Discovery and substrate specificity engineering of nucleotide halogenases

Jie Ni, Jingyuan Zhuang, Yiming Shi, Ying-Chih Chiang and Gui-Juan Cheng ()
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Jie Ni: The Chinese University of Hong Kong
Jingyuan Zhuang: The Chinese University of Hong Kong
Yiming Shi: The Chinese University of Hong Kong
Ying-Chih Chiang: The Chinese University of Hong Kong
Gui-Juan Cheng: The Chinese University of Hong Kong

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract C2′-halogenation has been recognized as an essential modification to enhance the drug-like properties of nucleotide analogs. The direct C2ʹ-halogenation of the nucleotide 2′-deoxyadenosine-5′-monophosphate (dAMP) has recently been achieved using the Fe(II)/α-ketoglutarate-dependent nucleotide halogenase AdaV. However, the limited substrate scope of this enzyme hampers its broader applications. In this study, we report two halogenases capable of halogenating 2ʹ-deoxyguanosine monophosphate (dGMP), thereby expanding the family of nucleotide halogenases. Computational studies reveal that nucleotide specificity is regulated by the binding pose of the phosphate group. Based on these findings, we successfully engineered the substrate specificity of these halogenases by mutating second-sphere residues. This work expands the toolbox of nucleotide halogenases and provides insights into the regulation mechanism of nucleotide specificity.

Date: 2024
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DOI: 10.1038/s41467-024-49147-7

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