Multicomponent Bioluminescence Imaging with a π-Extended Luciferin.

Publisher: American Chemical Society Country of Publication: United States NLM ID: 7503056 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-5126 (Electronic) Linking ISSN: 00027863 NLM ISO Abbreviation: J Am Chem Soc Subsets: MEDLINE

Publication: Washington, DC : American Chemical Society
Original Publication: Easton, Pa. [etc.]

Luminescent Measurements*; Firefly Luciferin/*chemistry ; Luciferases/*chemistry ; Luminescent Agents/*chemistry; Firefly Luciferin/chemical synthesis ; Luciferases/metabolism ; Luminescence ; Luminescent Agents/chemical synthesis ; Molecular Structure

Bioluminescence imaging with luciferase-luciferin pairs is commonly used for monitoring biological processes in cells and whole organisms. Traditional bioluminescent probes are limited in scope, though, as they cannot be easily distinguished in biological environments, precluding efforts to visualize multicellular processes. Additionally, many luciferase-luciferin pairs emit light that is poorly tissue penetrant, hindering efforts to visualize targets in deep tissues. To address these issues, we synthesized a set of π-extended luciferins that were predicted to be red-shifted luminophores. The scaffolds were designed to be rotationally labile such that they produced light only when paired with luciferases capable of enforcing planarity. A luciferin comprising an intramolecular "lock" was identified as a viable light-emitting probe. Native luciferases were unable to efficiently process the analog, but a complementary luciferase was identified via Rosetta-guided enzyme design. The unique enzyme-substrate pair is red-shifted compared to well-known bioluminescent tools. The probe set is also orthogonal to other luciferase-luciferin probes and can be used for multicomponent imaging. Four substrate-resolved luciferases were imaged in a single session. Collectively, this work provides the first example of Rosetta-guided design in engineering bioluminescent tools and expands the scope of orthogonal imaging probes.

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R01 GM107630 United States GM NIGMS NIH HHS

0 (Luminescent Agents)
5TBB02N29K (Firefly Luciferin)
EC 1.13.12.- (Luciferases)

Date Created: 20200814 Date Completed: 20210415 Latest Revision: 20240330

20240330

PMC7867379

10.1021/jacs.0c01064

32787261