The pterin-containing molybdenum cofactor (Moco) is a remarkable metal center that lies at the catalytic heart of a variety of enzymes. The Moco has the same basic core structure in all mononuclear molybdenum enzymes (MMEs) and is found in all forms of life. The ability of this cofactor to mediate oxygen atom transfer and hydroxylation reactions, has given rise to the diverse family of MMEs. Similarly, constituted, MMEs include dehydrogenases (e.g., formate, ethylbenzene), oxidases (e.g., sulfite, xanthine, arsenite), and reductases (e.g., nitrate, arsenate, selenate). In humans, xanthine oxidase and sulfite oxidase fulfill crucial functions in redox reactions in purine and sulfur metabolism, respectively. Human molybdenum cofactor (MCD) deficiency is a pleiotropic autosomal recessive genetic disorder due to the loss of sulfite oxidase, xanthine oxidase and aldehyde oxidase. Patients show progressive neurological damage with early childhood death resulting in most cases. An experimental treatment with a precursor to the cofactor has shown significant promise in treating this disease for which no commercial treatment is currently available. A fundamental question in biology and medicine is how has the basic unit of Moco been tuned to fulfill the various functions. The ultimate goal of our program is to understand how the different components of Moco contribute to its overall reactivity. To address this goal we have devised three specific aims to synthesize and characterize several organic and inorganic molecules, and propose detailed investigation of their chemistry. Successful completion of this project will help better understand the reactivity of different components of the complex cofactor. In accordance with the guideline of R15 program we will continue to train next generation of scientists.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
3R15GM061555-04A1S1
Application #
8367995
Study Section
Macromolecular Structure and Function A Study Section (MSFA)
Program Officer
Anderson, Vernon
Project Start
2000-07-01
Project End
2014-07-31
Budget Start
2011-08-15
Budget End
2014-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$81,416
Indirect Cost
$29,716
Name
Duquesne University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
004501193
City
Pittsburgh
State
PA
Country
United States
Zip Code
15282
Hille, Russ; Hall, James; Basu, Partha (2014) The mononuclear molybdenum enzymes. Chem Rev 114:3963-4038
Sparacino-Watkins, Courtney E; Tejero, Jesús; Sun, Bin et al. (2014) Nitrite reductase and nitric-oxide synthase activity of the mitochondrial molybdopterin enzymes mARC1 and mARC2. J Biol Chem 289:10345-58
Sparacino-Watkins, Courtney; Stolz, John F; Basu, Partha (2014) Nitrate and periplasmic nitrate reductases. Chem Soc Rev 43:676-706
Pimkov, Igor V; Peterson, Antoinette; Vaccarello, David N et al. (2014) A Regioselective Synthesis of the Dephospho DIthiolene Protected Molybdopterin. RSC Adv 4:19072-19076
Basu, Partha; Kail, Brian W; Adams, Andrew K et al. (2013) Quantitation of the ligand effect in oxo-transfer reactions of dioxo-Mo(VI) trispyrazolyl borate complexes. Dalton Trans 42:3071-81
Basu, Partha; Burgmayer, Sharon J N (2011) Pterin chemistry and its relationship to the molybdenum cofactor. Coord Chem Rev 255:1016-1038
Basu, Partha; Kail, Brian W; Young, Charles G (2010) Influence of the oxygen atom acceptor on the reaction coordinate and mechanism of oxygen atom transfer from the dioxo-Mo(VI) complex, Tp(iPr)MoO(2)(OPh), to tertiary phosphines. Inorg Chem 49:4895-900
Basu, Partha; Nigam, Archana; Mogesa, Benjamin et al. (2010) Synthesis, characterization, spectroscopy, electronic and redox properties of a new nickel dithiolene system. Inorganica Chim Acta 363:2857-2864
Perera, Eranda; Basu, Partha (2009) Synthesis, characterization and structure of a low coordinate desoxomolybdenum cluster stabilized by a dithione ligand. Dalton Trans :5023-8
Hadt, Ryan G; Nemykin, Victor N; Olsen, Joseph G et al. (2009) Comparative calculation of EPR spectral parameters in [Mo(V)OX4]-, [Mo(V)OX5]2-, and [Mo(V)OX4(H2O)]- complexes. Phys Chem Chem Phys 11:10377-84

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