Recent studies establish that the glycolytic protein, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), is not simply a classical metabolic protein involved in energy production. Instead, it is a multifunctional protein with defined functions in numerous subcellular processes. New investigations establish a primary role for GAPDH in a variety of critical nuclear pathways apart from its already recognized role in apoptosis. These new roles include its requirement for transcriptional control of histone gene expression, its essential function in nuclear membrane fusion, its necessity for the recognition of fraudulently incorporated nucleotides in DNA, and its mandatory participation in the maintenance of telomere structure. Each of these new functions requires GAPDH association into a series of multienzyme complexes. Although other proteins in those complexes are variable, GAPDH remains the single constant protein in each structure. To undertake these new functions, GAPDH is recruited to the nucleus in S phase or its intracellular distribution is regulated as a function of drug exposure. Other investigations relate a substantial role for nuclear GAPDH in hyperglycemic stress and the development of metabolic syndrome. Considerations of future directions as well as the role of GAPDH post-translational modification as a basis for its multifunctional activities is suggested.

2005 Wiley-Liss, Inc