Cu(II)-mediated phenol oxygenation: Chemical evidence implicates a unique role of the enzyme active site in promoting the chemically difficult tyrosine monooxygenation in TPQ cofactor biogenesis of copper amine oxidases

•Discussing effects of reaction conditions on Cu(II)-catalyzed oxidation of phenols.•Revealing free phenoxy radicals is relatively inert to O2.•Dissociating ArO–Cu(II)–OO to phenoxy radical is difficult to phenol oxidation.•Tuning Cu(II)–trihistidinyl redox potential to promote phenol oxygenation by CuAOs.

Cu(II)-mediated autoxidations of 4-tert-butylphenol under various conditions was studied, the data confirmed imidazole is the best ligand to promote phenol oxygenation. The same reaction of 2,4-di-tert-butylphenol proceeded much more quickly to lead nearly exclusively to oxidative coupling rather than oxygenation under high pressure O2. These results suggested that Cu(II)-catalyzed phenol autoxidation by activating O2 and phenol in terms of a phenoxy radical (ArO)–Cu(II)–superoxide ternary complex, whereas selectivity between oxygenation and coupling depends mainly on the electronic structure of ArO. It is appeared that CuAOs could achieve stoichiometric tyrosine monooxygenation by modulating the redox potential of Cu(II) and stabilizing the ternary complex through protein conformational adjustment.

Graphical abstractCu(II)-catalyzed autoxidation of alkyl substituted phenols has been studied to gain insight into the mechanism of tyrosine phenol oxygenation step in TPQ biogenesis of CAOs. The results suggest that the difficulty of Cu(II)-catalyzed phenol oxygenation is not the inability of Cu(II) to activate phenol and O2, but is the high tendency of the ternary complex ArO–Cu(II)–OO to dissociate into free phenoxy radicals. The conclusion is further supported by the great ease of Cu(II)-catalyzed oxygenation of hydroquinone, catechols and resorcinols.Figure optionsDownload full-size imageDownload as PowerPoint slide