Copper-Oxygen Dynamics in the Tyrosinase Mechanism

Angew Chem Int Ed Engl. 2020 Aug 3;59(32):13385-13390. doi: 10.1002/anie.202004733. Epub 2020 May 26.


The dinuclear copper enzyme, tyrosinase, activates O2 to form a (μ-η22 -peroxido)dicopper(II) species, which hydroxylates phenols to catechols. However, the exact mechanism of phenolase reaction in the catalytic site of tyrosinase is still under debate. We herein report the near atomic resolution X-ray crystal structures of the active tyrosinases with substrate l-tyrosine. At their catalytic sites, CuA moved toward l-tyrosine (CuA1 → CuA2), whose phenol oxygen directly coordinates to CuA2, involving the movement of CuB (CuB1 → CuB2). The crystal structures and spectroscopic analyses of the dioxygen-bound tyrosinases demonstrated that the peroxide ligand rotated, spontaneously weakening its O-O bond. Thus, the copper migration induced by the substrate-binding is accompanied by rearrangement of the bound peroxide species so as to provide one of the peroxide oxygen atoms with access to the phenol substrate's ϵ carbon atom.

Keywords: active site dynamics; copper; copper enzymes; dioxygen activation; tyrosinase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aspergillus oryzae / enzymology
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / metabolism
  • Biocatalysis
  • Catalytic Domain
  • Copper / chemistry
  • Copper / metabolism*
  • Crystallography, X-Ray
  • Fungal Proteins / chemistry
  • Fungal Proteins / metabolism
  • Models, Chemical
  • Monophenol Monooxygenase / chemistry
  • Monophenol Monooxygenase / metabolism*
  • Oxygen / chemistry
  • Oxygen / metabolism*
  • Protein Binding
  • Streptomyces / enzymology
  • Tyrosine / chemistry
  • Tyrosine / metabolism*


  • Bacterial Proteins
  • Fungal Proteins
  • Tyrosine
  • Copper
  • Monophenol Monooxygenase
  • Oxygen