5279-78-7Relevant articles and documents
Controllable stereoinversion in DNA-catalyzed olefin cyclopropanationviacofactor modification
Cheng, Yu,Hao, Jingya,Jia, Guoqing,Li, Can,Lu, Shengmei,Miao, Wenhui
, p. 7918 - 7923 (2021/06/16)
The assembly of DNA with metal-complex cofactors can form promising biocatalysts for asymmetric reactions, although catalytic performance is typically limited by low enantioselectivities and stereo-control remains a challenge. Here, we engineer G-quadruplex-based DNA biocatalysts for an asymmetric cyclopropanation reaction, achieving enantiomeric excess (eetrans) values of up to +91% with controllable stereoinversion, where the enantioselectivity switches to ?72% eetransthrough modification of the Fe-porphyrin cofactor. Complementary circular dichroism, nuclear magnetic resonance, and fluorescence titration experiments show that the porphyrin ligand of the cofactor participates in the regulation of the catalytic enantioselectivityviaa synergetic effect with DNA residues at the active site. These findings underline the important role of cofactor modification in DNA catalysis and thus pave the way for the rational engineering of DNA-based biocatalysts.
A de novo peroxidase is also a promiscuous yet stereoselective carbene transferase
Stenner, Richard,Steventon, Jack W.,Seddon, Annela,Anderson, J.L. Ross
, p. 1419 - 1428 (2020/01/28)
By constructing an in vivo-assembled, catalytically proficient peroxidase, C45, we have recently demonstrated the catalytic potential of simple, de novo-designed heme proteins. Here, we show that C45's enzymatic activity extends to the efficient and stereoselective intermolecular transfer of carbenes to olefins, heterocycles, aldehydes, and amines. Not only is this a report of carbene transferase activity in a completely de novo protein, but also of enzyme-catalyzed ring expansion of aromatic heterocycles via carbene transfer by any enzyme.
Origin of High Stereocontrol in Olefin Cyclopropanation Catalyzed by an Engineered Carbene Transferase
Tinoco, Antonio,Wei, Yang,Bacik, John-Paul,Carminati, Daniela M.,Moore, Eric J.,Ando, Nozomi,Zhang, Yong,Fasan, Rudi
, p. 1514 - 1524 (2019/02/03)
Recent advances in metalloprotein engineering have led to the development of a myoglobin-based catalyst, Mb(H64V,V68A), capable of promoting the cyclopropanation of vinylarenes with high efficiency and high diastereo- and enantioselectivity. Whereas many enzymes evolved in nature often exhibit catalytic proficiency and exquisite stereoselectivity, how these features are achieved for a non-natural reaction has remained unclear. In this work, the structural determinants responsible for chiral induction and high stereocontrol in Mb(H64V,V68A)-catalyzed cyclopropanation were investigated via a combination of crystallographic, computational (DFT), and structure-activity analyses. Our results show the importance of steric complementarity and noncovalent interactions involving first-sphere active site residues, heme-carbene, and the olefin substrate in dictating the stereochemical outcome of the cyclopropanation reaction. High stereocontrol is achieved through two major mechanisms: first, by enforcing a specific conformation of the heme-bound carbene within the active site, and second, by controlling the geometry of attack of the olefin on the carbene via steric occlusion, attractive van der Waals forces, and protein-mediated π-π interactions with the olefin substrate. These insights could be leveraged to expand the substrate scope of the myoglobin-based cyclopropanation catalyst toward nonactivated olefins and to increase its cyclopropanation activity in the presence of a bulky α-diazo-ester. This work sheds light on the origin of enzyme-catalyzed enantioselective cyclopropanation, furnishing a mechanistic framework for both understanding the reactivity of current systems and guiding the future development of biological catalysts for this class of synthetically important, abiotic transformations.
