Studies toward the development of monoamine oxidase B specific inhibitors

描述（由申请人提供）：单胺氧化酶A和B（MAO A和MAO B）是外线粒体结合黄素蛋白，负责生物胺神经递质以及膳食胺的氧化代谢，防止后者作为假神经递质。催化是通过胺氧化成相应的醛来完成的。这两种酶的底物特异性不同，然而MAO A和MAO B共有约72%的序列同一性。由于两种异构体的催化功能在性质上相似，因此底物空腔的结构是观察到的特异性的原因。作为一个高分辨率的晶体结构的测定的结果，已确定的门控残留物是唯一的MAOB揭示了潜在的机制B基板的选择。这一发现是特别感兴趣的，由于开发的选择性抑制剂的单胺氧化酶B作为一个目标的药物治疗，以预防神经退行性疾病。具体来说，西方世界最常见的两种神经退行性疾病是阿尔茨海默病和帕金森病。这些疾病的病理特征是皮层和海马（阿尔茨海默病）或黑质（帕金森病）中神经元的损失。已知神经元组织中MAO B水平的年龄相关性增加以及过氧化氢的催化产生（导致活性氧物质）有助于细胞凋亡和随后的神经变性。因此，本项目的目的是通过鉴定负责其底物特异性的氨基酸残基和设计靶向该酶作为神经保护剂的特异性抑制剂来探索MAO B的结构/功能关系。本项目的目标是：具体目标1。确定MAO B特有的Ile-199残基的作用;特异性目标2.阐明了纳摩尔抑制剂莫非吉林（MDL 72.974 A）抑制MAO B的机制。公共卫生相关性本项目的目标是通过鉴定负责底物特异性的氨基酸残基并设计靶向这些氨基酸残基的抑制剂作为治疗帕金森病和阿尔茨海默病的神经保护剂来探索酶单胺氧化酶B的结构/功能关系。

DESCRIPTION (provided by applicant): Monoamine oxidases A and B (MAO A and MAO B) are outer mitochondria bound flavoproteins responsible for the oxidative metabolism of biogenic amine neurotransmitters as well as dietary amines which prevent the latter from behaving as false neurotransmitters. Catalysis is accomplished through amine oxidation to the corresponding aldehyde. These two enzymes differ in their substrate specificities, however MAO A and MAO B share about 72% sequence identity. Because the catalytic function of the two isoforms are similar in nature, the structure of the substrate cavity is responsible for the observed specificity. As a result of the determination of a high resolution crystal structure of MAO B, a gating residue has been identified that is unique to MAO B revealing a potential mechanism for MAO B substrate selection. This finding is of particular interest due to the development of selective inhibitors for MAO B as a target for drug therapy for prevention of neurodegenerative disorders. Specifically, the two most common neurodegenerative disorders in the western world are Alzheimer's disease and Parkinson's disease. The pathological hallmarks of these diseases are the loss of neurons in either the cortex and hippocampus (Alzheimer's disease) or the substantia nigra (Parkinson's disease). It is known that the age-related increase in MAO B levels in neuronal tissue together with the catalytic production of hydrogen peroxide (leading to reactive oxygen species) contributes to cellular apoptosis and subsequent neurodegeneration. Therefore, the purpose of this project is to explore the structure/function relationships of MAO B by identifying amino acid residues responsible for its substrate specificity and designing specific inhibitors that target the enzyme as neuroprotecting agents. The project goal will be realized though: Specific Aim 1. the determination of the role of the lle-199 residue unique to MAO B; Specific Aim 2. the elucidation of the mechanism of inhibition of MAO B with a nanomolar inhibitor, mofegiline (MDL 72.974A). PUBLIC HEALTH RELEVANCE The goal of this project is to explore the structure/function relationship of the enzyme, monoamine oxidase B, by identifying amino acid residues responsible for substrate specificity and designing inhibitors that target these amino acid residues for their applications as neuroprotecting agents for the treatment of Parkinson's disease and Alzheimer's disease.