|Chemical Biology of Nitrogen Oxides; New Detection Techniques and Donors of Nitrogen Oxides;
Nitric oxide (NO), which is synthesized in the body via enzymatic
oxidation of L-arginine, is critical to numerous
physiological functions but also can contribute to the severity of
diseases such as cancer or pathophysiological conditions such as
stroke. This diversity in the responses to NO biosynthesis is a
reflection of the diverse chemistry of NO. For instance NO can alter
the function of enzymes by binding to metal centers. This type of
interaction could result in outcomes as disparate as control of blood
pressure or death of an invading bacterium. NO can also be readily
converted to higher nitrogen oxides such as N2O3,
NO2 or ONOOH, which have discrete chemical and biological
properties. The ultimate result will depend upon numerous factors,
particularly the location and concentration of NO produced.
Therefore, site-specific modulation of NO concentration offers
intriguing therapeutic possibilities for an expanding list of
The overall goal of my research is to provide pharmacological
therapies for diseases such as cancer, heart failure and stroke.
Accomplishing this goal requires both the development of compounds to
deliver NO and other nitrogen oxides and a full understanding of the
biological consequences of nitrogen oxide production by these
compounds. To this end, we are currently engaged in the
investigation of the reactivity of nitrogen oxides at the molecular,
biomolecular, systemic and whole organism levels.
Our current projects are designed to answer questions of potential
medical importance through a multi-disciplinary approach, including
analytical, synthetic, inorganic and biochemical techniques. The
project categories include:
1. development and utilization of analytical techniques for detection
and measurement of NO and other nitrogen oxides as well as the
resultant chemistry of these species
2. synthesis of potential donors of NO and other nitrogen oxides
3. chemical characterization of these compounds (spectroscopic
features, kinetics, mechanisms and profiles of nitrogen oxide
4. biological characterization of these compounds (assay of effects
on biological compounds, mechanisms and pathways, in vitro
determination of potential for therapeutic utility, etc.)
5. identification of potential targets, such as enzymes, for
treatment of disease through exposure to nitrogen oxide donors
D.J. Salmon, C.L. Torres de Holding, L. Thomas, K.V. Peterson, G.P. Goodman, J.E. Saavedra, A.Srinivansan, K.M. Davies, L.K. Keefer, K.M. Miranda. "HNO and NO release from a primary amine-based diazeniumdiolate as a function of PH." Inorg. Chem., 50, 3262-3270 (2011).
D. Andrei, D.J. Salmon, S. Donzelli, A. Wahab, J.R. Klose, M.L. Cintro, J.E. Saavedra, D.A. Wink, K.M. Miranda, L.K. Keefer. "Dual mechanisms of HNO generation by a nitroxyl prodrug of the diazeniumdiolate (NONOate) class." J. Am. Chem. Soc., 132, 16526-16532 (2010).
M.R. Kumar, J.M. Fukuto, K.M. Miranda, P.J. Farmer. "Reactions of HNO with heme proteins: new routes to HNO-heme complexes and insight into physiological effects." Inorg. Chem., 49, 6283-6292 (2010).
T.W. Miller, M.E. Cherney, N.Franco, P.J. Farmer, S.B. King, A.J. Hobbs, K.M. Miranda, J.N. Burstyn, J.M. Fukuto. "The effects of nitroxyl (HNO) on soluble guanylate cyclase activity: interactions at ferrous heme and cysteine thiols." J. Biol. Chem, 284, 21788-21796 (2009).
S. Donzelli, M.G. Espey, W. Flores-Santana, C.H. Switzer, G.C. Yeh, J. Huang, D. Stuehr, S.B. King, K.M. Miranda, D.A. Wink. "Generation of nitroxyl by heme protein-mediated peroxidation of hydroxylamine but not N-hydroxy-L-arginine." Free Radic. Biol. Med., 45, 578-584 (2008).
A.S. Dutton, C.P. Suhrada, K.M. Miranda, D.A. Wink, J.M. Fukuto, K.N. Houlk. "Mechanism of pH dependent decomposition of monoalkylamine diazeniumdiolates to form HNO and NO, deduced from Density Functional Theory and CBS-QB3 calculations." Inorg. Chem., 45, 2448-2456 (2006).
S. Donzelli, M.G. Espey, D.D. Thomas, D. Mancardi, C.G. Tocchetti, L.A. Ridnour, N. Paolocci, S.B. King, K.M. Miranda, G. Lazzarino, J.M. Fukuto, D.A. Wink. "Discriminating formation of HNO from other reactive nitrogen oxide species." Free Radic. Biol. Med., 40, 1056-1066 (2006).
K.M. Miranda, T. Katori, C.L. Torres de Holding, L. Thomas, L.A. Ridnour, W.J. McLendon, A.S. Dutton, H.C. Champion, D. Mancardi, C.G. Tocchetti, J. Saavedra, L.K. Keefer, K.N. Houk, J.M. Fukuto, D.A. Kass, N. Paolocci, D.A. Wink. "Comparison of the NO and HNO donating properties of diazeniumdiaolates. Primary amine adducts release HNO in vivo." J. Med. Chem., 48, 8220-8228 (2005).
K.M. Miranda, H. Nagasawa, J. Toscano. "Donors of HNO." Curr. Topics Med. Chem., 5, 649-664 (2005).
K.M. Miranda, A.S. Dutton, L.A. Ridnour, C.A. Foreman, E. Ford, N. Paolocci, T. Katori, D. Mancardi, D.D. Thomas, M.G. Espey, K.N. Houk, J.M. Fukuto, D.A. Wink. "Mechanism of aerobic decomposition of Angeli's salt at physiological pH." J. Am. Chem. Soc., 127, 722-731 (2005).
K.M. Miranda. "The chemistry of niroxyl (HNO) and implications in biology." Coordin. Chem. Rev., 249, 433-455 (2005).
K.M. Miranda, N. Paolocci, T. Katori, D.D. Thomas, M.D. Bartberger, M.G. Espey, D.A. Kass, M. Feelisch, J.M. Fukuto, D.A. Wink. "A biochemical rationale for the orthogonal behavior of nitroxyl and nitric oxide in the cardiovascular system." Proc. Natl. Acad. Sci. USA, 100, 9196-9201 (2003).
N. Paolocci, T. Katori, H.C. Champion, M.E. St. John, K.M. Miranda, J.M. Fukuto, D.A. Wink, D.A. Kass. "Positive inotropic and lusitropic effects of HNO/NO in failing hearts; independence from ß-adrenergic signaling." Proc. Natl. Acad. Sci. USA, 100, 5537-5542 (2003).
K.M. Miranda, R.W. Nims, D.D. Thomas, M.G. Espey, D. Citrin, M.D. Bartberger, N. Paolocci, J.M. Fukuto, M. Feelisch, A. Wink. "Comparison of the reactivity of nitric oxide and nitroxyl with heme proteins. A chemical discussion of the differential biological effects of these redox related products of NOS." J. Inorg. Biochem., 93, 52-60 (2003).
N. Paolocci, W.F. Saavedra, K.M. Miranda, C. Martignani, T. Isoda, J.M. Hare, M.G. Espey, J.M. Fukuto, M. Feelisch, D.A. Wink, D.A. Kass. "Nitroxyl anion exerts redox-sensitive positive cardiac inotropy in vivo by calcitonin gene related peptide signaling." Proc. Natl. Acad. Sci. USA, 98, 10463-10468 (2001).
K.M. Miranda, M.G. Espey, D.A. Wink. "A rapid, simple spectrophotometric method for detection of nitrate and nitrite." Nitric Oxide, 5, 96-71 (2001), cover feature.