Research

Copper Enzymes

Enzymatic Function, Substrate Specificity, and Mechanistic Studies

Aerobic life on earth harnesses the oxidizing power of molecular oxygen (O₂) through a diverse range of enzyme cofactors and employs that high oxidation potential to mediate numerous oxidative transformations during metabolic functions. Many of these cofactors are coupled binuclear sites consisting of two metal centers such as copper and iron in close proximity. Our team focuses on fundamental research in the field of bioinorganic chemistry and aims to address several intriguing questions about the potential roles of redox aromatic active amino acids such as tyrosine and tryptophan chains in the enzyme mechanism and function.

We work on three different classes of O₂-utilizing copper enzymes including cytochrome c oxidase (CcO) which reduces O₂ to water, multicopper oxidase (MCO) which couples that reaction to four one-electron oxidations of the substrates, and a new class of copper enzymes called BURP domain cyclases which catalyze 2-electron oxidative macrocyclization of the Tyr/Trp chains in peptide substrates. In all these enzymes, O₂ serves as a terminal electron acceptor.

In all three classes, appropriately tuned and positioned Tyr/Trp chains play different roles either as an integral part of the active site (i.e., CcO) or they may be assigned a mediatory role to provide an alternative path for oxidation of the more challenging substrates (i.e., MCO). They may even act as the direct substrate for the active site (i.e., Cu-dependent BURP domain cyclases). In all cases, despite the diverse use of these chains, their main function is to delicately supply the electron/proton needed for the O₂ reduction. How are these residues designed/optimized for a particular function? What are the similarities and differences between these enzymes? Our studies aim to reveal the potential role of these Tyr/Trp chains play in enzymatic function and mechanism and address some of the questions about copper biochemistry and aerobic metabolism.