As a classic glycolytic enzyme
, glyceraldehyde-3-phosphate dehydrogenase (GAPDH)
is an old beast. In the light of moonlighting enzymes
, enzymes that seem
to serve multiple functions in the cell, GAPDH has become the focus of research
in fields of biology unrelated to metabolic biochemistry
. Here are some of the
other biochemical functions of this amazing enzyme:
- 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 (tRNAmet) 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
- 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.
- 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