View source for Glyceraldehyde 3-phosphate dehydrogenase

{{short description|Enzyme of the glycolysis metabolic pathway}}
{{cs1 config|name-list-style=vanc}}
{{other uses|Glyceraldehyde-3-phosphate dehydrogenase (disambiguation)}}
{{Use dmy dates|date=April 2016}}
{{Infobox_gene}}
{{Infobox protein family
| Symbol = Gp_dh_N
| Name = Glyceraldehyde 3-phosphate dehydrogenase, NAD binding domain
| image = PDB 1cer EBI.jpg
| width =
| caption = determinants of enzyme thermostability observed in the molecular structure of thermus aquaticus d-glyceraldehyde-3-phosphate dehydrogenase at 2.5 angstroms resolution
| Pfam = PF00044
| Pfam_clan = CL0063
| InterPro = IPR020828
| SMART =
| PROSITE = PDOC00069
| MEROPS =
| SCOP = 1gd1
| TCDB =
| OPM family =
| OPM protein =
| CAZy =
| CDD =
}}
{{Infobox protein family
| Symbol = Gp_dh_C
| Name = Glyceraldehyde 3-phosphate dehydrogenase, C-terminal domain
| image = PDB 2czc EBI.jpg
| width =
| caption = crystal structure of glyceraldehyde-3-phosphate dehydrogenase from pyrococcus horikoshii ot3
| Pfam = PF02800
| Pfam_clan = CL0139
| InterPro = IPR020829
| SMART =
| PROSITE = PDOC00069
| MEROPS =
| SCOP = 1gd1
| TCDB =
| OPM family =
| OPM protein =
| CAZy =
| CDD =
}}
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'''Glyceraldehyde 3-phosphate dehydrogenase''' (abbreviated '''GAPDH''') ({{EC number|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 (genetics)|transcription]] activation, initiation of [[apoptosis]],<ref name="Tarze_2007">{{cite journal | vauthors = Tarze A, Deniaud A, Le Bras M, Maillier E, Molle D, Larochette N, Zamzami N, Jan G, Kroemer G, Brenner C | title = GAPDH, a novel regulator of the pro-apoptotic mitochondrial membrane permeabilization | journal = Oncogene | volume = 26 | issue = 18 | pages = 2606–2620 | date = April 2007 | pmid = 17072346 | doi = 10.1038/sj.onc.1210074 | s2cid = 20291542 | doi-access =  }}</ref> [[COPI|ER-to-Golgi vesicle shuttling]], and fast axonal, or [[axoplasmic transport]].<ref name="Zala_2013">{{cite journal | vauthors = Zala D, Hinckelmann MV, Yu H, Lyra da Cunha MM, Liot G, Cordelières FP, Marco S, Saudou F | title = Vesicular glycolysis provides on-board energy for fast axonal transport | journal = Cell | volume = 152 | issue = 3 | pages = 479–491 | date = January 2013 | pmid = 23374344 | doi = 10.1016/j.cell.2012.12.029 | doi-access = free }}</ref> In sperm, a testis-specific [[isoenzyme]] [[GAPDHS]] is expressed.

== Structure ==

Under normal cellular conditions, [[cytoplasm]]ic GAPDH exists primarily as a [[tetramer]]. This form is composed of four identical 37-[[kDa]] subunits containing a single catalytic [[thiol]] group each and critical to the enzyme's catalytic function.<ref name=pmid20727968>{{cite journal | vauthors = Tristan C, Shahani N, Sedlak TW, Sawa A | title = The diverse functions of GAPDH: views from different subcellular compartments | journal = Cellular Signalling | volume = 23 | issue = 2 | pages = 317–323 | date = February 2011 | pmid = 20727968 | pmc = 3084531 | doi = 10.1016/j.cellsig.2010.08.003 }}</ref><ref name="Nicholls_2012">{{cite journal | vauthors = Nicholls C, Li H, Liu JP | title = GAPDH: a common enzyme with uncommon functions | journal = Clinical and Experimental Pharmacology & Physiology | volume = 39 | issue = 8 | pages = 674–679 | date = August 2012 | pmid = 21895736 | doi = 10.1111/j.1440-1681.2011.05599.x | s2cid = 23499684 }}</ref> Nuclear GAPDH has increased [[isoelectric point]] (pI) of pH 8.3–8.7.<ref name="Nicholls_2012"/> Of note, the [[cysteine]] [[amino acid|residue]] C152 in the enzyme's [[active site]] is required for the induction of apoptosis by [[oxidative stress]].<ref name="Nicholls_2012"/> Notably, [[post-translational modification]]s of cytoplasmic GAPDH contribute to its functions outside of glycolysis.<ref name=pmid20727968/>

