Multi-copper oxidases share with heme, copper oxidases the ability to catalyze the 4-electron of dioxygen to 2H2O and typically have low or sub-micromolar Michaelis constants for O2. This latter property suggested that MCOs represent an early adaptation to the aerobiosis of the Earth’s atmosphere ~2.5 Gy BCE. MCOs vary widely in the reducing substrate reactivity exhibited, from dihydroascobic acid and phenols and aryl amines to a relatively small cohort that accept electrons from low valent metals ions, e.g. Mn(II), Fe(II) and Cu(I). This cuprous oxidase activity appears related to a role in copper resistance in those organisms expressing such MCO proteins. We have correlated the structure and cuprous oxidase activity of a group of MCOs and provide evidence that this substrate specificity is related to one of four structural motifs all of which involve methionine residues as Cu(I) specificity elements. With this information we have conducted a detailed cladistic analysis to determine the origin of these elements and whether they are homologous or analgous structural motifs. This analysis is consistent with the first appearance of the MCO signature cupredoxin domains ~1.5 Gy BCE or considerably later than wide-spread geologic aerobiosis. We conclude that a primary MCO function has been in its role in suppressing the pro-oxidant activity of Cu(I).

Cuprous oxidase motifs in multi-copper oxidases: Structural identification and cladistic analysis

251st National Meeting (2016)

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