N-Formimidoylation/-iminoacetylation modification in aminoglycosides requires FAD-dependent and ligand-protein NOS bridge dual chemistry

Yung-Lin Wang, Chin-Yuan Chang, Ning-Shian Hsu, I-Wen Lo, Kuan-Hung Lin, Chun-Liang Chen, Chi-Fon Chang, Zhe-Chong Wang, Yasushi Ogasawara, Tohru Dairi, Chitose Maruyama, Yoshimitsu Hamano () and Tsung-Lin Li ()
Additional contact information
Yung-Lin Wang: Academia Sinica
Chin-Yuan Chang: National Yang Ming Chiao Tung University
Ning-Shian Hsu: Academia Sinica
I-Wen Lo: Academia Sinica
Kuan-Hung Lin: Academia Sinica
Chun-Liang Chen: Academia Sinica
Chi-Fon Chang: Academia Sinica
Zhe-Chong Wang: Academia Sinica
Yasushi Ogasawara: Hokkaido University, Kita-ku
Tohru Dairi: Hokkaido University, Kita-ku
Chitose Maruyama: Fukui Prefectural University, Eiheiji-cho
Yoshimitsu Hamano: Fukui Prefectural University, Eiheiji-cho
Tsung-Lin Li: Academia Sinica

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract Oxidized cysteine residues are highly reactive and can form functional covalent conjugates, of which the allosteric redox switch formed by the lysine-cysteine NOS bridge is an example. Here, we report a noncanonical FAD-dependent enzyme Orf1 that adds a glycine-derived N-formimidoyl group to glycinothricin to form the antibiotic BD-12. X-ray crystallography was used to investigate this complex enzymatic process, which showed Orf1 has two substrate-binding sites that sit 13.5 Å apart unlike canonical FAD-dependent oxidoreductases. One site could accommodate glycine and the other glycinothricin or glycylthricin. Moreover, an intermediate-enzyme adduct with a NOS-covalent linkage was observed in the later site, where it acts as a two-scissile-bond linkage facilitating nucleophilic addition and cofactor-free decarboxylation. The chain length of nucleophilic acceptors vies with bond cleavage sites at either N–O or O–S accounting for N-formimidoylation or N-iminoacetylation. The resultant product is no longer sensitive to aminoglycoside-modifying enzymes, a strategy that antibiotic-producing species employ to counter drug resistance in competing species.

Date: 2023
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DOI: 10.1038/s41467-023-38218-w

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