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: 10445980
• 负责人: Alexey Silakov
• 金额: $ 35.45万
• 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/10445980
• 关键词: Address; Anions; Architecture; Azides; Biomedical Engineering; C-terminal; Carbon; Cell Nucleus; Chemicals; Complex; Coupling; Crystallization; Cyclization; Data; Drug Industry; Electrons; Enzymes; Family; Frequencies; Geometry; Glutarates; Halogens; Histidine; Hydrogen Bonding; Hydroxylation; Implant; Individual; Iron; Isomerism; Isotopes; Kinetics; Knowledge; Letters; Ligands; Location; Magnetism; Maps; Measures; Mediating; Membrane Proteins; Metals; Methodology; Methods; Mixed Function Oxygenases; Natural Product Drug; Natural Products; Outcome; Oxygen; Oxygenases; Pathway interactions; Pharmacologic Substance; Phenotype; Positioning Attribute; Process; Proteins; Reaction; Role; Site; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis; Structure; Synthesis Chemistry; System; Vanadyl; Variant; Work; X-Ray Crystallography; adduct; alpha ketoglutarate; analog; cofactor; dehydrogenation; drug synthesis; experimental study; ferryl iron; geometric structure; halogenation; innovation; insight; member; neurotensin mimic 2; nitroxyl; novel; novel therapeutics; orientation selectivity; oxidation; preference; synthetic drug; vibration

Project Summary/Abstract 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.

项目摘要/摘要 铁（II） - 和2-（OXO）谷氨酸酯依赖性（Fe/2og）氧酶催化羟基化，卤素化， 脂肪族碳中心的环化，脱氢和立体化，C – H键激活反应 这共同代表了合成化学的圣杯。重要自然的生物合成途径 产品药物被这些酶取代，制药行业开始利用 将Fe/2og氧酶的进化版本作为其合成药物的“绿色”过程的生物催化剂。最近的 宾夕法尼亚州立组的Fe/2og羟化酶，卤代酶和周期的研究表明，处置 底物相对于共同铁（IV）-Oxo（Ferryl）和铁（III） - 羟基/底物 - 激进 中间体对于控制反应结果至关重要。根据到目前为止可用的数据，我们 假设金属生产者而不是基板定位的结构重排是 指导调节器的主要因素。因此，在这项工作中，我们将执行光谱表征 忠实的反应状态类似物，以获得有关单个酶如何调整结构的第一手见解 活跃的复合物和直接在Fe/2og超家族中的共同模式 氧酶。在这个项目中，我们将创新并部署一套新颖的中级模仿和光谱镜 解决药物相关的关键中间状态的几何形状的问题/方法论 Fe/2og酶的子类。我们阐明辅助因子结构和相对处置 底层决定分歧的结果将为发现这个超家族的新颖成员而努力，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信息 用于药物合成的生物催化剂。