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Thermodynamic, Electronic, Structural, and Kinetic Characterizations of Cytochrome P450 Compounds I & II

Award Number: R01GM101390
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: 04/01/2012
PERIOD OF PERFORMANCE END DATE: 03/31/2029

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Thermodynamic, Electronic, Structural, and Kinetic Characterizations of Cytochrome P450 Compounds I & II - Project Summary The research outlined in this proposal seeks to further our understanding of the factors that govern C-H bond activation in cytochrome P450 catalysis. Over the past several years my group has made significant contributions to this area. Our results have impacted not only the way people think about P450 catalysis but also metal-oxo mediated C-H bond activation in general. We have led the way in the capture and characterization of critical intermediates in the P450 catalytic cycle and developed theories to describe how Nature biases enzymes for C-H bond activation. Still, much remains to be done. Our understanding of the factors that govern C-H bond activation in P450s remains incomplete. Importantly, results from our last funding period have shown that P450 can serve as a platform from which to attack some of the most important and fundamental questions in the field of C-H bond activation. There remains a debate in the field about the factors that govern reactivity in metal-oxo driven C-H bond activation. The debate centers on whether ground state thermodynamics, in the form of bond strengths, play the dominant role in determining reactivity or whether some other property of the system (e.g., spin density on the oxo ligand, metal-oxo basicity, access to low-lying excited states, or enhanced H-atom tunneling facilitated by strong electron donation from the axial ligand) can provide an intrinsic lowering of the activation barrier. The examination of this fundamental issue has been hindered not only by the difficulty of measuring these quantities for reactive high-valent species but also by the lack of a series of isoelectronic and isostructural compounds over which these quantities can be varied. We have shown that P450 can fill this void. During the previous funding period we expanded the range of P450s in which we can prepare compounds I and II for experimental studies. We now have access to an isoelectronic series of P450 intermediates with varying axial ligation. This and other innovations will allow us to measure the ground state thermodynamics of C-H bond cleavage, quantify the degree of H-atom tunneling and ferryl basicity, determine the amount of oxyl-radical character in compound I, examine the accessibility of low-lying excited states, and, importantly, track how these quantities (and the reactivity towards C-H bonds) change as a function of electron donation from the axial ligand. There is currently no other system, synthetic or biological, that allows for a similar set of measurements and discovery.


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: 2026 ( Subtotal = $318,337 )
2026	2026	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Biomedical Research and Research Training	000	11	4/2/2026	NON-COMPETING CONTINUATION	$318,337
														Subtotal = $318,337

Issue Date FY: 2025 ( Subtotal = $320,351 )
2025	2025	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Biomedical Research and Research Training	001	10	5/2/2025	COMPETING CONTINUATION	$320,356
2025	2021	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Biomedical Research and Research Training	000	9	11/14/2024	NON-COMPETING CONTINUATION	-$5
														Subtotal = $320,351

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Biomedical Research and Research Training	000	9	4/20/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $327,680 )
2021	2021	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Biomedical Research and Research Training	000	9	4/1/2021	NON-COMPETING CONTINUATION	$327,680
														Subtotal = $327,680

Issue Date FY: 2020 ( Subtotal = $327,680 )
2020	2020	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Biomedical Research and Research Training	000	8	4/13/2020	NON-COMPETING CONTINUATION	$327,680
														Subtotal = $327,680

Issue Date FY: 2019 ( Subtotal = $327,680 )
2019	2019	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Biomedical Research and Research Training	000	7	4/18/2019	NON-COMPETING CONTINUATION	$327,680
														Subtotal = $327,680

Issue Date FY: 2018 ( Subtotal = $313,904 )
2018	2018	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Biomedical Research and Research Training	000	6	6/18/2018	COMPETING CONTINUATION	$313,904
2018	2015	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Biomedical Research and Research Training	001	5	6/19/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $313,904

Issue Date FY: 2016 ( Subtotal = $12,097 )
2016	2015	PENNSYLVANIA STATE UNIVERSITY	110 TECHNOLOGY CENTER BUILDING	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	4	4/4/2016	NON-COMPETING CONTINUATION	-$173,986
2016	2015	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Biomedical Research and Research Training	001	5	4/5/2016	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$186,083
														Subtotal = $12,097

Issue Date FY: 2015 ( Subtotal = $255,277 )
2015	2015	PENNSYLVANIA STATE UNIVERSITY	110 TECHNOLOGY CENTER BUILDING	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	4	3/17/2015	NON-COMPETING CONTINUATION	$255,277
														Subtotal = $255,277

Issue Date FY: 2014 ( Subtotal = $255,586 )
2014	2014	PENNSYLVANIA STATE UNIVERSITY	110 TECHNOLOGY CENTER BUILDING	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	3	2/25/2014	NON-COMPETING CONTINUATION	$255,586
														Subtotal = $255,586

Issue Date FY: 2013 ( Subtotal = $246,923 )
2013	2013	PENNSYLVANIA STATE UNIVERSITY	110 TECHNOLOGY CENTER BUILDING	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	001	2	6/20/2013	NON-COMPETING CONTINUATION	$16,632
2013	2013	PENNSYLVANIA STATE UNIVERSITY	110 TECHNOLOGY CENTER BUILDING	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	2	2/22/2013	NON-COMPETING CONTINUATION	$230,291
														Subtotal = $246,923

Issue Date FY: 2012 ( Subtotal = $256,155 )
2012	2012	PENNSYLVANIA STATE UNIVERSITY	110 TECHNOLOGY CENTER BUILDING	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	1	3/29/2012	NEW	$256,155
														Subtotal = $256,155

Grand Total All Awards = $2,961,670

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Thermodynamic, Electronic, Structural, and Kinetic Characterizations of Cytochrome P450 Compounds I & II

Award Number: R01GM101390

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: 04/01/2012

PERIOD OF PERFORMANCE END DATE: 03/31/2029

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