Metal Coordination Dynamics Governs Selective Halogenation in α‐KG/Fe‐Dependent Halogenase SyrB2
Abstract
ABSTRACT α‐Ketoglutarate (α‐KG)‐dependent nonheme iron enzymes catalyze a diverse array of oxidative transformations essential for natural product biosynthesis. However, the mechanism by which α‐KG/Fe‐dependent halogenases achieve selective halogenation while circumventing the thermodynamically favored hydroxylation pathway remains a subject of intense debate. In this study, we elucidate the halogenation mechanism in SyrB2 through extensive computational and crystallographic investigations. Our work reveals that metal coordination dynamics plays a pivotal role in controlling selective C─H bond activation and chlorination in SyrB2. The transformation of the Fe(IV)‐oxo species from an equatorial to an axial conformation enables hydrogen atom transfer from the substrate C─H bond. Subsequent re‐isomerization of the Fe(III)‐OH intermediate to the equatorial conformation is critical for promoting selective chlorination while minimizing competitive hydroxylation. The proposed mechanism is supported by multiple experimental observations, including Mössbauer spectroscopy, nuclear resonance vibrational spectroscopy (NRVS), 2 H‐HYSCORE spectroscopy, and kinetic analysis of reactions with various substrates.
Article Details
Authors (13)
Wenli Yuan
Beijing National Laboratory for Molecular Sciences, CAS Laboratory of Colloid and Interface and Thermodynamics, CAS Research/Education Center for Excellence in Molecular Sciences, Center for Carbon Neutral Chemistry
Jiayong Huang
Jia Liu
Jianqiang Feng
Institute of Molecular Engineering Plus, College of Chemistry, Fuzhou University 2 , Fuzhou 350108,
Shengheng Yan
State Key Laboratory of Physical Chemistry of Solid Surfaces and Fujian Provincial Key Laboratory of Theoretical and Computational Chemistry, College of Chemistry and Chemical Engineering
Lina Dong
State Key Laboratory of Physical Chemistry of Solid Surfaces and Fujian Provincial Key Laboratory of Theoretical and Computational Chemistry College of Chemistry and Chemical Engineering Xiamen University Xiamen P. R. China
Yangyang Song
Qingdao Institute for Theoretical and Computational Sciences and Center for Optics Research and Engineering Shandong University Qingdao P. R. China
Zikuan Wang
Max-Planck-Institut für Kohlenforschung
Xiaoyun Xiao
Lanteng Wang
State Key Laboratory of Quantitative Synthetic Biology
Jiahai Zhou
School of Food Science and Pharmaceutical Engineering
Sason Shaik
Institute of Chemistry, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram, Jerusalem 9190401, Israel
Binju Wang
State Key Laboratory of Physical Chemistry of Solid Surfaces and Fujian Provincial Key Laboratory of Theoretical and Computational Chemistry, College of Chemistry and Chemical Engineering