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Functional Synthetic Models of Cu-dependent Monooxygenases

Award Number: R35GM137914
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: 09/01/2020
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Functional Synthetic Models of Cu-dependent Monooxygenases - Project Summary: In this research project, we develop synthetic inorganic copper complexes to understand the fundamental aspects of structure and function in Cu-dependent monooxygenase enzymes. These metalloenzymes contain 1 or 2 Cu ions in their active center and they couple the reduction of O2 with the oxidation of substrates via formation of transient Cun/O2 species. We are particularly interested in studying the reactivity of mononuclear Cu/O2 intermediates since they have been proposed as active oxidants in the hydroxylation of strong C-H bonds in enzymes such as particulate methane monooxygenases (pMMOs) and lytic polysaccharide monooxygenases (LPMOs). Many questions concerning the identity of the active Cu/O2 species remain unanswered, including: i) oxidation state of Cu (CuI vs. CuII vs. CuIII); ii) reduction/protonation state of O2 (O2−,(H)O22−, (H)O2−) and the pKa and redox potentials associated with these Cu/O2 species; iii) mechanism by which the Cu/O2 intermediates carry out C-H hydroxylations (e.g. O-O cleavage mechanism before or after C-H oxidation?; generation of high-valent Cu-oxyl species before substrate hydroxylation?). In this research proposal, we tackle this problem using two different approaches: 1) We utilize ligand scaffolds (L) that contain C-H substrates covalently attached to their structure (substrate- ligands) that permit us to generate and characterize LCu/O2 species and evaluate their reactivity towards intramolecular C-H hydroxylation. Substrate-ligand modifications will permit us to: i) evaluate the ability of the Cu/O2 species to oxidize sp3 C-H bonds and sp2 C-H bonds; ii) control the stereo-electronic properties of the Cu complexes by the use of different ligand donors (i.e. N2, N3, N4) that will lead to the generation of mononuclear and dinuclear LCu/O2 species, and analyze their reactivity towards intramolecular C-H hydroxylation including characterization of reaction intermediates, kinetics and computations; iii) utilize this approach (Cu-directed hydroxylations) to develop synthetic protocols to promote challenging organic transformations such as enantioselective C-H hydroxylations and one-pot synthesis of 1,3-oxazines. 2) We synthesize mononuclear Cu complexes bearing redox-active ligands with tunable H-bonds that stabilize Cu-hydroxo and Cu-oxyl cores. These unusual Cu complexes are able to reach multiple oxidation states via oxidation of the metal and/or ligand scaffold. These high-valent CuO(H) cores will be characterized by various spectroscopic methods and their ability to perform biorelevant intermolecular 2e− C-H hydroxylations will be examined systematically using the Bordwell equation (i.e. species with higher redox potential and higher pKa should be capable of oxidizing stronger C-H bonds), kinetic experiments and analysis of the reactions products derived from hydroxylation (e.g. organic product(s) and oxidation/protonation state of the final Cu complexes). Overall, these studies will contribute to a broader understanding of the biochemical role of Cu ions involved in O2 reduction and biologically relevant oxidations.


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: 2024 ( Subtotal = $370,960 )
2024	2024	CARNEGIE MELLON UNIVERSITY	5000 FORBES AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Biomedical Research and Research Training	000	6	8/30/2024	NON-COMPETING CONTINUATION	$370,960
														Subtotal = $370,960

Issue Date FY: 2023 ( Subtotal = $370,960 )
2023	2023	CARNEGIE MELLON UNIVERSITY	5000 FORBES AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Biomedical Research and Research Training	000	5	8/24/2023	NON-COMPETING CONTINUATION	$370,960
														Subtotal = $370,960

Issue Date FY: 2022 ( Subtotal = $370,960 )
2022	2022	CARNEGIE MELLON UNIVERSITY	5000 FORBES AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Biomedical Research and Research Training	000	4	8/11/2022	NON-COMPETING CONTINUATION	$370,960
														Subtotal = $370,960

Issue Date FY: 2021 ( Subtotal = $348,134 )
2021	2021	CARNEGIE MELLON UNIVERSITY	5000 FORBES AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Biomedical Research and Research Training	002	3	8/27/2021	NON-COMPETING CONTINUATION	$370,960
2021	2020	SOUTHERN METHODIST UNIVERSITY	6425 BOAZ LANE	DALLAS	TX	75205	DALLAS	USA	Biomedical Research and Research Training	000	1	6/3/2021	NEW	-$252,325
2021	2020	CARNEGIE MELLON UNIVERSITY	5000 FORBES AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Biomedical Research and Research Training	001	2	6/3/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$229,499
														Subtotal = $348,134

Issue Date FY: 2020 ( Subtotal = $252,325 )
2020	2020	SOUTHERN METHODIST UNIVERSITY	6425 BOAZ LANE	DALLAS	TX	75205	DALLAS	USA	Biomedical Research and Research Training	000	1	8/5/2020	NEW	$252,325
														Subtotal = $252,325

Grand Total All Awards = $1,713,339

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Functional Synthetic Models of Cu-dependent Monooxygenases

Award Number: R35GM137914

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: 09/01/2020

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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