The broad purpose of the research in this proposal is to determine the fundamental relationships between the structures of active sites in metalloproteins and function. A bio-inspired synthetic approach is utilized that incorporates structural components found in active sites, specifically those that control the microenvironment (secondary coordination sphere) surrounding metal ion(s). Organic compounds are being developed which create rigid structures around a bound metal ion, forming specific microenvironments that emulate motifs found within protein active sites. Regulation is achieved via non- covalent interactions (e.g., hydrogen bonds) that are strategically placed proximal to the metal ions to affect function;in particular the binding and activation of dioxygen, which are processes directly linked to the maintenance of human health and aging. These synthetic systems allow for the stabilization of high-energy transients that are often proposed, but rarely observed, in non-heme metalloenzymes: their detection provides new avenues to explore mechanistic aspects of these biological essential reactions. Long-term goals include developing structure function relationships in metal-assisted oxidative catalysis. Metalloproteins perform functions not yet achieved in synthetic systems. Our hypothesis is that the lack of control of the secondary coordination sphere in synthetic compounds is a major obstacle to desired functions. Results from structural biology show that non-covalent interactions within the secondary coordination spheres of metalloproteins are instrumental in regulating function. Therefore the function and dysfunction of health-related metalloproteins can be understood in the context of changes in their microenvironments. It is still unclear, even in biomolecules, how non-covalent interactions are able to influence metal-mediated processes. Investigations into these effects require basic reactivity and mechanistic studies in which the effects of single components can be analyzed individually. We have developed synthetic systems whereby site-specific modulations in structure can be readily accomplished, in order to establish correlations with function, these types of studies will lead to fundamental mechanistic insights into biochemical processes. Ultimately, this research will provide insights into the properties of biological catalysts and lead to new classes of synthetic catalysts that incorporate the exquisite control of reactivity characteristic of metalloenzymes.

Public Health Relevance

Dioxygen binding and activation by metalloproteins are processes linked directly to the maintenance of human health and aging. The protein-induced microenvironments surrounding the active metal center(s) are instrumental in regulating these functions;therefore the function and dysfunction of health-related metalloproteins can be understood in the context of changes in their microenvironments. Non-covalent interactions, including hydrogen bonds, are acknowledged as the major forces that control microenvironmental effects, but it is still unclear how they are able to influence metal-mediated processes;thus these effects require basic reactivity and mechanistic studies in which the effects of single components can be analyzed individually as described in this research.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM050781-20
Application #
8258160
Study Section
Macromolecular Structure and Function E Study Section (MSFE)
Program Officer
Anderson, Vernon
Project Start
1994-04-01
Project End
2015-12-31
Budget Start
2012-01-15
Budget End
2012-12-31
Support Year
20
Fiscal Year
2012
Total Cost
$277,868
Indirect Cost
$77,868
Name
University of California Irvine
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Cook, Sarah A; Ziller, Joseph W; Borovik, A S (2014) Iron(II) complexes supported by sulfonamido tripodal ligands: endogenous versus exogenous substrate oxidation. Inorg Chem 53:11029-35
Sickerman, Nathaniel S; Peterson, Sonja M; Ziller, Joseph W et al. (2014) Synthesis, structure and reactivity of Fe(II/III)-NH3 complexes bearing a tripodal sulfonamido ligand. Chem Commun (Camb) 50:2515-7
Usharani, Dandamudi; Lacy, David C; Borovik, A S et al. (2013) Dichotomous hydrogen atom transfer vs proton-coupled electron transfer during activation of X-H bonds (X = C, N, O) by nonheme iron-oxo complexes of variable basicity. J Am Chem Soc 135:17090-104
Park, Young Jun; Cook, Sarah A; Sickerman, Nathaniel S et al. (2013) Heterobimetallic Complexes with M(III)-(*-OH)-M(II) Cores (M(III) = Fe, Mn, Ga; M(II) = Ca, Sr, and Ba): Structural, Kinetic, and Redox Properties. Chem Sci 4:717-726
Cook, Sarah A; Borovik, A S (2013) Inorganic chemistry: Deconstructing water oxidation. Nat Chem 5:259-60
Gupta, Rupal; Taguchi, Taketo; Borovik, A S et al. (2013) Characterization of monomeric Mn(II/III/IV)-hydroxo complexes from X- and Q-band dual mode electron paramagnetic resonance (EPR) spectroscopy. Inorg Chem 52:12568-75
Sano, Yohei; Weitz, Andrew C; Ziller, Joseph W et al. (2013) Unsymmetrical bimetallic complexes with M(II)-(*-OH)-M(III) cores (M(II)M(III) = Fe(II)Fe(III), Mn(II)Fe(III), Mn(II)Mn(III)): structural, magnetic, and redox properties. Inorg Chem 52:10229-31
Park, Young Jun; Ziller, Joseph W; Borovik, A S (2011) The effects of redox-inactive metal ions on the activation of dioxygen: isolation and characterization of a heterobimetallic complex containing a Mn(III)-(?-OH)-Ca(II) core. J Am Chem Soc 133:9258-61
Stone, Kari L; Borovik, A S (2009) Lessons from nature: unraveling biological CH bond activation. Curr Opin Chem Biol 13:114-8
Parsell, Trenton H; Yang, Meng-Yin; Borovik, A S (2009) C-H bond cleavage with reductants: re-investigating the reactivity of monomeric Mn(III/IV)-oxo complexes and the role of oxo ligand basicity. J Am Chem Soc 131:2762-3

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