Modeling Bioinorganic Nitric Oxide Signaling Chemistry
Warren, Tim H
Nitrite (NO2-) is an important reservoir of nitric oxide (NO), which participates in a wide range of physiological activities such as neurotransmission, vasodilation, and immune response. Nitrite represents a tightly regulated and important circulating reservoir for NO in biological systems. Here, we attempt to identify and mechanistically study new anaerobic pathways by which copper sites can activate NO and NO2- to generate oxidants capable of modifying a range of biologically relevant substrates.Chapter 1 aims to provide a detailed overview of the different species involved in the chemistry of NO signaling as well as how transition metals play a key role in the biological activity of nitrite- and NO-related enzymes. Model complexes are one of the most powerful tools that are used to better understand the chemistry behind metalloproteins, therefore, the most important synthetic small molecules that help us to have a better handle on nitrite and NO will be discussed.While copper containing enzymes are known to reduce nitrite to nitric oxide, in Chapter 2, we report a new pathway to release nitric oxide via oxygen atom transfer (OAT) from nitrite at a copper(II) site. In this chapter, employing -diketiminato copper(II) nitrites [CuII](2-O2N), we mechanistically outline the O-atom transfer (OAT) from nitrite to electron-rich substrates that generates nitric oxide. This study reveals a new pathway that could be operative in nitrosative and oxidative stress under hypoxic conditions to ensure NO generation is not impaired due to lack of bioavailable oxygen.In Chapter 3, reaction of the -diketiminato model complex [Cl2NNF6]Cu(2-O2N) with phenols outlines the coupled generation of NO with phenol oxidation by nitrite at copper(II). Kinetic studies support nucleophilic attack of the hydroxyl group of phenols ArOH on the bound nitrite in [CuII](2-O2N) to give the copper(II) hydroxide [CuII]-OH along with the O-nitrosated phenol ArONO that ultimately leads to the corresponding biphenol or o-nitrophenol. The especially electron-rich antioxidant -tocapherol (vitamin E) quickly generates NO upon interaction with [CuII](2-O2N). X-ray analysis of the oxidation products of the -tocapherol analogue PMC reveal formation of an elusive O-quinone methide bound to [CuI], revealing two-electron oxidation of PMC by [CuII](2-O2N). These studies illustrate anaerobic pathways that generate NO from nitrite at copper(II) sites that result in phenol oxidation.
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Williams, Kamille D. (Georgetown University, 2016)The N-O functionality is ubiquitous endogenously. The wide range of oxidation states of the nitrogen atom, (+5 to -3), is attributed to the various biologically relevant congeners containing the NO functionality. The ...