View source for Glyceraldehyde phosphate dehydrogenase

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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
{{GNF_Protein_box
 | image = 2-Glyceraldehyde-3-phosphate dehydrogenase 3GPD wpmp.png
 | image_source = [[Protein Data Bank|PDB]] rendering based on 3GPD.
 | PDB = {{PDB2|1j0x}}, {{PDB2|1u8f}}, {{PDB2|1znq}}
 | Name = Glyceraldehyde-3-phosphate dehydrogenase
 | HGNCid = 4141
 | Symbol = GAPDH
 | AltSymbols =; G3PD; GAPD; MGC88685
 | OMIM = 138400
 | ECnumber =  
 | Homologene = 81613
 | MGIid = 3646088
 | GeneAtlas_image1 = PBB_GE_GAPDH_212581_x_at_tn.png
 | GeneAtlas_image2 = PBB_GE_GAPDH_213453_x_at_tn.png
 | GeneAtlas_image3 = PBB_GE_GAPDH_217398_x_at_tn.png
 | Function = {{GNF_GO|id=GO:0004365 |text = glyceraldehyde-3-phosphate dehydrogenase (phosphorylating) activity}} {{GNF_GO|id=GO:0016491 |text = oxidoreductase activity}} {{GNF_GO|id=GO:0051287 |text = NAD binding}} 
 | Component = {{GNF_GO|id=GO:0005737 |text = cytoplasm}} 
 | Process = {{GNF_GO|id=GO:0006006 |text = glucose metabolic process}} {{GNF_GO|id=GO:0006096 |text = glycolysis}} 
 | Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 2597
    | Hs_Ensembl = ENSG00000111640
    | Hs_RefseqProtein = NP_002037
    | Hs_RefseqmRNA = NM_002046
    | Hs_GenLoc_db =  
    | Hs_GenLoc_chr = 12
    | Hs_GenLoc_start = 6513872
    | Hs_GenLoc_end = 6517780
    | Hs_Uniprot = P04406
    | Mm_EntrezGene = 622339
    | Mm_Ensembl =  
    | Mm_RefseqmRNA = NM_001081297
    | Mm_RefseqProtein = NP_001074766
    | Mm_GenLoc_db =  
    | Mm_GenLoc_chr =  
    | Mm_GenLoc_start =  
    | Mm_GenLoc_end =  
    | Mm_Uniprot =  
  }}
}}


<!-- lead section -->
'''Glyceraldehyde 3-phosphate dehydrogenase''' (abbreviated as '''GAPDH''' or less commonly as G3PDH) ({{EC number|1.2.1.12}}) is an [[enzyme]] 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 (genetics)|transcription]] activation, initiation of [[apoptosis]] <ref name="pmid17072346">{{cite journal |author= A. Tarze, A. Deniaud, M. Le Bras, E. Maillier, D. Molle, N. Larochette, N. Zamzami, G. Jan, G. Kroemer, and C. Brenner |title= GAPDH, a novel regulator of the pro-apoptotic mitochondrial membrane permeabilization |journal=Oncogene |volume=26 |issue=18 |pages=2606-2620 |year=2007 |pmid= 17072346}}</ref> , and [[COPI|ER to Golgi vesicle shuttling]].
<!-- lead section end -->

== Metabolic function ==

Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) catalyses the conversion of [[glyceraldehyde 3-phosphate]] as the name indicates. This is the 6th step of the breakdown of glucose ([[glycolysis]]), an important pathway of energy and carbon molecule supply located in the [[cytosol]] of eukaryotic cells. Glyceraldehyde 3-phosphate is converted to <small>D</small>-[[glycerate 1,3-bisphosphate]] in two coupled steps. The first is favourable and allows the second unfavourable step to occur.

=== Overall reaction catalysed ===
{{Enzymatic Reaction
|foward_enzyme=[[glyceraldehyde phosphate dehydrogenase]]
|reverse_enzyme=
|substrate=[[glyceraldehyde 3-phosphate]]
|product=<small>D</small>-[[glycerate 1,3-bisphosphate]]
|reaction_direction_(forward/reversible/reverse)=reversible
|minor_foward_substrate(s)=NAD<sup>+</sup> '''+''' P<sub>i</sub>
|minor_foward_product(s)=NADH '''+''' H<sup>+</sup>
|minor_reverse_substrate(s)=NADH '''+''' H<sup>+</sup>
|minor_reverse_product(s)=NAD<sup>+</sup> '''+''' P<sub>i</sub>
|substrate_image=D-glyceraldehyde-3-phosphate_wpmp.png
|product_image=1,3-bisphospho-D-glycerate_wpmp.png
}}


=== Two-step conversion of glyceraldehyde 3-phosphate===

The first reaction is the oxidiation of [[glyceraldehyde 3-phosphate]] at the carbon 1 position (the 4th carbon from glycolysis which is shown in the diagram), 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.

