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Mechanisms and Control of O2 and C–H Activation within "Privileged" Enzyme Architectures

Award Number: R35GM161700
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: 04/01/2026
PERIOD OF PERFORMANCE END DATE: 03/31/2031

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Mechanisms and Control of O2 and C–H Activation within "Privileged" Enzyme Architectures - Project Summary/Abstract Enzymes that activate dioxygen or (su)peroxide at transition metal cofactors to cleave strong X– H bonds (X = C/N/O) are prevalent in central and specialized metabolic pathways in organisms from all three domains of life. Their abilities to generate highly reactive carbon and heteroatom radicals and direct them down specific reaction pathways bestow a chemical versatility that inspires admiration and mimicry among synthetic chemists. Within several highly represented (privileged) protein architectures, Nature has evolved diverse reactivities from nearly identical cofactors and common reactivities from structurally distinct cofactors, including cofactors made up of different metal ions. The three classes of metalloenzymes under study in the proposed program exemplify these phenomena. Iron(II) and 2-oxoglutarate-dependent (Fe/2OG) oxygenases (Project 1) use a common iron(II) cofactor and oxoiron(IV) intermediate to promote hydroxylation, halogenation, desaturation, chain/ring-expansion, and cyclization reactions. Heme- oxygenase like diiron enzymes (HDOs) (Project 2) use unstable diiron(II) clusters that are (dis)assembled in concert with profound protein conformational changes to form µ- (hydro)peroxodiiron(III) intermediates that cleave strong X–H bonds to initiate N-oxygenation and complex fragmentation reactions. Class I ribonucleotide reductases (RNRs) (Project 3) use diverse diiron, manganese/iron, dimanganese, or flavin cofactors to form protein radicals that initiate – again, by cleaving a C–H bond – the common reduction reaction that provides all organisms with DNA precursors. The proposed program aims to use biochemical, biophysical and computational methods to understand (1) how largely conserved protein scaffolds can initiate different reactivities from similar cofactors or a common outcome from diverse cofactors and (2) how these diverse outcomes and cofactor usage have evolved. The emerging understanding will be tested in experiments aiming either to rationally redirect reactions to different outcomes (Projects 1 and 2) or to alter cofactor usage (Project 3) and will ultimately be useful in formulating directed evolution of new-to-nature reactivities.


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 = $750,554 )
2026	2026	THE PENNSYLVANIA STATE UNIVERSITY	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	1	3/26/2026	NEW	$750,554
														Subtotal = $750,554

Grand Total All Awards = $750,554

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Mechanisms and Control of O2 and C–H Activation within "Privileged" Enzyme Architectures

Award Number: R35GM161700

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: 04/01/2026

PERIOD OF PERFORMANCE END DATE: 03/31/2031

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