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

Award Number: R35GM150762
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $399,836 )
2025	2025	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Biomedical Research and Research Training	001	3	7/29/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$399,836
2025	2024	UNIVERSITY OF NORTH CAROLINA AT GREENSBORO	1000 SPRING GARDEN ST	GREENSBORO	NC	27412	GUILFORD	USA	Biomedical Research and Research Training	000	2	7/28/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $399,836

Issue Date FY: 2024 ( Subtotal = $360,282 )
2024	2024	UNIVERSITY OF NORTH CAROLINA AT GREENSBORO	1000 SPRING GARDEN ST	GREENSBORO	NC	27412	GUILFORD	USA	Biomedical Research and Research Training	000	2	5/15/2024	NON-COMPETING CONTINUATION	$360,282
														Subtotal = $360,282

Issue Date FY: 2023 ( Subtotal = $343,060 )
2023	2023	UNIVERSITY OF NORTH CAROLINA AT GREENSBORO	1000 SPRING GARDEN STREET	GREENSBORO	NC	27412	GUILFORD	USA	Biomedical Research and Research Training	000	1	7/17/2023	NEW	$343,060
														Subtotal = $343,060

Grand Total All Awards = $1,103,178

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

Award Number: R35GM150762

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/01/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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