Studies toward the development of monoamine oxidase B specific inhibitors

描述(申请人提供)：单胺氧化酶A和B(MAO A和MAO B)是与线粒体结合的黄素蛋白，负责生物胺神经递质和膳食胺的氧化代谢，防止后者充当虚假的神经递质。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，但MAO A和MAO B的序列同源性约为72%。由于两种异构体的催化功能在性质上相似，底物空腔的结构导致了观察到的特异性。通过对MAO B高分辨晶体结构的测定，确定了MAO B所特有的门控残基，揭示了MAO B底物选择的潜在机制。这一发现特别令人感兴趣，因为MAO B选择性抑制剂的开发是预防神经退行性疾病的药物治疗的靶点。具体地说，西方世界最常见的两种神经退行性疾病是阿尔茨海默氏症和帕金森氏症。这些疾病的病理特征是皮层和海马区(阿尔茨海默病)或黑质(帕金森氏病)神经元丢失。众所周知，随着年龄的增长，神经元组织中MAO B水平的增加，以及过氧化氢的催化产生(导致活性氧物种)，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确定与MAO B底物专一性有关的氨基酸残基，并设计针对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。项目目标将通过：具体目标1.确定MAO B特有的LLE-199残基的作用；具体目标2.阐明纳米分子抑制剂莫非吉兰(MDL 72.974A)抑制MAO B的机制。公共卫生相关性本项目的目标是通过识别负责底物特异性的氨基酸残基，并设计针对这些氨基酸残基的抑制剂，将其用作治疗帕金森氏病和阿尔茨海默病的神经保护剂，从而探索单胺氧化酶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.