Abstract

This research project involves computational studies of the biologically relevant chemistry of NO and derivatives using state-of-the-art theoretical methods. The principal goals of the research are to answer the following questions: 1. What chemistry occurs when N-hydroxyarginine, an intermediate in NO synthesis by NO synthase, is released from the enzyme? 2. What is the mechanism of decomposition of OONO-, as well as radical and nitration chemistry of this species, upon protonation or reactions with CO2 or ketones. Are the HO ONO and NO2 CO3- radical pairs in water involved? Can the """"""""sticky cage"""""""" account for the peculiar properties which have led to postulation of an excited intermediate HOONO? 3. How are nitrosothiols formed from thiols, and how is NO released? What controls the stabilities of nitrosothiols and how NO, NO-, and NO+ are released or transferred under specific conditions? Can a catalog of rates and thermodynamics of reactions involving NO and its ions be created? Collaborations with experimental groups provide challenging problems and stringent tests of the results of theory.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM059446-02
Application #
6351307
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Schwab, John M
Project Start
2000-02-01
Project End
2003-01-31
Budget Start
2001-02-01
Budget End
2002-01-31
Support Year
2
Fiscal Year
2001
Total Cost
$137,022
Indirect Cost

  Institution

Name
University of California Los Angeles
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095

  Publications

Jackson, Matthew I; Han, Tae H; Serbulea, Laura et al. (2009) Kinetic feasibility of nitroxyl reduction by physiological reductants and biological implications. Free Radic Biol Med 47:1130-9
Gunaydin, Hakan; Houk, K N (2009) Mechanisms of peroxynitrite-mediated nitration of tyrosine. Chem Res Toxicol 22:894-8
Gunaydin, Hakan; Houk, K N (2008) Molecular dynamics simulation of the HOONO decomposition and the HO*/NO2* caged radical pair in water. J Am Chem Soc 130:10036-7
Miranda, Katrina M; Dutton, Andrew S; Ridnour, Lisa A et al. (2005) Mechanism of aerobic decomposition of Angeli's salt (sodium trioxodinitrate) at physiological pH. J Am Chem Soc 127:722-31
Zhao, Yi-Lei; McCarren, Patrick R; Houk, K N et al. (2005) Nitrosonium-catalyzed decomposition of s-nitrosothiols in solution: a theoretical and experimental study. J Am Chem Soc 127:10917-24
Houk, K N; Hietbrink, Bruce N; Bartberger, Michael D et al. (2003) Nitroxyl disulfides, novel intermediates in transnitrosation reactions. J Am Chem Soc 125:6972-6
Cho, Jennifer Y; Dutton, Andrew; Miller, Tom et al. (2003) Oxidation of N-hydroxyguanidines by copper(II): model systems for elucidating the physiological chemistry of the nitric oxide biosynthetic intermediate N-hydroxyl-L-arginine. Arch Biochem Biophys 417:65-76
Bartberger, Michael D; Liu, Wei; Ford, Eleonora et al. (2002) The reduction potential of nitric oxide (NO) and its importance to NO biochemistry. Proc Natl Acad Sci U S A 99:10958-63