IMIDAZOLINE BINDING DOMAIN ON MAO-B

描述：(摘自摘要)各种咪唑啉和胍类化合物 衍生物在周围组织和组织中引起不同的细胞反应 在中枢神经系统中，通常很难归因于 受体信号系统。这种分子还表现出对 区别于的膜蛋白(咪唑啉结合部位) 已知激素的受体并识别内源性生物活性 模拟这些化合物的某些作用的物质(S)。这些 观察表明，这是一种以前未被描述过的细胞信号系统。 然而，咪唑啉结合位点的官能度仍未得到解决。 出人意料和特别重要的是，最近的数据表明，有两个 咪唑啉结合蛋白的成员与A和B相同 单胺氧化酶(MAO)的异构体，催化儿茶酚胺的酶 神经递质和外源生物物质。MAO上的咪唑啉结合域是 与识别机制的酶活性部位不同 抑制剂，如帕吉林和扑热息痛，在 所有的纸巾。咪唑啉结构域在MAO-B上的有限可及性 是本应用程序的重点。 具体目标：1.确定单胺氧化酶的结构域 与咪唑啉-胍类配体相互作用。2.确定是否有 MAO-B在酶表现出的组织中的结构差异 其咪唑啉结合域的不同可及性。3.确定 如果MAO B上咪唑啉结合部位的明显不可访问性 某些组织涉及与细胞特定辅助蛋白的相互作用 或者是一种内源性遮盖物质。 MAO是治疗某些情绪障碍的靶点， 帕金森氏病的早期阶段和酶活性可能有助于 其他神经退行性疾病的发病。证明了一些人 人类体内咪唑啉结合蛋白的类型确实是单胺氧化酶 异构体表明，MAO接受多个调控输入，可能是 在各种疾病状态的病因学和/或管理中具有重要意义。 从拟议的研究中产生的信息可能牵涉到一部小说 探讨这种酶的调节。

DESCRIPTION: (Taken from the Abstract) Various imidazoline and guanidinium derivatives elicit diverse cellular responses in both peripheral tissues and in the central nervous system that are often difficult to attribute to known receptor signalling systems. Such molecules also exhibit high affinity for membrane proteins (imidazoline binding sites) that are distinct from receptors for known hormones and recognize an endogenous bioactive substance(s) that mimics some of the effects of these compounds. These observations suggest a previously uncharacterized cell signalling system. However, the functionality of imidazoline binding sites remains unresolved. Unexpectedly and of particular significance, recent data indicate that two members of imidazoline binding proteins are identical to the A and B isoforms of monoamine oxidase (MAO), enzymes that catalyze catecholamine neurotransmitters and xenobiotics. The imidazoline binding domain on MAO is distinct from the enzyme active site that recognizes the mechanism based inhibitors such as pargyline and deprenyl and is not equally accessible in all tissues. The limited accessibility of the imidazoline domain on MAO-B is the focus of this application. Specific Aims: 1. Identify the structural domains of monoamine oxidase interacting with imidazoline-guanidinium ligands. 2. Determine if there are structural differences in MAO-B in tissues where the enzyme exhibits differential accessibility of its imidazoline binding domain. 3. Determine if the apparent inaccessibility of the imidazoline binding site on Mao B in certain tissues involves interaction with cell specific accessory proteins or an endogenous masking substance. MAO is a therapeutic target in the management of certain mood disorders, the early phases of Parkinson's Disease and enzyme activity may contribute to the onset of other neurodegenerative disorders. The demonstration that some types of imidazoline binding proteins in humans are indeed monoamine oxidase isoforms suggests that MAO receives multiple regulatory inputs that may be of significance in the etiology and/or management of various disease states. Information generated from the proposed studies may implicate a novel approach to the regulation of this enzyme.