Mechanistic & spectroscopic studies on O2-activation and reactivity by coupled binuclear copper enzymes

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Coupled binuclear copper (CBC) enzymes constitute a major family of O2-activating metalloenzymes that catalyze a wide range of oxidation and oxygenation reactions. The most predominant member of this enzyme family, tyrosinase (Ty) in its dicopper(I) reduced form (deoxy-Ty) binds O2 to form a μ-η2:η2-peroxide dicopper(II) intermediate (oxy-Ty) that can monooxygenate para-substituted monophenols to catechols, which in its native function constitutes the initial step in melanin biosynthesis in a wide range of organisms, from soil bacteria to humans. The mechanism of this important monooxygenation reaction has not been fully understood, with its key reaction intermediates remaining elusive. This thesis presents advancements in defining the monophenol monooxygenation mechanism of Ty by (i) trapping and spectroscopically characterizing key reaction intermediates, (ii) investigating their reactivity by kinetic methods, and (iii) correlating experimental results to quantum-mechanics/molecular-mechanics (QM/MM) calculations. Analysis of our experimental and computational results provides a molecular-level definition of the reaction coordinate for the monophenol monooxygenation reaction of Ty. This mechanism is different from the general paradigm based on previous model complex studies and provides new insights into how Nature employs Cu2O2 active sites to perform enzymatic catalysis.


Alternative title Mechanistic and spectroscopic studies on O2-activation and reactivity by coupled binuclear copper enzymes
Type of resource text
Form electronic resource; remote; computer; online resource
Extent 1 online resource.
Place California
Place [Stanford, California]
Publisher [Stanford University]
Copyright date 2022; ©2022
Publication date 2022; 2022
Issuance monographic
Language English


Author Kipouros, Ioannis
Degree supervisor Solomon, Edward I
Thesis advisor Solomon, Edward I
Thesis advisor Cegelski, Lynette
Thesis advisor Stack, T. (T. Daniel P.), 1959-
Degree committee member Cegelski, Lynette
Degree committee member Stack, T. (T. Daniel P.), 1959-
Associated with Stanford University, Department of Chemistry


Genre Theses
Genre Text

Bibliographic information

Statement of responsibility Ioannis Kipouros.
Note Submitted to the Department of Chemistry.
Thesis Thesis Ph.D. Stanford University 2022.

Access conditions

© 2022 by Ioannis Kipouros
This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).

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