratory classroom.This award from the National Science Foundation, Division of Chemistry, Chemistry of Life Processes Program is funding Dr. Graham R. Moran from the University of Wisconsin-Milwaukee to characterize a newly discovered enzyme, renalase that would appear to be important for efficient metabolic activity in living organisms. The award will fund a range of research activities that will define the chemical mechanism of renalase, the structural basis for the activity, and the metabolic importance of this activity. The methods employed will use a combination of rapid-mixing pre-steady state spectrophotometric kinetic techniques, structural elucidation of substrate analog and product enzyme complexes, numerous biophysical approaches that take advantage of the spectrophotometric reporting power of the enzyme's cofactor and site directed mutagenesis of conserved active site amino acids. In addition, Dr. Moran intends to develop an undergradaute laboratory course in which students discover new examples of this chemistry in a broad range of organisms such that the course will provide new avenues of investigation by which the full importance of and context for this activity can be established.

近十年来，肾氨酸酶一直是一种生物功能未知的酶。虽然它被描述为一种新的肾脏激素，由肾脏分泌到血液中来消耗肾上腺素，从而降低血压和减慢心率，但从未有令人信服的证据证明这一活动。根据首席研究人员最近的一项发现，似乎真正的功能与血压无关。相反，肾氨酸酶似乎是一种抢救酶，可以防止所有活着的有机体中新陈代谢核心的分子丢失。这种分子有一种改变其结构的趋势，使其在新陈代谢中毫无用处。肾氨酸酶通过将非活性分子重新转变为正确的活性结构，防止非活性分子的积累，从而挽救或挽救它们。肾氨酸酶的这种功能涉及前所未有的酶化学，很可能被发现是普遍存在的，被许多形式的生命利用，如果不是所有的形式。这一奖项的目的是建立对这种奇怪的新化学活动的基础性理解。作为一门新兴的酶化学，肾酶的研究将为研究生提供一个很好的教学平台。此外，首席研究人员将把发现的这种活动的新例子整合到生物化学实验室的入门课程中，这样本科生就可以通过在实验室课堂上做出真正的科学发现，直接参与到这项研究的推进中。这项来自国家科学基金会生命过程化学部门的奖项是由威斯康星大学密尔沃基分校的格雷厄姆·R·莫兰博士资助的，以表征一种新发现的酶，肾氨酸酶，它似乎对活体中有效的新陈代谢活动非常重要。该奖项将资助一系列研究活动，这些活动将确定肾氨酸酶的化学机制、活动的结构基础以及该活动的代谢重要性。所采用的方法将结合使用快速混合预稳态分光光度动力学技术、底物类似物和产物酶复合体的结构确定、利用酶辅因子的分光光度报告能力的多种生物物理方法以及保守活性部位氨基酸的定点突变。此外，莫兰博士打算开发一门本科生实验室课程，让学生在广泛的生物体中发现这种化学的新例子，这样这门课程将提供新的调查途径，通过这种途径可以充分确定这一活动的重要性和背景。