Is Glyceraldehyde-3-Phosphate Dehydrogenase a Central Redox Mediator?
D-Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is an immensely important enzyme carrying out a vital step in glycolysis and is found in all living organisms. Although there are several isoforms identified in many species, it is now recognized that cytosolic GAPDH has numerous moonlighting roles and is found in a variety of intracellular locations, but also is associated with external membranes and the extracellular environment. The switch of GAPDH function, from what would be considered as its main metabolic role, to its alternate activities, is often under the influence of redox active compounds. Reactive oxygen species (ROS), such as hydrogen peroxide, along with reactive nitrogen species (RNS), such as nitric oxide, are produced by a variety of mechanisms in cells, including from metabolic processes, with their accumulation in cells being dramatically increased under stress conditions. Overall, such reactive compounds contribute to the redox signaling of the cell. Commonly redox signaling leads to post-translational modification of proteins, often on the thiol groups of cysteine residues. In GAPDH the active site cysteine can be modified in a variety of ways, but of pertinence, can be altered by both ROS and RNS, as well as hydrogen sulfide and glutathione. Other redox modifications are also possible, while some redox-driven GAPDH post-translational modifications (PTMs) may occur through indirect mechanisms. With the abundance of redox mediators targeting GAPDH, and the range of moonlighting activities that might ensue, this enzyme can be considered as being central to ensuring correct redox signaling in cells in a wide range of species.
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