Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 120, Issue 12, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2214512120
Keywords
biocatalysis; enzymology; bioinorganic chemistry; structural biology; C-H activation
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This study investigates the application of enzyme-catalyzed C-H activation in selective halogenation, and elucidates the crucial role of substrate-binding lid in selective halogenation through crystal structures of HalB and HalD, providing guidance for the development of halogenases with biocatalytic applications.
Biocatalytic C???H activation has the potential to merge enzymatic and synthetic strategies for bond formation. FeII/??KG-dependent halogenases are particularly dis-tinguished for their ability both to control selective C???H activation as well as to direct group transfer of a bound anion along a reaction axis separate from oxygen rebound, enabling the development of new transformations. In this context, we elucidate the basis for the selectivity of enzymes that perform selective halogena-tion to yield 4-Cl-lysine (BesD), 5-Cl-lysine (HalB), and 4-Cl-ornithine (HalD), allowing us to probe how site-selectivity and chain length selectivity are achieved. We now report the crystal structure of the HalB and HalD, revealing the key role of the substrate-binding lid in positioning the substrate for C4 vs C5 chlorination and recognition of lysine vs ornithine. Targeted engineering of the substrate-binding lid further demonstrates that these selectivities can be altered or switched, showcasing the potential to develop halogenases for biocatalytic applications.
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