Glyceraldehyde 3-phosphate dehydrogenase

Glyceraldehyde-3-phosphate dehydrogenase

PDB rendering based on 3GPD.

Available structures: 1j0x, 1u8f, 1znq

Identifiers

Symbol(s)

GAPDH; G3PD; GAPD; MGC88685

External IDs

OMIM: 138400 MGI: 3646088 Homologene: 81613

Gene Ontology
Molecular Function:	• glyceraldehyde-3-phosphate dehydrogenase (phosphorylating) activity • oxidoreductase activity • NAD binding
Cellular Component:	• cytoplasm
Biological Process:	• glucose metabolic process • glycolysis

RNA expression pattern

More reference expression data

Orthologs

Human

Mouse

Entrez

2597

622339

Ensembl

ENSG00000111640

Uniprot

P04406

Refseq

NM_002046 (mRNA)
NP_002037 (protein)

NM_001081297 (mRNA)
NP_001074766 (protein)

Location

Chr 12: 6.51 - 6.52 Mb

Pubmed search

[1]

[2]

Glyceraldehyde 3-phosphate dehydrogenase (abbreviated as GAPDH or less commonly as G3PDH) (apoptosis ^[1] , and ER to Golgi vesicle shuttling.

Metabolic function

Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) catalyses the conversion of glycerate 1,3-bisphosphate in two coupled steps. The first is favourable and allows the second unfavourable step to occur.

Overall reaction catalysed

glyceraldehyde 3-phosphate	glyceraldehyde phosphate dehydrogenase		D-glycerate 1,3-bisphosphate

	NAD⁺ + P_i	NADH + H⁺

	NAD⁺ + P_i	NADH + H⁺

Compound C00118 at KEGG Pathway Database. Enzyme 1.2.1.12 at KEGG Pathway Database. Reaction R01063 at KEGG Pathway Database. Compound C00236 at KEGG Pathway Database.

Two-step conversion of glyceraldehyde 3-phosphate

The first reaction is the oxidiation 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.

Mechanism of catalysis

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 thiol group of the enzyme's cysteine residue.

Additional functions

GAPDH is multifunctional like an increasing number of enzymes. In addition to catalysing the 6th step of glycolysis, recent evidence implicates GAPDH in other cellular processes. This came as a surprise to researchers but it makes evolutionary sense to re-use and adapt an existing proteins instead of evolving a novel protein from scratch.

Transcription and apoptosis

Zheng et al. discovered in 2003 that GAPDH can itself activate metabolism. GAPDH moves between the cytosol and the nucleus and may thus link the metabolic state to gene transcription. ^[2]

In 2005, Hara et al. showed that GAPDH initiates degradation, thus initiating controlled cell shutdown. ^[3] 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. ^[4]

ER to Golgi transport

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. It was found that GAPDH is recruited by Src. ^[5]

Cellular location

All steps of glycolysis take place in the cytosol and so does the reaction catalysed by GAPDH. Research in red blood cells indicates that GAPDH and several other glycolytic enzymes assemble in complexes on the inside of the cell membrane. The process appears to be regulated by phosphorylation and oxygenation. ^[6] Bringing several glycolytic enzymes close to each other is expected to greatly increased the overall speed of glucose breakdown.

Sources

Glycolysis text book references

Voet, D. and Voet, J. G. (2004) Biochemistry, Third Edition. J. Wiley & Sons, Hoboken, NJ.
Berg, Jeremy M., Tymoczko, John L., & Stryer, Lubert (2007) Biochemistry, Sixth Edition. W. H. Freeman and Co., NY.
diagram of the GAPDH reaction mechanism from Lodish MCB at NCBI bookshelf
similar diagram from Alberts The Cell at NCBI bookshelf

Cited research

^ A. Tarze, A. Deniaud, M. Le Bras, E. Maillier, D. Molle, N. Larochette, N. Zamzami, G. Jan, G. Kroemer, and C. Brenner (2007). "GAPDH, a novel regulator of the pro-apoptotic mitochondrial membrane permeabilization". Oncogene 26 (18): 2606-2620. PMID 17072346.
^ Zheng L, Roeder RG, Luo Y (2003). "S phase activation of the histone H2B promoter by OCA-S, a coactivator complex that contains GAPDH as a key component". Cell 114 (2): 255-66. PMID 12887926.
^ Hara MR, Agrawal N, Kim SF, et al (2005). "S-nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following Siah1 binding". Nat. Cell Biol. 7 (7): 665-74. doi:10.1038/ncb1268. PMID 15951807.
^ Hara MR, Thomas B, Cascio MB, et al (2006). "Neuroprotection by pharmacologic blockade of the GAPDH death cascade". Proc. Natl. Acad. Sci. U.S.A. 103 (10): 3887-9. doi:10.1073/pnas.0511321103. PMID 16505364.
^ Tisdale EJ, Artalejo CR (2007). "A GAPDH mutant defective in Src-dependent tyrosine phosphorylation impedes Rab2-mediated events". Traffic 8 (6): 733-41. doi:10.1111/j.1600-0854.2007.00569.x. PMID 17488287.
^ Campanella ME, Chu H, Low PS (2005). "Assembly and regulation of a glycolytic enzyme complex on the human erythrocyte membrane". Proc. Natl. Acad. Sci. U.S.A. 102 (7): 2402-7. doi:10.1073/pnas.0409741102. PMID 15701694.