Oxygen-based compounds are an instrumental part of the group of small, relatively reactive molecules which control cellular activities. Traditionally such molecules have been referred to as the reactive oxygen species (ROS) and include hydrogen peroxide (H2O2), superoxide (O2∙−), and hydroxyl radicals (∙OH). However, several other reactive signaling molecules also contain oxygen, although referred to as reactive nitrogen species (RNS). These include nitric oxide (NO) and peroxynitrite (ONOO−), and therefore could be grouped together with the ROS as oxygen-based compounds.
The sequential oxidation of molecule oxygen produces O2∙−, then H2O2, and finally the hydroxyl radical (∙OH) before the four election reduction results in water. Therefore, once the O2∙− anion is formed, a cascade of further products is likely. As discussed below, there are side reactions likely here too. For example, hypochlorous acid can be produced in the presence of the enzyme myeloperoxidase .
H2O2 has been the focus of ROS signaling . One of the ways in which H2O2 is known to alter cell function is by the oxidation of thiol groups in proteins , and such modifications can be analyzed by proteomic techniques . The -SH group is converted to the sulfenic acid group, -SOH. This is in many ways akin to phosphorylation, and like phosphorylation, the formation of the -SOH group is likely to force a conformational change on the proteins and thus alter its activity. This is not necessarily activation. In tyrosine phosphatase, the interaction with H2O2 leads to the formation of a sulfenyl-amide intermediate and inhibition of the enzyme . This means in the cell that the levels of tyrosine phosphorylation are likely to increase, with the concomitant effects that leads to.
NO has been found to be involved in the mediation of a wide range of biological functions, from controlled blood flow in humans , to controlling stomatal apertures in plants . In animals, the main source is NOS. In humans, there are three isoforms of this enzyme: eNOS, iNOS, and nNOS . However, the existence of such an enzyme in plants has been hotly contested and it is unlikely to exist, at least in the form that would be easily recognizable . It is more likely that in plants the main source of NO is the enzyme nitrate reductase (NR) , although as mentioned above there are other sources of NO in biological systems.
A universal mechanism of NO signaling is the modification of protein thiol groups, in what has been dubbed S-nitrosylation . However, this terminology is technically incorrect, and this modification should preferably be called S-nitrosation . Either way, this is the formation of the -SNO group, and like the formation of -SOH by H2O2, this formation of -SNO causes a conformational change on the protein and therefore a modulation of its activity or function. As this is a reversable reaction it is again akin to phosphorylation. However, the thiols are also able to be oxidized, as discussed, so there is likely to be competition for the thiol between the oxidation by ROS and nitrosation by NO. Furthermore, the same thiols may be under attack by H2S, in S-sulfhydration , as well as being able to be glutathionylated . Which thiol modification actually results depends on the environment of the thiol and the relative concentrations of the molecule trying to attack it. As many of these reactions are reversible, the whole system is likely to be very dynamic, allowing different modifications happening with time and in different locations.
Proteins can also be nitrated on tyrosine. Therefore, NO can mediate the modification of polypeptides in more than one manner , and such changes are not mutually exclusive.
Last, NO can partake in some direct reactions with other important redox molecules. One of the most significant is the generation of S-nitrosoglutathione (GSNO). This not only removes glutathione from its important role as a redox mediator, especially in ROS metabolism, as discussed above , but it also creates a new signaling molecule. It has been suggested that GSNO is a buffer for NO, GSNO formation being reversed by S-nitrosoglutathione reductase (GSNOR) , but it may also be able to be moved around an organism in the vasculature , so allowing long-range NO signaling. NO can also react with H2S in the formation of nitrosothiol, which can act as a signal as well .
In a similar manner to ROS and RNS, CO is inherently toxic . It can inhibit the activity of Complex IV of the mitochondrial ETC, for example. Even so, as it can inherently interact with metal containing proteins, it is known to modulate the activities of several enzymes, and this can lead to changes to the accumulation of ROS and NO. It can also alter cGMP levels, an instrumental intracellular signaling molecule. Furthermore, CO effects can be mediated by MAPK pathways and by changes in the activity of ion channels . One of the mechanisms of action of H2 is thought to be mediated by heme oxygenase , which would then impinge on CO signaling.