Shall we dance? How a multicopper oxidase chooses its electron transfer partner

Area of Science:

• Biochemistry
• Enzymology
• Protein Science

Background:

• Multicopper oxidases (MCOs) are ubiquitous enzymes found across Eukarya, Bacteria, and Archaea.
• These proteins feature four copper atoms (T1, T2, and T3 sites) essential for their catalytic activity.
• MCOs catalyze the four-electron reduction of dioxygen to water, a function shared only with heme-containing oxidases.

Purpose of the Study:

• To analyze the structure-activity features of MCOs that dictate substrate specificity.
• To investigate the factors influencing the broad substrate specificity of MCOs towards organic reductants and metal ions.
• To apply Marcus theory to understand the origin of substrate specificity in multicopper ferroxidases.

Main Methods:

• Bioinformatic analysis of MCO genomes.
• Structural analysis of copper sites within MCOs.
• Application of Marcus theory to electron transfer mechanisms.

Main Results:

• MCOs exhibit diverse substrate specificities, with some acting as metallo-oxidases for Fe(II), Cu(I), and Mn(II).
• The T1 copper site is crucial for outer-sphere electron transfer from reductants.
• Marcus theory provides a framework for understanding substrate specificity in MCO ferroxidases.

Conclusions:

• The unique arrangement of four copper sites in MCOs underlies their diverse catalytic functions.
• Structure-activity relationships are key determinants of MCO substrate specificity.
• Understanding these relationships, particularly via Marcus theory, can guide the design of MCOs with tailored activities.