Multinuclear Dioxygen-Utilizing Copper Enzymes: Diverse Roles for Aromatic Redox Active Amino Acids

多核双氧利用铜酶：芳香族氧化还原活性氨基酸的多种作用

• 批准号: 10714992
• 负责人: Shabnam Hematian
• 金额: $ 34.31万
• 依托单位: UNIVERSITY OF NORTH CAROLINA GREENSBORO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10714992
• 关键词: Active Sites; Address; Adopted; Aerobic; Amino Acids; Aromatic Amino Acids; Biochemistry; Bioinorganic Chemistry; Cell Respiration; Coenzymes; Copper; Coupled; Couples; Dioxygen; Electrons; Enzymes; Iron; Life; Mediating; Metabolic; Metals; Molecular; Nature; Nuclear; Oxidants; Oxidation-Reduction; Oxygen; Peptides; Planet Earth; Play; Positioning Attribute; Process; Protons; Reaction; Role; Side; Site; Source; Tryptophan; Tyrosine; Water; cofactor; copper oxidase; cytochrome c oxidase; design; enzyme mechanism; fundamental research; metalloenzyme; oxidation

PROJECT SUMMARY Aerobic life on earth harnesses the oxidizing power of molecular oxygen (O2) through a diverse range of enzyme cofactors and employs that high oxidation potential to mediate numerous oxidative transformations during metabolic functions. Many of these cofactors are coupled binuclear sites consisting of two metal centers such as copper and iron in close proximity. This proposal details fundamental research in the field of bioinorganic chemistry and aims to address several intriguing questions about the potential roles of redox aromatic active amino acids such as tyrosine and tryptophane chains in the enzyme mechanism and function. We identified three different classes of O2-utilizing copper enzymes including cytochrome c oxidase (CcO) which reduces O2 to water, multicopper oxidase (MCO) which couples that reaction to four one-electron oxidations of the substrates, and a new class of copper enzymes called BURP domain cyclases which catalyze 2-electron oxidative macrocyclization of the Tyr/Trp chains in peptide substrates.The use of O2 as either a substrate or terminal electron acceptor has been established in these enzymes except for the BURP domain enzymes which is yet to be confirmed. In all three classes, appropriately tuned and positioned Tyr/Trp chains play different roles either as an integral part of the active site (i.e., CcO) or they may be assigned a mediatory role to provide an alternative path for oxidation of the more challenging substrates (i.e., MCO). They may even act as the direct substrate for the active site (i.e., Cu-dependent BURP domain cyclases). In all cases, despite the diverse use of these chains, their main function is to delicately supply the electron/proton needed for the O2 reduction. How are these residues designed/optimized for a particular function? What are the similarities and differences between these enzymes? Our studies aim to reveal the potential role of these Tyr/Trp chains play in enzymatic function and mechanism and address some of the questions about copper biochemistry and aerobic metabolism.

项目摘要 地球上有氧寿命利用分子氧（O2）的氧化能力通过多种范围 酶辅因子并采用高氧化潜力来介导许多氧化转化 在代谢功能期间。这些辅助因子中有许多是耦合的双核位点，由两个金属中心组成 例如铜和铁紧邻。该建议详细介绍了该领域的基础研究 生物无机化学，旨在解决有关氧化还原潜在作用的几个有趣的问题 酶机制和功能中的芳族活性氨基酸，例如酪氨酸和色氨酸链。 我们确定了包括细胞色素C氧化酶（CCO）的三种不同类别的O2利用铜酶 将O2降低到水，多型氧化酶（MCO），伴侣反应四个单电子 底物的氧化和一种新的称为Burp域循环酶的铜酶，它们催化 肽底物中Tyr/TRP链的2电子氧化大环化。 除了BURP结构域以外，在这些酶中已经建立了底物或末端电子受体 尚未确认的酶。 在所有三个班级中，适当调整和定位的Tyr/TRP链作为一个不同 活动站点的整体部分（即CCO），否则可以将其分配给替代角色 更具挑战性底物的氧化路径（即MCO）。他们甚至可以充当直接的基板 活性位点（即Cu依赖性的BURP域Cyclases）。在所有情况下，尽管有多样的使用 链条，其主要功能是优惠提供o2还原所需的电子/质子。这些怎么样 为特定功能设计/优化的残留物？这些之间有什么相似之处和差异 酶？我们的研究旨在揭示这些Tyr/TRP链在酶促功能和 机制并解决了有关铜生物化学和有氧代谢的一些问题。