Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH)
As an enzyme, GAPDH plays a central role in glycolysis where it catalyzes the sixth step of glycolysis. The functionally active molecule is a homo tetramer that catalyzes the conversion of glyceraldehyde-3-phosphate in the presence of NAD+ to 1, 3 bisphosphoglycerate and NADH. In addition to its role in glycolysis, it has numerous alternate functions in both prokaryotes and eukaryotes. This protein is present in different intracellular compartments, on the cell surface, and is also secreted into the extracellular milieu. The alternate functions include: vesicular trafficking; cytoskeletal reorganization; apoptosis; transcriptional and posttranscriptional gene regulation; and transferrin iron uptake (Sirover 2011). Some of these moonlighting roles of human GAPDH have been implicated in pathological conditions as diverse as cancer, neurodegenerative disorders, and diabetes and also infectious diseases such as malaria and brucellosis (Sirover 1999). Likewise, GAPDH from many bacterial species has been reported to possess alternate functions that include adhesion, immune evasion, and plasminogen binding (Pancholi and Chhatwal 2003; Maeda etal. 2004; Jin et al. 2005; Terao et al. 2006). GAPDH of both mammalian and bacterial origin have not been found to contain specific secretory sequences; like many other secreted multifunctional glycolytic enzymes, GAPDH is therefore broadly grouped as a “non-classically” secreted protein (Cleves et al. 1996; Nombela et al. 2006). Until recently, very little was known as to how these proteins are secreted. Recent reports now suggest that the alternate localization and multiple functions of mammalian GAPDH may depend upon the presence of specific posttranslational modifications, rather than typical signal sequences (Sirover 2012).