Abstract

AbstractThe cohort of enzymes designated as multicopper oxidases (MCOs) are expressed by species in all organismal domains. As an enzyme class, these proteins minimally possess a catalytic quartet of copper prosthetic groups that are organized specifically into two, spatially separated (by ∼13 Å) copper centers: (i) a mononuclear copper site—designated as a Type 1 Cu(II)—whose electronic structure and reactivity is dominated by strong S → Cu charge transfer involving an invariant sulfur ligand contributed by a protein cysteine residue; and (ii) a trinuclear copper cluster (TNC) that is linked to the mononuclear site by an invariant –HCH‐sequence motif in which the Cys residue is ligand to the Type 1 Cu and the two His residues are each ligand to one of the Cu atoms in the TNC. This connectivity provides efficient electronic coupling matrix elements for intramolecular electron transfer from the Type 1—as Cu(I)—to the TNC. In MCO turnover, a reducing substrate shuttles electrons to the Type 1 Cu(II) by an outer‐sphere electron transfer pathway; the HCH motif couples this reduced Type 1 Cu(I) to the TNC where O2is reduced to 2H2O. MCOs are therefore members of a few enzyme classes that reduce dioxygen to water, members that include at the least the terminal heme‐copper oxidases, cytochromebdoxidases, and type A flavoproteins found in some methanogenic and other bacteria that contain a unique coenzyme F420. The Type 1 Cu site in an MCO is homologous to the copper site found in small (∼120 kDa) “blue” copper proteins, for example, azurin and plastocyanin; the Type 1 Cu in an MCO is likely metallated in a process similar to how those proteins characterized by a single cupredoxin domain acquire their prosthetic group. The assembly of the TNC, however, is unique to MCOs and has not been well characterized. This chapter reviews the structural properties of MCO family members and discusses how cell copper trafficking might lead to the activation of these widely distributed members of the copper protein family.

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