What causes the different functionality in type-III-copper enzymes? A state of the art perspective

[Display omitted] •Tyrosinases and catechol oxidases share a very similar active site architecture.•However, these two enzyme classes catalyse different reactions.•The structural motifs responsible for the different activity remain elusive.•Possible strategies to resolve this long-standing issue are presented. The structural difference between tyrosinase and catechol oxidase as the basis for their catalytic activity is still a puzzle although several crystal structures of both enzymes exist. In this review we discuss the structural motifs that had been proposed to be responsible for the lack of hydroxylase activity. However, up to now, all worked out structural restrictions could be disproved by more recent crystal structures of type-III-copper enzymes. The search for the function-determining amino acids continues and after decades of intensive research we still do not know more than that the substrate binding residues must be directly responsible for the mono- and/or diphenolase activity. In the last part the review discusses possibilities to address the topic in the future: What causes the different functionality in type-III-copper enzymes?