Small Molecule Signaling Agents: The Integrated Chemistry and Biochemistry of Nitrogen Oxides, Oxides of Carbon, Dioxygen, Hydrogen Sulfide, and Their Derived Species

Abstract

Several small molecule species formally known primarily as toxic gases have, over the past 20 years, been shown to be endogenously generated signaling molecules. The biological signaling associated with the small molecules NO, CO, H2S (and the nonendogenously generated O2), and their derived species have become a topic of extreme interest. It has become increasingly clear that these small molecule signaling agents form an integrated signaling web that affects/regulates numerous physiological processes. The chemical interactions between these species and each other or biological targets is an important factor in their roles as signaling agents. Thus, a fundamental understanding of the chemistry of these molecules is essential to understanding their biological/physiological utility. This review focuses on this chemistry and attempts to establish the chemical basis for their signaling functions.

Examining the reaction of NO and H 2 S and the possible cross-talk between the two signaling pathways

“…At first glance, it appears that all of these molecules share some important chemical reactivities that may serve as clues to their biological functions (4). Clearly, all these species are capable of coordinating metals, especially ironhemes.…”

Hydrogen sulfide as an oxygen sensor

“…Two-step reduction of a disulfide bond involving two H 2 S (7). Reactions with nitrogenous compounds include an H 2 S reaction with S-nitrosols to produce thionitrous acid (HSNO) (8), an HSNO reaction with excess H 2 S to form HSSNO (SSNO -), which slowly decomposes to nitric oxide (NO), and interaction of H 2 S/HS -and NO as the former is a diamagnetic reductant or nucleophile, whereas NO is a paramagnetic free radical (43,75,86). However, one-electron reduction of H 2 S/HS -to produce the thiyl radical (HS ) or a one-electron oxidized species of NO, such as nitrite (NO 2 -), can react to produce HSNO/SNO - (40).…”

Nitric oxide releasing-dendrimers: an overview

“…Chemical, biological (Fukuto et al, 2012;Toledo, Augusto, 2012) and medical aspects of nitric oxide (NO) have been subject of great interest since the discovery that mammalian cells are able to synthesize it (Palmer, Ashton, Moncada, 1988;Pagliaro, 2003;Pacher, Beckman, Liaudet, 2007). This uncharged diatomic molecule is generated endogenously by three nitric oxide synthases (NOS) enzymes -endothelial NOS, neuronal NOS and inducible NOS -which catalyses the conversion of L-arginine to L-citrulline, yielding NO (Palmer, Ashton, Moncada, 1988;Ignarro, 1990;Zweier et al, 1995;Zhou, Zhu, 2009).…”

“…This uncharged diatomic molecule is generated endogenously by three nitric oxide synthases (NOS) enzymes -endothelial NOS, neuronal NOS and inducible NOS -which catalyses the conversion of L-arginine to L-citrulline, yielding NO (Palmer, Ashton, Moncada, 1988;Ignarro, 1990;Zweier et al, 1995;Zhou, Zhu, 2009). Nitric oxide, a small molecule signaling agent (Fukuto et al, 2012), is associated with many biological processes (Toledo, Augusto, 2012) as vasodilatation (Furchgott, Zawadzki, 1980;Hu et al, 2003;Yetik-Anacak, Catravas, 2006;Pacher, Beckman, Liaudet, 2007), immune response (Bogdan, 2001; Bogdan, Röllinghoff, Diefenbach, 2000;…”

“…NO can be administered in gaseous form (respiratory route) in specific cases (Serafim et al, 2012), but this compound is known to react with a wide number of molecules (proteins, thiols, heme proteins, metals and others) and also can be oxidized in solution to NO 2 by O 2 (Fukuto et al, 2012;Toledo, Augusto, 2012). In addition, the NO lifetime in biological media varies from 10 ms to 1 sec (Thomas et al, 2001;Flores-Santana et al, 2009).…”