Site-selective tyrosine bioconjugation via photoredox catalysis for native-to-bioorthogonal protein transformation

Beryl X. Li, Daniel K. Kim, Steven Bloom, Richard Y.C. Huang, Jennifer X. Qiao, William R. Ewing, Daniel G. Oblinsky, Gregory D. Scholes, David W.C. MacMillan

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

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. [Figure not available: see fulltext.]

Original languageEnglish (US)
Pages (from-to)902-908
Number of pages7
JournalNature chemistry
Volume13
Issue number9
DOIs
StatePublished - Sep 2021

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Chemical Engineering(all)

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