. 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 in?uence 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; speci?cally 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 speci?c 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.

Public Health Relevance

. Under this initiative we will probe the properties and reactivity of the protonated, coordinated Ni-S(H+)-Cys moiety, which we suspect is vital to the function of several nickel containing metalloenzymes. There are no known Ni-containing mammalian metalloenzymes, however, many pathogenic bacteria contain enzymes requiring a nickel co-factor. Successful completion of the proposal will therefore lead to an understanding of this unique structural element, and possibly lead to new therapeutic strategies for certain pathogenic bacteria.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
7R15GM120641-02
Application #
9825169
Study Section
Macromolecular Structure and Function A Study Section (MSFA)
Program Officer
Anderson, Vernon
Project Start
2016-09-01
Project End
2019-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Trinity University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
008133456
City
San Antonio
State
TX
Country
United States
Zip Code
78212
Wang, Bin; Lee, Yong-Min; Tcho, Woon-Young et al. (2017) Synthesis and reactivity of a mononuclear non-haem cobalt(IV)-oxo complex. Nat Commun 8:14839
Gautam, Ritika; Astashkin, Andrei V; Chang, Tsuhen M et al. (2017) Interactions of Metal-Based and Ligand-Based Electronic Spins in Neutral Tripyrrindione ? Dimers. Inorg Chem 56:6755-6762