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
Yang, Jing; Mogesa, Benjamin; Basu, Partha et al. (2016) Large Ligand Folding Distortion in an Oxomolybdenum Donor-Acceptor Complex. Inorg Chem 55:785-93
Ratvasky, Stephen C; Mogesa, Benjamin; van Stipdonk, Michael J et al. (2016) A mixed valence zinc dithiolene system with spectator metal and reactor ligands. Polyhedron 114:370-377
Basu, Partha; Burgmayer, Sharon J Nieter (2015) Recent developments in the study of molybdoenzyme models. J Biol Inorg Chem 20:373-83
Mogesa, Benjamin; Perera, Eranda; Rhoda, Hannah M et al. (2015) Solution, Solid, and Gas Phase Studies on a Nickel Dithiolene System: Spectator Metal and Reactor Ligand. Inorg Chem 54:7703-16
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
van Stipdonk, Michael J; Basu, Partha; Dille, Sara A et al. (2014) Infrared multiple photon dissociation spectroscopy of a gas-phase oxo-molybdenum complex with 1,2-dithiolene ligands. J Phys Chem A 118:5407-18
Hille, Russ; Hall, James; Basu, Partha (2014) The mononuclear molybdenum enzymes. Chem Rev 114:3963-4038
Deibler, Kristine; Basu, Partha (2013) Continuing issues with Lead: Recent Advances in Detection. Eur J Inorg Chem 2013:1086-1096
Pimkov, Igor V; Nigam, Archana; Venna, Kiran et al. (2013) Dithiolopyranthione Synthesis, Spectroscopy and an Unusual Reactivity with DDQ. J Heterocycl Chem 50:879-886

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