=== 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 [[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 absence 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 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 ultimate step.  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.

== 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 [[transcription (genetics)|transcription]]. The ''OCA-S'' transcriptional coactivator complex contains GAPDH and [[lactate dehydrogenase]], two protein previously only thought to be involved in [[metabolism]]. GAPDH moves between the [[cytosol]] and the [[nucleus]] and may thus link the metabolic state to gene transcription.
<ref name="pmid12887926">{{cite journal |author=Zheng L, Roeder RG, Luo Y |title=S phase activation of the histone H2B promoter by OCA-S, a coactivator complex that contains GAPDH as a key component |journal=Cell |volume=114 |issue=2 |pages=255-66 |year=2003 |pmid=12887926 |doi=}}</ref>

In [[2005]], Hara et al. showed that GAPDH initiates [[apoptosis]]. This is not a third function, but can be seen as an activity mediated by GAPDH binding to [[DNA]] like in transcription activation, discussed above. The study demonstrated that GAPDH is [[Nitric oxide#Biological_functions|S-nitrosylated]] by NO in response to cell stress, which causes it to bind to the protein ''Siah1'', a [[ubiquitin ligase]]. The complex moves into the nucleus where Siah1 targets nuclear proteins for [[protein degradation|degradation]], thus initiating controlled cell shutdown.
<ref name="pmid15951807">{{cite journal |author=Hara MR, Agrawal N, Kim SF, ''et al'' |title=S-nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following Siah1 binding |journal=Nat. Cell Biol. |volume=7 |issue=7 |pages=665-74 |year=2005 |pmid=15951807 |doi=10.1038/ncb1268}}</ref>
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.
<ref name="pmid16505364">{{cite journal |author=Hara MR, Thomas B, Cascio MB, ''et al'' |title=Neuroprotection by pharmacologic blockade of the GAPDH death cascade |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=103 |issue=10 |pages=3887-9 |year=2006 |pmid=16505364 |doi=10.1073/pnas.0511321103}}</ref>

=== ER to Golgi transport ===

GAPDH also appears to be involved in the [[Vesicle (biology)#Vesicle_formation_and_transport|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 [[Rab (G-protein)|rab2]] to the [[vesicular-tubular clusters]] of the ER where it helps to form [[COPI|COP 1 vesicles]]. GAPDH is activated via [[tyrosine]] [[phosphorylation]] by [[Src (gene)|Src]].
<ref name="pmid17488287">{{cite journal |author=Tisdale EJ, Artalejo CR |title=A GAPDH mutant defective in Src-dependent tyrosine phosphorylation impedes Rab2-mediated events |journal=Traffic |volume=8 |issue=6 |pages=733-41 |year=2007 |pmid=17488287 |doi=10.1111/j.1600-0854.2007.00569.x}}</ref>

== 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. 
<ref name="pmid15701694">{{cite journal |author=Campanella ME, Chu H, Low PS |title=Assembly and regulation of a glycolytic enzyme complex on the human erythrocyte membrane |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=102 |issue=7 |pages=2402-7 |year=2005 |pmid=15701694 |doi=10.1073/pnas.0409741102}}</ref>
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.
*[http://www.ncbi.nlm.nih.gov/books/bv.fcgi?highlight=glyceraldehyde+3+phosphate+dehydrogenase&rid=mcb.figgrp.4342&WebEnv=0bpB8XePphZ8qSS3b9o1BB3FMZtXPr7yFc3MxfLR12WUi7sKapf987mBijj9A0v-LwF_W_lLjUKNwY%40D45D6EC76612AEB0_0018SID&WebEnvRq=1 diagram of the GAPDH reaction mechanism] from Lodish MCB at NCBI bookshelf
*[http://www.ncbi.nlm.nih.gov/books/bv.fcgi?highlight=glyceraldehyde+3+phosphate+dehydrogenase&rid=mboc4.figgrp.297&WebEnv=0qL7ctlqrxJxTMzSHUlui3y2aeU6B8K6Tblugar02bi5Eetekc7g1j_m9gRDhWr1NM3L7U4G-5GFjf%40D45D6EC76612AEB0_0018SID&WebEnvRq=1 similar diagram] from Alberts The Cell at NCBI bookshelf

=== Cited research ===
{{reflist|2}}





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[[Category:EC 1.2.1]]
[[bg:Глицералдехид-3-фосфатдехидрогеназа]]
[[de:Glycerinaldehyd-3-phosphat-Dehydrogenase]]

{{glycolysis}}
{{Glycolysis enzymes}}
{{Aldehyde/Oxo oxidoreductases}}
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