The role of geometric structure in avoidance of oxygen rebound to enable aliphatic halogenation and oxacyclization by non-heme Fe(IV)-oxo (ferryl) complexes

几何结构在避免氧反弹以实现非血红素 Fe(IV)-氧代（铁基）络合物的脂肪族卤化和氧环化中的作用

• 批准号: 10798457
• 负责人: Alexey Silakov
• 金额: $ 4.7万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-10 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10798457
• 关键词: Award; Binding; Biomedical Engineering; Carbon; Chemicals; Complex; Cyclization; Data; Drug Industry; Enzymes; Geometry; Glutarates; Hydrogen Bonding; Hydroxylation; Individual; Iron; Knowledge; Medicine; Methodology; Mixed Function Oxygenases; Natural Product Drug; Natural Products; Outcome; Oxygen; Oxygenases; Parents; Pathway interactions; Phenotype; Positioning Attribute; Process; Reaction; Role; Structure; Synthesis Chemistry; Work; alpha ketoglutarate; analog; cofactor; dehydrogenation; drug synthesis; ferryl iron; geometric structure; halogenation; innovation; insight; member; novel; novel therapeutics; structural determinants; synthetic drug

Abstract of Parent Award: (R01 GM141284 “The role of geometric structure in avoidance of oxygen rebound to enable aliphatic halogenation and oxacyclization by non-heme Fe(IV)-oxo (ferryl) complexes”) Iron(II)- and 2-(oxo)glutarate-dependent (Fe/2OG) oxygenases catalyze hydroxylation, halogenation, cyclization, dehydrogenation, and stereoinversion of aliphatic carbon centers, C– H-bond-activation reactions that collectively represent a holy grail of synthetic chemistry. Biosynthetic pathways to important natural-product drugs are replete with these enzymes, and the pharmaceutical industry is beginning to leverage evolved versions of Fe/2OG oxygenases as biocatalysts for "green" processes to their synthetic drugs. Recent studies of Fe/2OG hydroxylases, halogenases and cyclases by the Penn State group show that the disposition of the substrate relative to the common iron(IV)-oxo (ferryl) and iron(III)-hydroxo/substrate-radical intermediates may be crucial for control of reaction outcome. On the basis of data available so far, we hypothesize that the structural rearrangement of the metallocofactor rather than the substrate positioning is the primary factor directing regioselectivity. Therefore, in this work, we will perform spectroscopic characterization of faithful reactive-state analogs to gain first-hand insight as to how the individual enzymes adjust the structure of the active complex and to uncover common modes that direct reactivities in the superfamily of Fe/2OG oxygenases. In this project, we will innovate and deploy a suite of novel intermediate mimics and spectroscopic probes/methodologies to resolve the geometries of the key intermediate states in the pharmaceutically relevant subclasses of Fe/2OG enzymes. Our elucidation of how the cofactor structures and relative dispositions of the substrates dictate the divergent outcomes will inform efforts to discover novel members of this superfamily and assign their phenotypes. Ultimately, information obtained in this project will be instrumental in developing new biocatalysts for drug synthesis.

家长奖摘要：(R01 GM141284《几何结构在避免 氧反弹使非血红素Fe(IV)-oxo能够进行脂肪族卤化和氧环化 (铁基)配合物“) 依赖铁(II)和2-(氧)戊二酸(Fe/2OG)的加氧酶催化羟化， 脂肪族碳中心的卤化、环化、脱氢和立体转化，C- 氢键活化反应，共同代表着合成化学的圣杯。 重要的天然产物药物的生物合成途径充满了这些酶，并且 制药业开始利用进化版本的Fe/20G加氧酶作为 用于“绿色”过程的生物催化剂，用于他们的合成药物。Fe/2OG的研究近况 宾夕法尼亚州立大学小组的羟基酶、卤代酶和环化酶表明， 底物相对于常见的铁(IV)-氧代(铁基)和铁(III)-羟基/底物-自由基 中间体可能是控制反应结果的关键。根据可获得的数据 到目前为止，我们假设是金属辅因子的结构重排，而不是 底物定位是决定区域选择性的主要因素。因此，在这项工作中，我们 将对忠实的反应态类似物进行光谱表征，以获得第一手资料 洞察单个酶如何调整活性复合体的结构并 揭示在Fe/2OG加氧酶超家族中指导反应的常见模式。在这 项目，我们将创新和部署一套新的中间体模拟和光谱 探索/方法来解决关键中间状态的几何问题 与药物相关的Fe/2OG酶亚类。我们对辅因子如何 底物的结构和相对配置决定了不同的结果将 努力发现这个超家族的新成员并指定他们的表型。最终， 该项目所获得的信息将有助于开发新的药物生物催化剂。 综合。