The broad, long-term objectives of the proposed research are to understand geometric and electronic structure contributions to the function of pyranopterin molybdenum enzymes, with particular relevance to understanding the mechanism of activity in xanthine oxidase, aldehyde oxidase and sulfite oxidase as these are key enzymes found in humans.
The specific aims of the proposed research plan are to 1) develop a comprehensive understanding of the reductive half-reaction in xanthine oxidase (XO), 2) use small molecule analogues of the XO related carbon monoxide dehydrogenase (CODH) active site to understand electronic structure contributions to catalysis, 3) correlate electronic and geometric structure contributions to oxygen atom and electron transfer reactivity in sulfite oxidase (SO), and 4) determine how the DMSO reductase site symmetry contributes to enzymatic catalysis. Individuals suffering from molybdenum cofactor deficiency display severe neurological symptoms and early childhood death. The physiological function of XO appears to be quite complex, and is exemplified by the fact that XO has recently been suggested to play a central role in the function of the innate immune system, and in postischemic reperfusion injury. Both AO and XO have recently been implicated in pro-drug activation, drug metabolism and, under specific conditions, NO synthase activity. Compared to XO, very little is known concerning the full pathophysiological relevance of AO. However, AO catalyzes the reduction of sulfa drugs, the activation of anticancer prodrugs, and has recently been shown to metabolize famciclovir to the potent antiviral penciclovir, which has been found to be effective against such viral infections as herpes simplex, varicella zoster, Epstein-Barr, and hepatitis B. In vertebrates, SO is found in the mitochondria! intermembrane space where the physiologically important oxidation of sulfite represents the terminal step in the oxidative degradation of cysteine and methionine. The research plan will utilize a combined spectroscopic approach, complimented by computational studies, on both models and enzymes to develop a detailed electronic structure description of the active site and how this electronic structure contributes to their mechanism of activity. Molybdenum enzymes are of key importance to human health. Our emerging understanding of their role in drug metabolism, free-radical damage, and the immune system underscore their role in a variety of health related issues.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM057378-12
Application #
7768453
Study Section
Macromolecular Structure and Function A Study Section (MSFA)
Program Officer
Fabian, Miles
Project Start
1998-06-01
Project End
2011-07-31
Budget Start
2010-01-01
Budget End
2011-07-31
Support Year
12
Fiscal Year
2010
Total Cost
$290,902
Indirect Cost
Name
University of New Mexico
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
868853094
City
Albuquerque
State
NM
Country
United States
Zip Code
87131
Yang, Jing; Dong, Chao; Kirk, Martin L (2017) Xanthine oxidase-product complexes probe the importance of substrate/product orientation along the reaction coordinate. Dalton Trans 46:13242-13250
Sugimoto, Hideki; Sato, Masanori; Asano, Kaori et al. (2016) A Model for the Active-Site Formation Process in DMSO Reductase Family Molybdenum Enzymes Involving Oxido-Alcoholato and Oxido-Thiolato Molybdenum(VI) Core Structures. Inorg Chem 55:1542-50
Yang, Jing; Mogesa, Benjamin; Basu, Partha et al. (2016) Large Ligand Folding Distortion in an Oxomolybdenum Donor-Acceptor Complex. Inorg Chem 55:785-93
Stein, Benjamin W; Kirk, Martin L (2015) Electronic structure contributions to reactivity in xanthine oxidase family enzymes. J Biol Inorg Chem 20:183-94
Brines, Lisa M; Coggins, Michael K; Poon, Penny Chaau Yan et al. (2015) Water-soluble Fe(II)-H2O complex with a weak O-H bond transfers a hydrogen atom via an observable monomeric Fe(III)-OH. J Am Chem Soc 137:2253-64
Yang, Jing; Giles, Logan J; Ruppelt, Christian et al. (2015) Oxyl and hydroxyl radical transfer in mitochondrial amidoxime reducing component-catalyzed nitrite reduction. J Am Chem Soc 137:5276-9
Stein, Benjamin W; Kirk, Martin L (2014) Orbital contributions to CO oxidation in Mo-Cu carbon monoxide dehydrogenase. Chem Commun (Camb) 50:1104-6
Giles, Logan J; Ruppelt, Christian; Yang, Jing et al. (2014) Molybdenum site structure of MOSC family proteins. Inorg Chem 53:9460-2
Dong, Chao; Yang, Jing; Leimk├╝hler, Silke et al. (2014) Pyranopterin dithiolene distortions relevant to electron transfer in xanthine oxidase/dehydrogenase. Inorg Chem 53:7077-9
Cutsail 3rd, George E; Stein, Benjamin W; Subedi, Deepak et al. (2014) EPR, ENDOR, and electronic structure studies of the Jahn-Teller distortion in an Fe(V) nitride. J Am Chem Soc 136:12323-36

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