Serotonin N Acetyltransferase Mechanism and Inhibition

描述(摘自申请人的摘要)： 此应用程序是对应用程序请求(RFP)的响应 “与空间环境有关的地面研究”(PA-00-088)。它 涉及酶5-羟色胺N-乙酰转移酶，负责日常 褪黑素的有节奏的产生。褪黑素是一种动物和人类的激素 被认为与昼夜节律的调节有关，生殖 生理和情绪。褪黑素的峰值水平似乎随着剂量的增加而下降 年龄。在松果体中产生的褪黑素水平在一年内变化高达100倍 24小时一天，主要是对外部光线、姿势和 磁场，而这种反应是由5-羟色胺介导的 N-乙酰转移酶。尽管5-羟色胺N-乙酰转移酶很重要， 目前对其酶的作用机制还知之甚少。没有具体说明 体内活性的5-羟色胺N-乙酰转移酶抑制剂 据报道。这个应用程序的主要目标是开发特定和强大的 5-羟色胺N-乙酰转移酶抑制剂。使用底物类似物， 诱变、X射线结晶学和动力学研究，对 将得到催化机理的过渡态，它将是 应用于选择性酶抑制剂的设计。设计与合成 将在一定程度上基于机理研究以及 官能团取代的系统分析。有效的抑制剂将 在体外进行分析，以确定其特异性和作用机制 有希望的化合物将在体内细胞培养试验中进行测试。特定的 5-羟色胺N-乙酰转移酶的抑制剂将有助于阐明 地面和太空中人体昼夜节律生物学中的褪黑素 旅行，并将作为治疗各种疾病的潜在有用的药物 可能影响平民和宇航员的临床条件，包括 睡眠和精神障碍。此外，这样的抑制剂可能会对 以了解其生理和病理生理学效应 通过在动物模型中模拟褪黑素的变化来改变老年人的褪黑激素 随着年龄的增长而产生的褪黑素。

DESCRIPTION(From applicant's abstract): This application is a response to the request for application (RFP) 'Earth-based Research Relevant to the Space Environment' (PA-00-088). It concerns the enzyme serotonin N-acetyltransferase, responsible for the daily rhythmic production of melatonin. Melatonin is an animal and human hormone thought to be involved in the regulation of circadian rhythm, reproductive physiology, and mood. Peak melatonin levels appear to fall off with increasing age. Produced in the pineal gland, melatonin levels vary up to 100-fold over a 24 h day, primarily in response to external light, posture, and changes in magnetic fields, and this response is mediated by serotonin N-acetyltransferase. Despite the importance of serotonin N-acetyltransferase, there is currently a poor understanding of its enzyme mechanism. No specific inhibitors of serotonin N-acetyltransferase that are active in vivo have been reported. The main goals of this application are to develop specific and potent inhibitors of serotonin N-acetyltransferase. Employing substrate analogs, mutagenesis, X-ray crystallography, and kinetic studies, insights into the transition state of the catalytic mechanism will be obtained which will be applied to the design of selective enzyme inhibitors. The design and synthesis of inhibitors will be in part based on mechanistic studies as well as a systematic analysis of functional group substitutions. Potent inhibitors will be analyzed in vitro to define their specificity and mechanism of action and promising compounds will be tested in vivo cell culture assays. Specific inhibitors of serotonin N-acetyltransferase will help clarify the role of melatonin in circadian rhythm biology in humans on the ground and during space travel and will be potentially useful as therapeutic agents for a variety of clinical conditions that can affect civilians as well as astronauts, including sleep and psychiatric disorders. Furthermore, such inhibitors could contribute to an understanding of the physiologic and pathophysiologic effects of melatonin changes in the elderly by mimicking in animal models the alterations in melatonin production that occur with aging.