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Metallopeptide Based Mimics of Mononuclear Nonheme Iron Enzymes: Understanding Enzymatic Reactivity Using Designed Metallopeptides

Award Number: R15GM141650
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: 04/01/2021
PERIOD OF PERFORMANCE END DATE: 03/31/2025

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Metallopeptide Based Mimics of Mononuclear Nonheme Iron Enzymes: Understanding Enzymatic Reactivity Using Designed Metallopeptides - Project Abstract. Mononuclear nonheme iron (mnhFe) enzymes perform an array of chemically diverse reactions that are vital to many different aspects of human health including: antibiotic biosynthesis, production of key metabolites, and DNA repair. Thus, the misregulation and dysfunction of mnhFe enzymes have been implicated in a number of disorders including neurodegeneration, cancers, diabetes, and cardiovascular diseases. A large class of mnhFe enzymes contains a reduced Fe(II) ion that activates dioxygen, forming a highly reactive FeIII-O2– species. Once formed, this FeIII-O2– intermediate can promote a large number of different reactions leading to an enormous diversity in chemical reactivity. Despite the surprising similarities in active-site (and sometimes substrate) structures, each enzyme promotes a highly specific reaction and yields a highly specific product. The factors leading to such high reaction specificity from these similar active-site structures are not fully understood. The overarching goal of the work proposed herein is to understand how the FeIII-O2– intermediate in two mnhFe enzymes, cysteine dioxygenase (CDO) and isopenicillin-N-synthase (IPNS), can selectively promote two vastly different reactions on structurally similar substrates: sulfur oxygenation (CDO) vs C-H atom abstraction (IPNS). Both CDO and IPNS modify a thiol-containing substrate once it is coordinated to the iron-center. We hypothesize that the differential reactivity in these two enzymes is promoted by the orientation of the nominal S(3p)-type orbital of the coordinated substrate, which will turn on or off a thermodynamically favored S-based oxygenation reaction. To explore this hypothesis, we will prepare a library of structurally related metallopeptides that will promote either CDO- or IPNS-like chemistries. The major difference between these peptides will be the orientation of the S(3p)-type orbital relative to the vector of attack of the superoxo ligand of the FeIII-O2– intermediate. Because the geometric and electronic structures of these peptides will all be nearly identical, all differences in reactivity will be attributable to the S(3p) orbital orientation. This research makes use of a large number of tools encountered in bioinorganic chemistry, thus providing an excellent training platform for undergraduate researchers. In addition to biomimietic metallopeptide design and synthesis, these systems will be subjected to mechanistic, spectroscopic (electronic absorption, EPR, (M)CD, X-ray absorption, vibrational and Mössbauer spectroscopies), and high-level computational studies. The use of metalloenzyme mimics in our investigations is especially noteworthy; few studies have been performed where insight into specific biochemical processes are revealed through metallopeptide based metalloenzyme mimics. Therefore, completion of this project will not only reveal interesting aspects of mnhFe biochemistry, but will also expand the limits of investigations concerning metallopeptide based metalloenzyme mimics.


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 = -$2,048 )
2025	2021	TRINITY UNIVERSITY	1 TRINITY PL	SAN ANTONIO	TX	78212	BEXAR	USA	Biomedical Research and Research Training	000	1	7/2/2025	NEW	-$2,048
														Subtotal = -$2,048

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	TRINITY UNIVERSITY	1 TRINITY PL	SAN ANTONIO	TX	78212	BEXAR	USA	Biomedical Research and Research Training	001	1	2/29/2024	SUPPLEMENT FOR EXPANSION	$0
2024	2021	TRINITY UNIVERSITY	1 TRINITY PL	SAN ANTONIO	TX	78212	BEXAR	USA	Biomedical Research and Research Training	000	1	2/29/2024	NEW	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $95,867 )
2023	2023	TRINITY UNIVERSITY	1 TRINITY PL	SAN ANTONIO	TX	78212	BEXAR	USA	Biomedical Research and Research Training	000	1	5/19/2023	SUPPLEMENT FOR EXPANSION	$95,867
														Subtotal = $95,867

Issue Date FY: 2021 ( Subtotal = $394,366 )
2021	2021	TRINITY UNIVERSITY	ONE TRINITY PL	SAN ANTONIO	TX	78212	BEXAR	USA	Biomedical Research and Research Training	000	1	3/11/2021	NEW	$394,366
														Subtotal = $394,366

Grand Total All Awards = $488,185

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Metallopeptide Based Mimics of Mononuclear Nonheme Iron Enzymes: Understanding Enzymatic Reactivity Using Designed Metallopeptides

Award Number: R15GM141650

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: 04/01/2021

PERIOD OF PERFORMANCE END DATE: 03/31/2025

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