Abiological catalysis by artificial haem proteins containing noble metals in place of iron

化学 卟啉 催化作用 组合化学 反应性(心理学) 基质(水族馆) 金属蛋白 活动站点 金属 立体化学 有机化学 医学 海洋学 地质学 病理 替代医学
作者
Hanna M. Key,Paweł Dydio,Douglas S. Clark,John F. Hartwig
出处
期刊:Nature [Nature Portfolio]
卷期号:534 (7608): 534-537 被引量:404
标识
DOI:10.1038/nature17968
摘要

Replacing the iron atom in Fe-porphyrin IX proteins with a noble-metal atom enables the creation of enzymes that catalyse reactions not catalysed by native Fe-enzymes or other metalloenzymes; this approach could be used to generate other artificial enzymes that could catalyse a wide range of abiological transformations. Naturally occurring metalloenzymes are promising alternatives to transition-metal catalysts and non-metal enzymes for the synthesis of chemicals and biologically active compounds, but they catalyse only a narrow range of reactions. One way of broadening that range is to replace the native catalytic metal with an abiological metal. John Hartwig and colleagues report the effect of substituting the iron atom in Fe-porphyrin IX (Fe-PIX) proteins. Myoglobin variants containing an Ir(Me) site catalyse the functionalization of C–H bonds to form C–C bonds and add carbenes to β-substituted vinylarenes and unactivated aliphatic α-olefins. Directed evolution of the Ir(Me)-myoglobin generates mutants that form either enantiomer of the products of C–H insertion and catalyse the enantio- and diastereoselective cyclopropanation of unactivated olefins. The rich chemistry of free metalloporphyrins and the ease of preparation and evolution of substituted haem proteins using the methods adopted here open the way to the creation of many artificial metalloenzymes. Enzymes that contain metal ions—that is, metalloenzymes—possess the reactivity of a transition metal centre and the potential of molecular evolution to modulate the reactivity and substrate-selectivity of the system1. By exploiting substrate promiscuity and protein engineering, the scope of reactions catalysed by native metalloenzymes has been expanded recently to include abiological transformations2,3. However, this strategy is limited by the inherent reactivity of metal centres in native metalloenzymes. To overcome this limitation, artificial metalloproteins have been created by incorporating complete, noble-metal complexes within proteins lacking native metal sites1,4,5. The interactions of the substrate with the protein in these systems are, however, distinct from those with the native protein because the metal complex occupies the substrate binding site. At the intersection of these approaches lies a third strategy, in which the native metal of a metalloenzyme is replaced with an abiological metal with reactivity different from that of the metal in a native protein6,7,8. This strategy could create artificial enzymes for abiological catalysis within the natural substrate binding site of an enzyme that can be subjected to directed evolution. Here we report the formal replacement of iron in Fe-porphyrin IX (Fe-PIX) proteins with abiological, noble metals to create enzymes that catalyse reactions not catalysed by native Fe-enzymes or other metalloenzymes9,10. In particular, we prepared modified myoglobins containing an Ir(Me) site that catalyse the functionalization of C–H bonds to form C–C bonds by carbene insertion and add carbenes to both β-substituted vinylarenes and unactivated aliphatic α-olefins. We conducted directed evolution of the Ir(Me)-myoglobin and generated mutants that form either enantiomer of the products of C–H insertion and catalyse the enantio- and diastereoselective cyclopropanation of unactivated olefins. The presented method of preparing artificial haem proteins containing abiological metal porphyrins sets the stage for the generation of artificial enzymes from innumerable combinations of PIX-protein scaffolds and unnatural metal cofactors to catalyse a wide range of abiological transformations.
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