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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)

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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 had 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 is currently 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 play the dominant role in determining reactivity or whether unpaired spin-density on the oxo 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. Our preliminary data show that P450 can fill this void. Innovations, from the last funding period, will allow us use P450 to measure the ground state thermodynamics of C-H bond activation (i.e. D(O-H), E0I, and pKaII), quantify the degree of oxyl-radical character in compound I, and, importantly, track how these quantities (and the reactivity towards C-H bonds) change as a function of electron donation from the axial ligand. The experiments outlined in this proposal will thus use an isoelectronic and isostructural system (cytochrome P450) to determine the importance of tunneling, thermodynamics, oxyl-radical character, and strong axial electron- donation in promoting C-H bond activation. There is currently no other system, synthetic or biological, that allows for a similar set of measurements and discovery. These experiments and others will evaluate our understanding of the electronic and geometric structures of compound I as well as the protective role of P450's axial thiolate ligand. We have proposed that P450's thiolate ligand can decrease the driving force for non- productive oxidations of the protein superstructure, effectively governing the partition between productive and non-productive oxidations, biasing the system towards C-H bond activation. This theory, which depends on the interplay of the one-electron reduction potential of compound I, the pKa of compound II, and the control of proton flow via substrate positioning and enzyme architecture, remains to be verified. Innovations from the last funding period will allow us to test this hypothesis.


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: 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 = $2,322,982

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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)

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