Glyceraldehyde-3-phosphate dehydrogenase

[C@2H]([OH])([C@2H2][O][P@2](=[O])([O-])[O-])[C](=[O])[O][P@2](=[O])([O-])[O-]

The mechanism:

                     O
                     | 
R-C=O -Cys-SH-> R-C-S-Cys (a thiohemiacetal) -NAD-> R-C=O
  |                  |                                      |
  H                  H                      (thioester) Cys-S

• membrane fusogenic activity: The process of merging cell bilayers is crucial to the function of many important cell processes including cell division, macrophagy and synaptic transmission. Studies have found GAPDH bound to the membrane. In erythrocytes, up to 70% of GAPDH is membrane bound. Other, unrelated studies had isolated a protein from rabbit muscle that seemed to be important for membranes to fuse together. When they sequenced this protein, they found it was GAPDH.
  
  
• tubulin binding: Tubulin is a crucial protein in the cytoskeleton of mammalian cells. It polymerizes into microtubules that assemble and disassemble dynamically for intracellular transport and other functions. GAPDH has been found to stimulate assembly of tubulin in vitro although the functional role of this activity is not known.
  
  
• GAPDH as a kinase: Kinases are enzymes that phosphorylate other proteins. Often, one can observe cascades of kinases that phosphorylate other kinases, resulting in a signal transduction pathway through the cell. GAPDH has been found to phosphorylate the HBV protein, which is a surface antigen of a core envelope protein on the Hepatitis B virus. It also may phosphorylate nm23, a signalling protein involved in tumor metastasis supression. GAPDH itself can be phosphorylated by a number of other kinases including protein kinase C, epidermal-growth-factor kinase and the calmodulin dependent protein kinase H.
  
  
• nuclear RNA export: GAPDH has been found complexed to transfer RNA for methionine (tRNA^met) and may be involved in transporting tRNA through the cytoplasm. This may also be a link between protein synthesis and the glycolytic cycle. GAPDH also binds to other RNA molecules, including those in the ribozyme, particularly to regions that are critical for regulation of RNA elements.
  
  
• DNA repair: DNA is subject to chemical degradation, photodegradation and mutation due to mistakes during replication. Lesions in DNA such as a cytosine deamination to uracil are repaired by Uracil DNA Glycosylases (UDGs). GAPDH can clearly function in DNA repair. GAPDH exists as either a monomer or a tetramer in the cell. As a tetramer, it functions in glycolysis. As a monomer, it has the DNA repair activity. There are also natural UDGs which carry out this function in the cell.

As a result of these multiple biochemical activities, GAPDH has been implicated in biolgical processes including endocytosis, microtubule bundling, translational regulation, nuclear RNA export, phosphotransferase functions, DNA replication, DNA repair, nitric oxide metabolism, apoptosis, neuronal disorders, viral pathogenesis and prostate cancer. Much still needs to be done to elucidate these multiple functions. Numerous other enzymes also function in multiple ways, giving robustness and diversity to biological systems.

References

• Sirover MA. New insights into an old protein: the functional diversity of mammalian glyceraldehyde-3-phosphate dehydrogenase. Biochimica et Biophysica Acta v 1432 (1999) p 159-184
• Meyer-Siegler et al. A human nuclear uracil DNA glycosylase is the 37-kDa subunit of glyceraldehyde-3-phosphate dehydrogenase. Proceedings of the National Academy of Sciences v 88 (1991) pp 8460-8464