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Glyceraldehyde-3-phosphate Dehydrogenase
(abbreviated as GAPDH or the less common G3PDH) (EC 1.2.1.12) ~37kDa catalyzes the sixth step of [glycolysis], a reversible cytosolic process in [eukaryotes] which involves the breakdown of glucose for energy and carbon molecules. Along with its role in glycolysis and [gluconeogenesis], recent research has determined that GAPDH is actually a multifunctional protein, as it has numerous defined, non-metabolic functions involved in multiple subcellular processes including [transcription] activation, ER to Golgi transportation, transcriptional control of histone [gene expression], nuclear membrane fusion, neuronal initiation of [apoptosis], recognizing fraudulently incorporated nucleotides in DNA, and maintaining [telomere] structures. Research also shows that it possibly has a direct involvement in cellular phenotype of human [neurodegenerative] disorders, especially those characterized by expansion of [CAG repeats].
Role in Glycolysis:
- In three coupled steps, GAPDH catalyzes the conversion of [glyceraldyhyde-3-phosphate] at carbon 1 to [1,3-bisphosphoglycerate] (1,3-BPG), by combining phosphorylation with oxidation in an overall [endergonic] reaction (ΔG°'=+6.3 kJ/mol (+1.5 kcal/mol)). First, the oxidation of glyceraldyhyde-3-phosphate to D-glycerate 1,3-bisphosphate takes place, in which an aldehyde is converted to carboxylic acid ((ΔG°'=-50 kJ/mol (-12 kcal/mol))and NAD+ ([Nicotinamide adenine dinucleotide]), an important co-factor and [ligand] found bound to the of GAPDH, is simultaneously reduced endergonically to NADH. This oxidation reaction is required for the initiation of the second reaction because it is highly [exergonic] and thus drives the endergonic second reaction ((ΔG°'=+50 kJ/mol (+12 kcal/mol)). In the second reaction a molecule of inorganic phosphate is transferred to a GAP intermediate to form a product with a high potential to transfer phosphates, 1,3-bisphosphoglycerate. Without GAPDH's use of covalent catalysis in the second step, the energy barrier of the reaction would be too high and the reaction would be too slow for living organisms.
Other roles:
The importance of GAPDH in transcription was discovered by Zheng et. al. in 2003. It was found that OCA's transcriptional coactivator complex contains GAPDH, which moves between the cytosol and nucleus and may link the metabolic state to gene transcription.
In 2005 the initiation of apoptosis was shown to be mediated by GAPDH by Hara et. al. when it was found to bind to DNA like it does in transcription activation.
GAPDH was also found to be involved in ER to Golgi transport because it is recruited by rab2 to vesicular-tubular clusters of the endoplasmic reticulum where it helps form COP 1 vesicles.
It was also found that GAPDH is plays a role in certain neruodegenerative disorders, as is able to find stretches which are encoded by the gene's CAG repeats and bind to the gene products formed from disorders such as Huntington's disease, Alzheimer’s disease, Parkinson’s disease and Machado-Joseph disease.
Use in the lab:
Overall, GAPDH is a “housekeeping gene” and is found in high levels in tissues and cells so it is commonly used in biological research as a loading control in western blot and RT-PCR, but it has to be carefully controlled because under specific conditions it can have various regulation.
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