Role of Nitric Oxide in GAPDH Bacterial Virulence
Nitric oxide (NO) is, simultaneously, the quintessential inter- and intracellular signaling molecule, an immunoprotective defense mechanism as well as a toxic agent capable of causing cell damage and inducing apoptosis. Initially isolated as endothelium-derived relaxing factor (Furchgott 1999), its characterization
Figure 8.3 GAPDH and nitric oxide: multipotential effects.
revealed fundamental mechanisms of cell information transfer through a complex series of biochemical pathways. Its induction by macrophage nitric oxide synthetases as a function of infection represents one of the earliest cellular responses to virulent pathogens. Lastly, its reaction with molecular oxygen results in the production of peroxynitrite, one of the most potent cellular damaging agents, and its role in the Fenton reaction results in the production of reactive oxygen species.
As illustrated in Figure 8.3, GAPDH may be a unique intracellular target for NO. GAPDH is nitrosylated at its active site cysteine (GAPDHcysNO). Apart from inhibition of catalytic activity, formation of GAPDHcysNO results in a complex series of cellular events (Sirover 2011, 2012, 2014). These include the induction of apoptosis, the regulation of gene expression (both through transcriptional and post-translational mechanisms), the control of heme synthesis through Fe++ metabolism, and, intriguingly, the ability of GAPDHcys-NO to act as a transnitros- ylase, transferring its nitroso group to acceptor proteins. Significantly, several of these functions require the dynamic movement of GAPDHcys-NO from one subcellular locale to another (Sirover 2012; Tristan et al. 2012). En toto, these cumulative findings indicate the significance of GAPDHcys-NO formation as the production of this single, “simple” molecule results in a series of pleiotropic changes in cell and organism function.