# Multinuclear Dioxygen-Utilizing Copper Enzymes: Diverse Roles for Aromatic Redox Active Amino Acids

> **NIH NIH R35** · UNIVERSITY OF NORTH CAROLINA GREENSBORO · 2024 · $360,282

## Abstract

PROJECT SUMMARY
 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. This proposal details 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 tryptophane chains in the enzyme mechanism and function.
 We identified 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.The use of O2 as either a
substrate or terminal electron acceptor has been established in these enzymes except for the BURP domain
enzymes which is yet to be confirmed.
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.

## Key facts

- **NIH application ID:** 10889134
- **Project number:** 5R35GM150762-02
- **Recipient organization:** UNIVERSITY OF NORTH CAROLINA GREENSBORO
- **Principal Investigator:** Shabnam Hematian
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $360,282
- **Award type:** 5
- **Project period:** 2023-08-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10889134

## Citation

> US National Institutes of Health, RePORTER application 10889134, Multinuclear Dioxygen-Utilizing Copper Enzymes: Diverse Roles for Aromatic Redox Active Amino Acids (5R35GM150762-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10889134. Licensed CC0.

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