BACTERIAL CYTOCHROME BC1: STRUCTURE, FUNCTION, BIOGENESIS

细菌细胞色素 BC1：结构、功能、生物发生

• 批准号: 8118695
• 负责人: M. FEVZI DALDAL
• 金额: $ 2.49万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-12-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8118695
• 关键词: Address; Aerobic; Aging; Air; Amino Acids; Anabolism; Apoptosis; Architecture; Binding; Biochemical; Biogenesis; Biological; Biological Models; Catalysis; Cell physiology; Cells; Cessation of life; Characteristics; Communication; Complex; Cytochrome bc1 Complex; Cytochromes; Cytochromes b; Defect; Degenerative Disorder; Development; Diagnosis; Disease; Electron Transport Complex III; Enzymes; Event; Exhibits; Funding; Generations; Genetic; Goals; Grant; Health; Human; Hydroquinones; Inherited; Knowledge; Life; Ligand Binding; Ligands; Link; Lipids; Malignant Neoplasms; Maps; Membrane; Mitochondria; Mitochondrial Diseases; Modeling; Molecular; Molecular Genetics; Myopathy; Neuropathy; Organelles; Organism; Ornithine; Oxidoreductase; Oxygen; Pain; Pathway interactions; Physiologic Thermoregulation; Physiological; Plants; Process; Production; Prokaryotic Cells; Property; Protein Disulfide Isomerase; Proteins; Protons; Reaction; Reactive Oxygen Species; Regulation; Research; Rhodobacter; Role; Signal Transduction; Site; Source; Stimulus; Structure; System; Thermogenesis; Trust; Variant; Wakefulness; base; cytochrome c; dimer; disulfide bond; human disease; innovation; insight; interdisciplinary approach; microbial; monomer; mutant; nervous system disorder; neuromuscular; novel; oxidation; public health relevance; response; sleep regulation

DESCRIPTION (provided by applicant): A vital characteristic of living systems is their ability to produce biological energy (ATP) efficiently. ATP is essential for cellular functions including biosynthesis, transport, signal transduction, chemo- and photo- taxis and thermogenesis. Energy producing complexes are widespread among organisms, and their improper function leads to devastating health problems and human diseases as well as low crop yields in plants. The long-term goal of this project is to understand the structure, mechanism of function and biogenesis of cytochrome (cyt) components of energy transduction pathways. These are important enzymes whose absence, or malfunction are the causes of multiple human diseases, including many muscular and neurological disorders. For these studies, prokaryotes provide simpler model systems that are evolutionarily conserved and closely related to eukaryotic organelles. This project uses molecular genetics, biochemical and biophysical approaches, with a sharp focus on the structure and function of the cyt bc1 or Complex III. The specific aims of this proposal include 1- the molecular basis of oxygen tolerance of the quinol oxidation site of the cyt bc1 to address how this aerobic enzyme avoids the production of unwanted reactive oxygen species in the presence of oxygen, 2- exploration of the Zn binding residues of cyt b at the Qo site to probe their involvement in H+ conduction, and 3- development and characterization of heterodimer cyt bc1 variants to address intra- and inter-monomer structural and functional communications and regulations within the cyt bc1, to probe the links between the dimeric architecture and the mechanism of function of this enzyme. These studies are expected to greatly enhance our understanding and knowledge of energy transduction enzymes. Information gained using the simpler bacterial system could be generally applicable to the structurally more complex but functionally similar and evolutionarily related organelle-derived enzyme, and could provide invaluable information for elucidating the molecular bases and diagnoses of mitochondrial and other human diseases, including neuropathies, myopathies and aging. PUBLIC HEALTH RELEVANCE: This research aims to define the structure-function and biogenesis of energy transduction enzymes. These proteins are the major sources of reactive oxygen species that are extremely harmful for human cells, and their biogenesis components form the molecular bases of many common mitochondrial diseases in humans. Malfunction of these enzymes induce multiple human illnesses, extending from maternally inherited mitochondrial diseases to neuromuscular degenerative disorders, as well as cancer and aging.

描述（由申请人提供）： 生命系统的一个重要特征是它们能够有效地产生生物能量（ATP）。ATP对细胞的生物合成、运输、信号转导、趋化性、趋光性和产热等功能都是必不可少的.能量生产复合体在生物体中广泛存在，它们的功能不正常会导致毁灭性的健康问题和人类疾病，以及植物的低产量。本计画的长期目标是了解能量传递途径中细胞色素（cyt）组成部分的结构、功能机制和生物起源。这些都是重要的酶，其缺失或功能障碍是多种人类疾病的原因，包括许多肌肉和神经系统疾病。对于这些研究，原核生物提供了更简单的模型系统，这些系统在进化上是保守的，并且与真核细胞器密切相关。该项目使用分子遗传学，生物化学和生物物理学方法，重点关注cyt bc 1或复合物III的结构和功能。该提议的具体目的包括1-细胞色素bc 1的醌醇氧化位点的氧耐受性的分子基础，以解决这种需氧酶如何避免在氧存在下产生不需要的活性氧物质，2-探索在Qo位点的细胞色素B的Zn结合残基，以探测它们参与H+传导，和3-异二聚体CytBC 1变体的开发和表征，以解决CytBC 1内单体内和单体间的结构和功能通讯和调节，以探测二聚体结构和该酶的功能机制之间的联系。这些研究有望极大地提高我们对能量转导酶的理解和知识。使用更简单的细菌系统获得的信息可以普遍适用于结构更复杂但功能相似且进化相关的细胞器衍生酶，并且可以为阐明线粒体和其他人类疾病（包括神经病，肌病和衰老）的分子基础和诊断提供宝贵的信息。 公共卫生相关性： 本研究的目的是确定能量转换酶的结构-功能和生物起源。这些蛋白质是对人体细胞极其有害的活性氧的主要来源，它们的生物合成成分构成了人类许多常见线粒体疾病的分子基础。这些酶的功能障碍会诱发多种人类疾病，从母系遗传的线粒体疾病到神经肌肉退行性疾病，以及癌症和衰老。