1U8F, 1ZNQ, 3GPD, 4WNC, 4WNI2597100042025ENSG00000111640n/aP04406P16858NM_001357943NM_001357944XM_001476707NP_001243728NP_001276674NP_001276675NP_002037NP_001344872NP_001276655NP_032110Glyceraldehyde 3-phosphate dehydrogenase (abbreviated GAPDH) (EC 1.2.1.12) is an enzyme of about 37kDa that catalyzes the sixth step of glycolysis and thus serves to break down glucose for energy and carbon molecules.

In addition to this long established metabolic function, GAPDH has recently been implicated in several non-metabolic processes, including transcription activation, initiation of apoptosis,[4] ER-to-Golgi vesicle shuttling, and fast axonal, or axoplasmic transport.

The first reaction is the oxidation of glyceraldehyde 3-phosphate (G3P) at the position-1 (in the diagram it is shown as the 4th carbon from glycolysis), in which an aldehyde is converted into a carboxylic acid (ΔG°'=-50 kJ/mol (−12kcal/mol)) and NAD+ is simultaneously reduced endergonically to NADH.

First, a cysteine residue in the active site of GAPDH attacks the carbonyl group of G3P, creating a hemithioacetal intermediate (covalent catalysis).

Deprotonation encourages the reformation of the carbonyl group in the subsequent thioester intermediate and ejection of a hydride ion.

Next, an adjacent, tightly bound molecule of NAD+ accepts the hydride ion, forming NADH while the hemithioacetal is oxidized to a thioester.

Finally, a molecule of inorganic phosphate attacks the thioester and forms a tetrahedral intermediate, which then collapses to release 1,3-bisphosphoglycerate, and the thiol group of the enzyme's cysteine residue.

This is the 6th step in the glycolytic breakdown of glucose, an important pathway of energy and carbon molecule supply which takes place in the cytosol of eukaryotic cells.

The OCA-S transcriptional coactivator complex contains GAPDH and lactate dehydrogenase, two proteins previously only thought to be involved in metabolism.

[19] In subsequent study the group demonstrated that deprenyl, which has been used clinically to treat Parkinson's disease, strongly reduces the apoptotic action of GAPDH by preventing its S-nitrosylation and might thus be used as a drug.

This inactivation re-routes temporally the metabolic flux from glycolysis to the pentose phosphate pathway, allowing the cell to generate more NADPH.

[22] Under stress conditions, NADPH is needed by some antioxidant-systems including glutaredoxin and thioredoxin as well as being essential for the recycling of gluthathione.

GAPDH also appears to be involved in the vesicle transport from the endoplasmic reticulum (ER) to the Golgi apparatus which is part of shipping route for secreted proteins.

GAPDH has been described to exhibit higher order multifunctionality in the context of maintaining cellular iron homeostasis,[24] specifically as a chaperone protein for labile heme within cells.

[30][31] GAPDH is overexpressed in multiple human cancers, such as cutaneous melanoma, and its expression is positively correlated with tumor progression.

It is proposed that hypometabolism may be one contributor to PD, but the exact mechanisms underlying GAPDH involvement in neurodegenerative disease remains to be clarified.