期刊
NATURE CHEMISTRY
卷 13, 期 9, 页码 902-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41557-021-00733-y
关键词
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资金
- U.S. Department of Energy, Office of Science, Basic Energy Sciences [DE-SC0019370]
- Princeton Center for Complex Materials
- National Science Foundation/Materials Research Science and Engineering Centers programme [DMR-1420541]
- U.S. Department of Energy (DOE) [DE-SC0019370] Funding Source: U.S. Department of Energy (DOE)
This study presents a novel method for site-selective tyrosine bioconjugation using photoredox catalysis, which allows for chemically modifying native proteins with high site-selectivity. The water-soluble photocatalyst lumiflavin has been demonstrated to induce oxidative coupling between a phenoxazine dialdehyde tag and a single tyrosine site on native proteins, even in the presence of multiple tyrosyl side chains, enabling the synthesis of structurally defined fluorescent conjugates.
The growing prevalence of synthetically modified proteins in pharmaceuticals and materials has exposed the need for efficient strategies to enable chemical modifications with high site-selectivity. While genetic engineering can incorporate non-natural amino acids into recombinant proteins, regioselective chemical modification of wild-type proteins remains a challenge. Herein, we use photoredox catalysis to develop a site-selective tyrosine bioconjugation pathway that incorporates bioorthogonal formyl groups, which subsequently allows for the synthesis of structurally defined fluorescent conjugates from native proteins. A water-soluble photocatalyst, lumiflavin, has been shown to induce oxidative coupling between a previously unreported phenoxazine dialdehyde tag and a single tyrosine site, even in the presence of multiple tyrosyl side chains, through the formation of a covalent C-N bond. A variety of native proteins, including those with multiple tyrosines, can successfully undergo both tyrosine-specific and single-site-selective labelling. This technology directly introduces aldehyde moieties onto native proteins, enabling rapid product diversification using an array of well-established bioorthogonal functionalization protocols including the alkyne-azide click reaction.
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