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Change of Institution: The Influence of Cysteinate Protonation in Nickel Containing Metalloenzymes

Award Number: R15GM120641
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. Cysteinate ligated nickel metalloenzymes are found in a number of pathogenic bacteria. Some of these nickel containing metalloenzymes, such as nickel-iron hydrogenase ([NiFe]H2ase) found in Helicobacter pylori, are found in microbes responsible for human diseases. At least two nickel containing metalloenzymes, nickel containing superoxide dismutase (NiSOD) and [NiFe]H2ase, possess a coordinated protonated cysteinate residue (Ni-S(H+)-Cys). We suspect that the Ni-S(H+)-Cys bond is involved in the enzymatic mechanism and also modulates the electronic structure and reactivity of these metalloenzymes. Our research will take advantage of functional metalloenzyme based mimics of NiSOD and small molecule mimics of [NiFe]H2ase. Metallopeptide based mimics of NiSOD that my group has prepared to date reproduce the structure and physical properties of the metalloenzyme. These metallopeptides are also catalytically active, effecting O2– disproportionation with rate constants approaching those observed in the metalloenzyme. Recent work by my group has demonstrated that these mimics facilitate O2– reduction to H2O2 via a unique proton coupled electron transfer (PCET) reaction from a Ni-S(H+)-Cys moiety to O2–. We will probe this reaction by preparing derivatives of these metallopeptides that will alter the fundamental nature of the PCET reaction. This will yield insight into the general scope of PCET reactions facilitated by such moieties. In addition, we will prepare metallopeptide based NiSOD mimics that more accurately replicate the enzymatic reaction mechanism. Preliminary work demonstrates that the mechanism of O2– reduction effected by the metallopeptide is distinct from NiSOD itself. By producing mimics that reproduce enzymatic reactivity we will gain a better understanding of the mechanism of O2– disproportionation effected by NiSOD itself. Also, we will investigate the inﬂuence of the Ni-S(H+)-Cys moiety on [NiFe]H2ase model compounds. We propose that the protonation of the coordinated cysteinate ligand is dramatically altering the electronic structure of the Ni-center in [NiFe]-H2ase; speciﬁcally it is reducing the hydricity of the mechanistically important Ni(III)-H intermediate biasing [NiFe]H2ase to perform H2 oxidation chemistry. This supposition will also be probed under this initiative. This research runs the gamut of tools utilized in bioinorganic chemistry. As with many of our studies synthetic, biochemical, spectroscopic, mechanistic, and computational studies will be brought to bear on understanding all aspects of the metallopeptides and small molecule mimics. 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 biologically important Ni-S(H+)-Cys moieties, but will also push 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: 2021 ( Subtotal = $0 )
2021	2016	TRINITY UNIVERSITY	ONE TRINITY PL	SAN ANTONIO	TX	78212	BEXAR	USA	Biomedical Research and Research Training	000	2	5/30/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2016	TRINITY UNIVERSITY	ONE TRINITY PL	SAN ANTONIO	TX	78212	BEXAR	USA	Biomedical Research and Research Training	000	2	8/17/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = -$10,007 )
2019	2016	NEVADA SYSTEM OF HIGHER EDUCATION	1664 N VIRGINIA ST	RENO	NV	89557	WASHOE	USA	Biomedical Research and Research Training	002	1	3/25/2019	NEW	-$2
2019	2016	NEVADA SYSTEM OF HIGHER EDUCATION	1664 N VIRGINIA ST	RENO	NV	89557	WASHOE	USA	Biomedical Research and Research Training	000	1	3/19/2019	NEW	-$202,630
2019	2016	TRINITY UNIVERSITY	ONE TRINITY PL	SAN ANTONIO	TX	78212	BEXAR	USA	Biomedical Research and Research Training	003	2	3/25/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$2
2019	2016	TRINITY UNIVERSITY	ONE TRINITY PL	SAN ANTONIO	TX	78212	BEXAR	USA	Biomedical Research and Research Training	001	2	3/20/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$192,623
														Subtotal = -$10,007

Issue Date FY: 2016 ( Subtotal = $424,240 )
2016	2016	UNIVERSITY OF NEVADA-RENO	**	RENO	NV	89557	WASHOE	USA	Biomedical Research and Research Training	000	1	8/17/2016	NEW	$424,240
														Subtotal = $424,240

Grand Total All Awards = $414,233

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Change of Institution: The Influence of Cysteinate Protonation in Nickel Containing Metalloenzymes

Award Number: R15GM120641

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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