Ubiquitous Alkyne Activity

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Science  29 Mar 2013:
Vol. 339, Issue 6127, pp. 1499
DOI: 10.1126/science.339.6127.1499-c

Over the past decade, the coupling of terminal alkynes with azides—so efficient it's been termed a “click” reaction—has become a prevalent means of linking together larger molecular fragments. One advantage of the scheme was that the alkynes appeared to be otherwise inert in cellular environments, thereby enabling high specificity in the design of various biochemical probes. Two studies now report that terminal alkynes do in fact react with certain enzymes. Ekkebus et al. show that appending the alkyne to the C terminus of ubiquitin leads to inhibition of deubiquitinating enzymes. Crystallography revealed covalent linkage to an active site cysteine, the product of formal Markovnikov addition of the thiol group across the carbon-carbon triple bond (though no reaction was observed with free thiol). Sommer et al. observed the same reaction of C-terminally propargylated small ubiquitin-like modifier (SUMO) with its protease. Scavenger experiments in both studies disfavor a radical mechanism. Both studies leveraged the observation for selective labeling of lysates and suggest that this reaction could have broad application in selective inhibition.

J. Am. Chem. Soc. 135, 2867; Bioorg. Med. Chem. 21, 10.1016/j.bmc.2013.02.039 (2013).

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