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Metallobiochemistry of Mn/Fe protein cofactors

Award Number: R35GM128852
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: 09/01/2018
PERIOD OF PERFORMANCE END DATE: 03/31/2031

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Metallobiochemistry of Mn/Fe protein cofactors - PROJECT SUMMARY/ABSTRACT The overarching objective of the PI’s research program is to understand how Nature harnesses new types of transition metal active sites within protein environments to carry out challenging chemical transformations, including selectively breaking unreactive carbon-hydrogen bonds using benign oxidants such as O2. This research program will center around investigating the structure and function of the recently discovered heterobimetallic manganese/iron (Mn/Fe) oxidase proteins, establishing the foundations for reactivity in this new paradigm of metalloprotein cofactors. Mn/Fe-containing proteins are prevalent in extremophiles and pathogenic organisms, including pathogenic strains of Chlamydia and Mycobacteria, and it has been suggested that the Mn/Fe active site may provide resistance against reactive nitrogen or oxygen species generated by the host immune system and therefore may serve as a therapeutic target. The proposed studies will probe this hypothesis using the Mn/Fe-containing “R2lox” proteins as a model scaffold, investigating the properties of the Mn/Fe cofactor relative to a traditional Fe/Fe active site. The project will leverage the PI’s expertise in advanced spectroscopies to both apply an array of existing techniques and develop new spectroscopic methods to establish robust relationships between electronic structure, geometry, and chemical reactivity across R2lox mutants and variants, which currently do not exist. The reactivity profile of the R2lox protein will be expanded using targeted changes in the protein scaffold and in the environment around the metallocofactor, which will reveal how the metal centers work in conjunction with the protein scaffold. In parallel, modern biochemical and “omics” techniques will be used together with spectroscopy to identify the biological function of R2lox in Mycobacterium smegmatis, a close relative of Mycobacterium tuberculosis, with the ultimate goal of targeting Mn/Fe proteins such as R2lox in therapeutic development. Finally, another new class of metallocofactor, the nickel-pincer active site of the lactate racemase (LarA) enzymes, will be pursued. These enzymes serve in a metabolic rescue pathway for the microbiome-relevant lactic acid bacteria, such as Lactiplantibacillus plantarum, and are part of a superfamily of proteins that use this otherwise unprecedented nickel-pincer active site. A semisynthetic approach will be employed to investigate the enzymatic mechanism, understand the biosynthetic pathway, and identify interactions with the protein scaffold that dictate substrate specificity. Ultimately, the proposed research program will provide fundamental insight into the structure-function relationships controlling reactivity in two newly discovered classes 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: 2026 ( Subtotal = $377,558 )
2026	2026	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Biomedical Research and Research Training	000	7	3/12/2026	COMPETING CONTINUATION	$377,558
														Subtotal = $377,558

Issue Date FY: 2024 ( Subtotal = $10,003 )
2024	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Biomedical Research and Research Training	005	6	7/19/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2024	2022	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	003	5	3/6/2024	NON-COMPETING CONTINUATION	-$1
2024	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Biomedical Research and Research Training	001	6	1/15/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$392,498
2024	2022	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	000	5	1/9/2024	NON-COMPETING CONTINUATION	-$382,495
2024	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Biomedical Research and Research Training	004	6	3/6/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$373,037
2024	2021	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	002	4	3/6/2024	NON-COMPETING CONTINUATION	-$373,036
														Subtotal = $10,003

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	000	5	10/26/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $382,496 )
2022	2022	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	000	5	8/29/2022	NON-COMPETING CONTINUATION	$382,496
														Subtotal = $382,496

Issue Date FY: 2021 ( Subtotal = $382,496 )
2021	2021	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	000	4	8/10/2021	NON-COMPETING CONTINUATION	$382,496
														Subtotal = $382,496

Issue Date FY: 2020 ( Subtotal = $382,496 )
2020	2020	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	000	3	8/20/2020	NON-COMPETING CONTINUATION	$382,496
														Subtotal = $382,496

Issue Date FY: 2019 ( Subtotal = $382,496 )
2019	2019	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	000	2	7/30/2019	NON-COMPETING CONTINUATION	$382,496
														Subtotal = $382,496

Issue Date FY: 2018 ( Subtotal = $349,198 )
2018	2018	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	000	1	7/27/2018	NEW	$349,198
														Subtotal = $349,198

Grand Total All Awards = $2,266,743

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Metallobiochemistry of Mn/Fe protein cofactors

Award Number: R35GM128852

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: 09/01/2018

PERIOD OF PERFORMANCE END DATE: 03/31/2031

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