Download MendeleyBiocatalytic control of site-selectivity and chain length-selectivity in radical amino acid halogenases.
Kissman, E.N., Neugebauer, M.E., Sumida, K.H., Swenson, C.V., Sambold, N.A., Marchand, J.A., Millar, D.C., Chang, M.C.Y.(2023) Proc Natl Acad Sci U S A 120: e2214512120-e2214512120
- PubMed: 36913566
- DOI: https://doi.org/10.1073/pnas.2214512120
- Primary Citation of Related Structures:
7U6H, 7U6I, 7U6J - PubMed Abstract:
Biocatalytic C-H activation has the potential to merge enzymatic and synthetic strategies for bond formation. Fe II /αKG-dependent halogenases are particularly distinguished 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 halogenation 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 C 4 vs C 5 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.
Organizational Affiliation:
Department of Chemistry, University of California, Berkeley, CA 94720.
