CATCHING TYROSINASE IN THE ACT

Tyrosinase is a ubiquitous enzyme prevalent in all domains of life and is responsible for the two initial enzymatic steps in the conversion of tyrosine to melanin. Many tyrosinase mutations are the leading cause of albinism in humans and it is a prominent biotechnology and pharmaceutical industry target. It has been believed that monophenols and diphenols bind differently at the active site thus explaining the different activities between tyrosinases and catechol oxidases which perform only the second oxidation step of diphenols.

We present crystal structures that show unequivocally that both monophenol hydroxylation and diphenol oxidation occur at the same site¹. It is suggested that concurrent presence of a phenylalanine above the active site and a restricting thioether bond on the histidine coordinating CuA prevent hydroxylation of monophenols by catechol oxidases. Furthermore, a conserved water molecule activated by E195 and N205, is proposed to mediate deprotonation of the monophenol at the active site. Overall, the new structures reveal precise steps in the enzymatic catalytic cycle as well as differences between tyrosinases and other type-3 copper enzymes.

¹ Goldfeder et al. (2014) Nat. Commun. 5:4505.