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，通过非血红素 Fe(IV)-oxo 实现脂肪族卤化和氧环化 （铁基）配合物”） 铁(II)-和2-(氧代)戊二酸依赖性(Fe/2OG)加氧酶催化羟基化， 脂肪族碳中心的卤化、环化、脱氢和立体反转，C– 氢键激活反应共同代表了合成化学的圣杯。 重要天然产物药物的生物合成途径充满了这些酶，并且 制药行业开始利用 Fe/2OG 加氧酶的进化版本作为 用于合成药物“绿色”工艺的生物催化剂。 Fe/2OG的最新研究 宾夕法尼亚州立大学小组的羟化酶、卤化酶和环化酶表明， 相对于常见的铁(IV)-氧代（铁基）和铁(III)-羟基/底物自由基 中间体对于控制反应结果可能至关重要。根据现有数据，所以 到目前为止，我们假设金属辅因子的结构重排而不是 底物定位是指导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 深入了解单个酶如何调整活性复合物的结构并 揭示指导 Fe/2OG 加氧酶超家族反应的常见模式。在这个 项目中，我们将创新并部署一套新颖的中间模拟物和光谱 解决关键中间态几何结构的探针/方法 Fe/2OG 酶的药学相关亚类。我们对辅因子如何的阐明 基材的结构和相对配置决定了不同的结果将告知 努力发现这个超家族的新成员并分配他们的表型。最终， 该项目获得的信息将有助于开发新的药物生物催化剂 合成。