Glyceraldehyde 3-phosphate dehydrogenase
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| glyceraldehyde-3-phosphate dehydrogenase | |||||||||
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Image:2-Glyceraldehyde-3-phosphate dehydrogenase 3GPD wpmp.png
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| Symbol(s): | GAPDH GAPD | ||||||||
| Genetic data | |||||||||
| Locus: | Chr. 12 p13 | ||||||||
| Database Links | |||||||||
| EC number: | 1.2.1.12 | ||||||||
| Entrez: | 2597 | ||||||||
| OMIM: | 138400 | ||||||||
| RefSeq: | NM_002046 | ||||||||
| UniProt: | P04406 | ||||||||
Glyceraldehyde 3-phosphate dehydrogenase (GAPDH or G3PDH, although this is not really correct) (EC 1.2.1.9) catalyzes the sixth step of glycolysis, comprised of two reactions. The first reaction is the oxidiation of glyceraldehyde 3-phosphate at the carbon 1 position, in which an aldehyde is converted into a carboxylic acid (ΔG°'=-50 kJ/mol (-12kcal/mol)). The energy released by this highly exergonic oxidation reaction drives the endergonic second reaction (ΔG°'=+50 kJ/mol (+12kcal/mol)), in which a molecule of inorganic phosphate is transferred to the GAP intermediate to form a product with high phosphoryl-transfer potential: 1,3-Biphosphoglycerate (1,3-BPG). This is an example of phosphorylation coupled to oxidation, and the overall reaction is somewhat endergonic (ΔG°'=+6.3 kJ/mol (+1.5)). Energy coupling here is made possible by GAPDH.
GAPDH uses covalent catalysis and general base catalysis to decrease the very large and positive activation energy of the second step of this reaction. First, a cysteine residue in the active site of GAPDH attacks the carbonyl group of GAP, creating a hemithioacetal intermediate (covalent catalysis). Next, an adjacent, tightly bound molecule of NAD+ accepts a hydride ion from GAP, forming NADH; GAP is concomitantly oxidized to a thioester intermediate using a molecule of water. This thioester species is much higher in energy than the carboxylic acid species that would result in the absense of GAPDH (the carboxylic acid species is so low in energy that the energy barrier for the second step of the reaction (phosphorylation) would be too great, and the reaction therefore too slow, for a living organism). Donation of the hydride ion by the hemithioacetal is facilitated by its deprotonation by a histidine residue in the enzyme's active site (general base catalysis). Deprotonation encourages the reformation of the carbonyl group in the thioester intermediate and ejection of of the hydride ion. NADH leaves the active site and is replaced by another molecule of NAD+, the positive charge of which stabilizes the negatively-charged carbonyl oxygen in the transition state of the next and ultimte step. Finally, a molecule of inorganic phosphate attacks the thioester and forms a tetrahedral intermediate, which then collapses to release 1,3-biphosphoglycerate, a molecule of water, and the thiol group of the enzyme's cysteine residue.
[edit] See also
[edit] Sources
Voet, D. and Voet, J. G. (2004) Biochemistry, Third Edition. J. Wiley & Sons, Hoboken, NJ.
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Berg, Jeremy M., Tymoczko, John L., & Stryer, Lubert (2007) Biochemistry, Sixth Edition. W. H. Freeman and Co., NY.
