We describe a class of bioconjugation reactions that

enables site-specific modification of proteins through

enzymatic generation of o-quinone from either tyrosine

residues or phenol reagents. The enzymatically generated

o-quinone rapidly reacts chemically with numerous

common nucleophiles and dienophiles, including thiols,

anilines, alkoxyamines, cyclooctynes, and cyclooctenes.

Nucleophilic chemoenzymatic reaction with engineered

tyrosine residues creates a hydroxytyrosine (HOT)

bridge; a similar reaction with phenols creates a hydroxyphenol

(HOP). Diels-alder cycloaddition following

o-quinone generation results in an arylbicyclodiketone (ABCD). The stability of each conjugate against

physiological pH and temperature varies from less than one day to multiple months in vitro.

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