Katrina M Miranda

Katrina M Miranda

Associate Professor, Chemistry and Biochemistry-Sci
Associate Professor, BIO5 Institute
Primary Department
Department Affiliations
Contact
(520) 626-3655

Work Summary

We seek to produce new drugs that harness molecules produced during the natural immune response in order to treat cancer and pain. Such compounds may also provide new treatments for heart failure and alcoholism.

Research Interest

Katrina Miranda, PhD, claims 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 or ONOOH, which have very different 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 ever expanding list of diseases, including cancer, heart failure and stroke. As a whole, Dr. Miranda is interested in elucidating the fundamental molecular redox chemistry of NO and in developing compounds to deliver or scavenge NO and other nitrogen oxides. These 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 five major disciplines. First, she will work on the 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. Second, she will synthesize potential donors or scavengers of NO and other nitrogen oxides. Third, it’s necessary to describe chemical characterization of these compounds (spectroscopic features, kinetics, mechanisms and profiles of nitrogen oxide release, etc.). Fourth, Dr. Miranda will try to describe the biological characterization of these compounds (assay of effects on biological compounds, mechanisms and pathways, in vitro determination of potential for therapeutic utility, etc.). Fifth, she will identify of potential targets, such as enzymes, for treatment of disease through exposure to nitrogen oxide donors. Keywords: cancer treatment, pain treatment

Publications

Miranda, K., Nims, R., Thomasa, D., Espey, M., Citrin, D., Bartberger, M., Paolocci, N., Fukuto, J., Feelisch, M., & Wink, D. (2002). 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. JOURNAL OF INORGANIC BIOCHEMISTRY, 93(1-2), 52-60.

Investigations on the biological effects of nitric oxide (NO) derived from nitric oxide synthase (NOS) have led to an explosion in biomedical research over the last decade. The chemistry of this diatomic radical is key to its biological effects. Recently, nitroxyl (HNO/NO-) has been proposed to be another important constituent of NO biology. However, these redox siblings often exhibit orthogonal behavior in physiological and cellular responses. We therefore explored the chemistry of NO and HNO with heme proteins in different redox states and observed that HNO favors reaction with ferric heme while NO favors ferrous, consistent with previous reports. Further results show that HNO and NO were equally effective in inhibiting cytochrome P450 activity, which involves ferric and ferrous complexes. The differential chemical behavior of NO and HNO toward heme proteins provides insight into mechanisms of activity that not only helps explain some of the opposing effects observed in NOS-mediated events, but offers a unique control mechanism for the biological action of NO. Published by Elsevier Science Inc.