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An Evolvable Metalloenzyme Platform for Stereoselective Radical Biocatalysis

Award Number: R35GM147387
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: 07/01/2022
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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An Evolvable Metalloenzyme Platform for Stereoselective Radical Biocatalysis - Project Summary Despite substantial advancements in small-molecule catalysis, general methods to control the stereoselectivity in radical-mediated transformations remain a formidable challenge facing synthetic chemists. On the other hand, enzymes are known for their ability to exert exquisite control over the stereochemical outcome of the reactions they catalyze. However, the catalytic repertoire of enzymes has been largely limited to their native biochemistry. Using an interdisciplinary approach combining ideas and technologies from organic chemistry, organometallic chemistry, biocatalysis, enzyme engineering and computational modeling, we will reprogram naturally occurring metalloenzymes to catalyze unnatural radical reactions with excellent stereoselectivity. Capitalizing on the innate redox property of metallocofactor present in a plethora of natural metalloproteins, we will develop metalloredox radical biocatalytic reactions with significant synthetic utility. First, we will develop new-to-nature metalloredox atom transfer radical addition reactions that proceed with excellent diastereo- and enantiocontrol. Second, we will advance stereoselective radical additions to aromatic compounds in a metalloenzyme-controlled fashion. Furthermore, enantioselective C-H functionalization reactions involving metalloenzymatically formed nitrogen- centered radicals will be developed. All the three aims are supported by strong preliminary data gathered in our laboratory. Together, these novel metalloredox biocatalytic processes constitute a powerful toolbox for the rapid assembly of diverse bioactive small molecules that are highly valuable in biomedical sciences. Furthermore, the development of new-to-nature catalytic functions will dramatically broaden the biochemical landscape of metalloenzymes.


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 = $363,758 )
2025	2025	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Biomedical Research and Research Training	000	4	4/9/2025	NON-COMPETING CONTINUATION	$363,758
														Subtotal = $363,758

Issue Date FY: 2024 ( Subtotal = $383,192 )
2024	2024	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Biomedical Research and Research Training	000	3	3/27/2024	NON-COMPETING CONTINUATION	$328,363
2024	2024	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Biomedical Research and Research Training	002	3	7/29/2024	NON-COMPETING CONTINUATION	$36,484
2024	2024	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Biomedical Research and Research Training	001	3	4/30/2024	SUPPLEMENT FOR EXPANSION	$18,345
														Subtotal = $383,192

Issue Date FY: 2023 ( Subtotal = $535,839 )
2023	2023	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Biomedical Research and Research Training	000	2	3/27/2023	NON-COMPETING CONTINUATION	$365,876
2023	2023	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Biomedical Research and Research Training	001	2	5/24/2023	SUPPLEMENT FOR EXPANSION	$169,963
														Subtotal = $535,839

Issue Date FY: 2022 ( Subtotal = $367,135 )
2022	2022	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Biomedical Research and Research Training	000	1	6/21/2022	NEW	$367,135
														Subtotal = $367,135

Grand Total All Awards = $1,649,924

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An Evolvable Metalloenzyme Platform for Stereoselective Radical Biocatalysis

Award Number: R35GM147387

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: 07/01/2022

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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