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来实现惊人的化学转变的能力， 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。 金属蛋白和金属酶，大自然在化学转化方面取得了显着的多样性 并通过生成可进一步修改的离子来调整铁离子等金属离子的新生特性 氧化还原活性辅助因子，如铁硫簇和血红素辅助因子中结合的铁，以实现这种多样性， 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 在此之上，给我们带来了多样化的化学——其中大部分是酶学和生物无机领域 波士顿大学埃利奥特小组目前仍在探索两个 NIGMS 资助的研究领域。 (1) 查询庞大的“AdoMet Radical Enzyme (ARE) superfamily”的结构-功能关系， 数以万计的反应被认为是由数十万个不同的成员催化的 ARE，通过研究 ARE 超家族中发现的铁硫簇的氧化还原特性； (2) 测试关于含有血红素的酶的结构和化学多样性的假设 在革兰氏阴性微生物中发现的称为“细菌细胞色素c过氧化物酶（bCCP）超家族”。 通过这两个相关项目，构成了当前R35提案的背景， 通过组合检查金属蛋白的结构、功能和氧化还原化学 电化学、生物物理、生物信息学和结构方法 ARE 的机制细节。 超家族仍在不断涌现，我们在这里提出了许多新的铁硫簇态； 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 关于 bCCP 超家族的热力学和动力学， 我们最近证明，可以通过以下方法发现该超家族酶的新反应形式： 我们超越了过去 20 年所审查的典型家庭成员。 建议检查其他新的家庭成员，这些成员被建议从事与以下相关的硫转化 这些研究将我们对生物信息学和人类健康的兴趣结合在一起。 生物物理化学，探索自然界氧化还原酶的多样性，不仅揭示了其中的可能性 这些非凡催化剂的化学性质，但大自然如何通过正确的方法掌握所需的反应性 金属辅因子。