Redox Cofactor Diversity in Enzymatic Superfamilies

酶超家族中氧化还原辅因子的多样性

• 批准号: 10411899
• 负责人: SEAN J ELLIOTT
• 金额: $ 49.5万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10411899
• 关键词: Area; Biochemistry; Bioinformatics; Biophysics; Boston; Catalysis; Chemicals; Chemistry; Cytochrome c Peroxidase; Environment; Enzymatic Biochemistry; Enzyme Reactivation; Enzymes; Family member; Funding; Generations; Health; Heme; Heme Group; Human; Ions; Iron; Kinetics; Metalloproteins; Metals; National Institute of General Medical Sciences; Nature; Organism; Oxidation-Reduction; Process; Property; Proteins; Reaction; Research; S-Adenosylmethionine; Scaffolding Protein; Structure; Structure-Activity Relationship; Sulfur; Testing; Thermodynamics; Universities; Ursidae Family; base; biophysical chemistry; catalyst; cofactor; design; interest; lens; member; metalloenzyme; microbiome; microorganism; novel; pathogen; protein folding; trait

PROJECT ABSTRACT Nature has mastered the ability to use bioavailable metals to achieve spectacular transformations of chemistry, by combining them with diverse protein folds, and unique coordination environments. Through the assembly of metalloproteins and metalloenzymes, Nature has achieved remarkable diversity in chemical transformations and in tuning the nascent properties of metal ions such as iron, through generating yet-further-modifiable redox-active cofactors, like iron-sulfur clusters and iron bound in heme cofactors. To achieve that diversity, specific protein scaffolds and arrangements of iron-sulfur clusters, and/or heme groups have been elaborated upon extensively, giving us diverse chemistry — much of which, the fields of enzymology and bioinorganic are still discovering today. Two NIGMS funded research areas ongoing in the Elliott Group at Boston University are (1) Query the structure-function relationships of the vast, “AdoMet Radical Enzyme (ARE) superfamily”, where tens of thousands of reactions are thought to be catalyzed by hundres of thousands of distinct members of the ARE, through the study of the redox traits of the iron sulfur clusters found in the ARE superfamily; and (2) Test hypotheses about structural and chemical diversity found with heme containing enzymes of the so- called “bacterial cytochrome c peroxidase (bCCP) superfamily” found within gram negative micro-organisms. Through these two related projects, which form the background of the current R35 proposal, the diversity of structures, function and redox chemistries of metalloproteins are examined through a combination of electrochemical, biophysical, bioinformatic, and structural approaches. The mechanistic details of the ARE superfamily are still forthcoming, where many novel states of iron-sulfur clusters have been proposed; here we will bring our electrochemical lens to bear upon the nature of those states, in order to understand the thermodynamics and kinetics of their generation and inter-conversion. With respect to the bCCP superfamily, we have recently demonstrated that novel forms of reactivity of enzymes of this superfamily can be found by looking beyond the canonical family members that have been examined for the past 20 years. Here we propose to examine other new family members that are suggested to engage in sulfur-conversions relevant to the microbiome and to human health. Together, these studies marry our interests in bioinformatics and biophysical chemistry, to probe the diversity of nature's redox enzymes, revealing not only what is possible in the chemistry of these remarkable catalysts, but how nature masters the desired reactivity with the correct metallocofactor.

项目摘要 大自然已经掌握了利用生物可利用金属实现化学惊人转变的能力， 通过将它们与不同的蛋白质折叠和独特的协调环境相结合。使用新型 金属蛋白和金属酶，自然界在化学转化方面取得了显着的多样性 以及通过产生尚未进一步修饰的金属离子来调整金属离子（如铁）的新生性质， 氧化还原活性辅因子，如铁硫簇和铁结合在血红素辅因子。为了实现这种多样性， 已经详细阐述了特定的蛋白质支架和铁硫簇和/或血红素基团的排列 广泛地，给我们不同的化学-其中大部分，酶学和生物无机领域是 直到今天还在发现。两个NIGMS资助的研究领域正在波士顿大学埃利奥特集团 是（1）质疑庞大的“蛋氨酸自由基酶（ARE）超家族”的结构-功能关系， 成千上万的反应被认为是由成千上万的不同成员催化的 通过研究ARE超家族中铁硫簇的氧化还原特性， (2)测试假设的结构和化学多样性发现与血红素含有酶的so- 称为“细菌细胞色素c过氧化物酶（bCCP）超家族”，发现于革兰氏阴性微生物中。 通过这两个相关的项目，形成了目前R35提案的背景， 金属蛋白质的结构、功能和氧化还原化学通过以下方法的组合进行检查： 电化学、生物物理学、生物信息学和结构方法。ARE的机械细节 超家族仍然即将到来，其中已经提出了许多新的铁硫簇的状态;在这里，我们 将使我们的电化学透镜对这些状态的性质产生影响，以便理解 它们的生成和相互转化的热力学和动力学。关于bCCP超家族， 我们最近已经证明，通过以下方法可以发现该超家族酶的新的反应性形式： 超越了过去20年来一直在研究的典型家庭成员。这里我们 建议审查其他新的家庭成员，建议从事硫转化相关 微生物组和人类健康。总之，这些研究结合了我们对生物信息学的兴趣， 生物物理化学，探索自然界的氧化还原酶的多样性，不仅揭示了什么是可能的， 这些非凡的催化剂的化学性质，但自然如何掌握所需的反应性与正确的 金属辅因子