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Bioorthogonal chemistry

The term bioorthogonal chemistry refers to any chemical reaction that can occur inside of living systems without interfering with native biochemical processes.[1][2][3] The term was coined by Carolyn R. Bertozzi in 2003.[4][5] Since its introduction, the concept of the bioorthogonal reaction has enabled the study of biomolecules such as glycans, proteins,[6] and lipids[7] in real time in living systems without cellular toxicity. A number of chemical ligation strategies have been developed that fulfill the requirements of bioorthogonality, including the 1,3-dipolar cycloaddition between azides and cyclooctynes (also termed copper-free click chemistry),[8] between nitrones and cyclooctynes,[9] oxime/hydrazone formation from aldehydes and ketones,[10] the tetrazine ligation,[11] the isocyanide-based click reaction,[12] and most recently, the quadricyclane ligation.[13]

Shown here is a bioorthogonal ligation between biomolecule X and reactive partner Y. To be considered bioorthogonal, these reactive partners cannot perturb other chemical functionality naturally found within the cell.

The use of bioorthogonal chemistry typically proceeds in two steps. First, a cellular substrate is modified with a bioorthogonal functional group (chemical reporter) and introduced to the cell; substrates include metabolites, enzyme inhibitors, etc. The chemical reporter must not alter the structure of the substrate dramatically to avoid affecting its bioactivity. Secondly, a probe containing the complementary functional group is introduced to react and label the substrate.

Although effective bioorthogonal reactions such as copper-free click chemistry have been developed, development of new reactions continues to generate orthogonal methods for labeling to allow multiple methods of labeling to be used in the same biosystems. Carolyn R. Bertozzi was awarded the Nobel Prize in Chemistry in 2022 for her development of click chemistry and bioorthogonal chemistry.[14]

  1. ^ Sletten, Ellen M.; Bertozzi, Carolyn R. (2009). "Bioorthogonal Chemistry: Fishing for Selectivity in a Sea of Functionality". Angewandte Chemie International Edition. 48 (38): 6974–98. doi:10.1002/anie.200900942. PMC 2864149. PMID 19714693.
  2. ^ Prescher, Jennifer A.; Dube, Danielle H.; Bertozzi, Carolyn R. (2004). "Chemical remodelling of cell surfaces in living animals". Nature. 430 (7002): 873–7. Bibcode:2004Natur.430..873P. doi:10.1038/nature02791. PMID 15318217. S2CID 4371934.
  3. ^ Prescher, Jennifer A; Bertozzi, Carolyn R (2005). "Chemistry in living systems". Nature Chemical Biology. 1 (1): 13–21. doi:10.1038/nchembio0605-13. PMID 16407987. S2CID 40548615.
  4. ^ Hang, Howard C.; Yu, Chong; Kato, Darryl L.; Bertozzi, Carolyn R. (2003-12-09). "A metabolic labeling approach toward proteomic analysis of mucin-type O-linked glycosylation". Proceedings of the National Academy of Sciences. 100 (25): 14846–14851. Bibcode:2003PNAS..10014846H. doi:10.1073/pnas.2335201100. ISSN 0027-8424. PMC 299823. PMID 14657396.
  5. ^ Sletten, Ellen M.; Bertozzi, Carolyn R. (2011). "From Mechanism to Mouse: A Tale of Two Bioorthogonal Reactions". Accounts of Chemical Research. 44 (9): 666–676. doi:10.1021/ar200148z. PMC 3184615. PMID 21838330.
  6. ^ Plass, Tilman; Milles, Sigrid; Koehler, Christine; Schultz, Carsten; Lemke, Edward A. (2011). "Genetically Encoded Copper-Free Click Chemistry". Angewandte Chemie International Edition. 50 (17): 3878–3881. doi:10.1002/anie.201008178. PMC 3210829. PMID 21433234.
  7. ^ Neef, Anne B.; Schultz, Carsten (2009). "Selective Fluorescence Labeling of Lipids in Living Cells". Angewandte Chemie International Edition. 48 (8): 1498–500. doi:10.1002/anie.200805507. PMID 19145623.
  8. ^ Baskin, J. M.; Prescher, J. A.; Laughlin, S. T.; Agard, N. J.; Chang, P. V.; Miller, I. A.; Lo, A.; Codelli, J. A.; Bertozzi, C. R. (2007). "Copper-free click chemistry for dynamic in vivo imaging". Proceedings of the National Academy of Sciences. 104 (43): 16793–7. Bibcode:2007PNAS..10416793B. doi:10.1073/pnas.0707090104. PMC 2040404. PMID 17942682.
  9. ^ Ning, Xinghai; Temming, Rinske P.; Dommerholt, Jan; Guo, Jun; Blanco-Ania, Daniel; Debets, Marjoke F.; Wolfert, Margreet A.; Boons, Geert-Jan; Van Delft, Floris L. (2010). "Protein Modification by Strain-Promoted Alkyne-Nitrone Cycloaddition". Angewandte Chemie International Edition. 49 (17): 3065–8. doi:10.1002/anie.201000408. PMC 2871956. PMID 20333639.
  10. ^ Yarema, K. J.; Mahal, LK; Bruehl, RE; Rodriguez, EC; Bertozzi, CR (1998). "Metabolic Delivery of Ketone Groups to Sialic Acid Residues. Application to Cell Surface Glycoform Engineering". Journal of Biological Chemistry. 273 (47): 31168–79. doi:10.1074/jbc.273.47.31168. PMID 9813021.
  11. ^ Blackman, Melissa L.; Royzen, Maksim; Fox, Joseph M. (2008). "The Tetrazine Ligation: Fast Bioconjugation based on Inverse-electron-demand Diels-Alder Reactivity". Journal of the American Chemical Society. 130 (41): 13518–9. doi:10.1021/ja8053805. PMC 2653060. PMID 18798613.
  12. ^ Stöckmann, Henning; Neves, André A.; Stairs, Shaun; Brindle, Kevin M.; Leeper, Finian J. (2011). "Exploring isonitrile-based click chemistry for ligation with biomolecules". Organic & Biomolecular Chemistry. 9 (21): 7303–5. doi:10.1039/C1OB06424J. PMID 21915395.
  13. ^ Sletten, Ellen M.; Bertozzi, Carolyn R. (2011). "A Bioorthogonal Quadricyclane Ligation". Journal of the American Chemical Society. 133 (44): 17570–3. doi:10.1021/ja2072934. PMC 3206493. PMID 21962173.
  14. ^ "The Nobel Prize in Chemistry". The Nobel Prize. Retrieved 6 October 2022.

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