| Title: |
N-Formimidoylation/-iminoacetylation modification in aminoglycosides requires FAD-dependent and ligand-protein NOS bridge dual chemistry |
| Authors: |
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, Tsung-Lin Li |
| Source: |
Nature Communications, Vol 14, Iss 1, Pp 1-14 (2023) |
| Publisher Information: |
Nature Portfolio, 2023. |
| Publication Year: |
2023 |
| Collection: |
LCC:Science |
| Subject Terms: |
Science |
| More Details: |
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. |
| Document Type: |
article |
| File Description: |
electronic resource |
| Language: |
English |
| ISSN: |
2041-1723 |
| Relation: |
https://doaj.org/toc/2041-1723 |
| DOI: |
10.1038/s41467-023-38218-w |
| Access URL: |
https://doaj.org/article/d86e54a33b7e49ebbea9cb2bf226eb74 |
| Accession Number: |
edsdoj.86e54a33b7e49ebbea9cb2bf226eb74 |
| Database: |
Directory of Open Access Journals |