GAPDH is encoded by a single gene that produces a single mRNA transcript with 8 splice variants, though an isoform does exist as a separate gene that is expressed only in [[spermatozoa]].<ref name="Nicholls_2012"/>

== Reaction ==

{{Enzymatic Reaction
|forward_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_forward_substrate(s)=NAD<sup>+</sup>''' ''' +P<sub>i</sub>
|minor_forward_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.svg
|substrate_image_size = 120 px
|product_image=D-glycerate 1,3-bisphosphate.svg
|product_image_size =120 px
}}
{{KEGG compound|C00118}} {{KEGG enzyme|1.2.1.12}} {{KEGG reaction|R01063}} {{KEGG compound|C00236}}

=== Two-step conversion of G3P ===

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.

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-bisphosphoglycerate]]''' (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 ===

GAPDH uses covalent catalysis and general base catalysis to decrease the very large activation energy of the second step (phosphorylation) of this reaction.

====1: Oxidation====

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

The hemithioacetal is deprotonated by a [[histidine]] residue in the enzyme's active site (general base 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 [[Nicotinamide adenine dinucleotide|NAD<sup>+</sup>]] accepts the [[hydride ion]], forming [[NADH]] while the hemithioacetal is oxidized to a [[thioester]].

This thioester species is much higher in energy (less stable) than the [[carboxylic acid]] species that would result if G3P were oxidized 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 high, and the reaction, therefore, too slow and unfavorable for a living organism).

====2: Phosphorylation====

NADH leaves the active site and is replaced by another molecule of NAD<sup>+</sup>, 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.

=== Regulation ===

This protein may use the [[morpheein]] model of [[allosteric regulation]].<ref name="Selwood_2012">{{cite journal | vauthors = Selwood T, Jaffe EK | title = Dynamic dissociating homo-oligomers and the control of protein function | journal = Archives of Biochemistry and Biophysics | volume = 519 | issue = 2 | pages = 131–143 | date = March 2012 | pmid = 22182754 | pmc = 3298769 | doi = 10.1016/j.abb.2011.11.020 }}</ref>

== Function ==

=== Metabolic ===

As its name indicates, glyceraldehyde 3-phosphate dehydrogenase (GAPDH) catalyses the conversion of [[glyceraldehyde 3-phosphate]] to <small>D</small>-[[glycerate 1,3-bisphosphate]]. 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 conversion occurs in two coupled steps. The first is favourable and allows the second unfavourable step to occur.

=== Adhesion ===
One of the GAPDH [[Protein moonlighting|moonlighting function]]s is its role in adhesion and binding to other partners. Bacterial GAPDH  from [[Mycoplasma]] and ''[[Streptococcus]]'' and fungal GAPDH from ''[[Paracoccidioides brasiliensis]]'' are known to bind with the human extracellular matrix component and act in adhesion.<ref>{{cite journal | vauthors = Dumke R, Hausner M, Jacobs E | title = Role of Mycoplasma pneumoniae glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in mediating interactions with the human extracellular matrix | journal = Microbiology | volume = 157 | issue = Pt 8 | pages = 2328–2338 | date = August 2011 | pmid = 21546586 | doi = 10.1099/mic.0.048298-0 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Brassard J, Gottschalk M, Quessy S | title = Cloning and purification of the Streptococcus suis serotype 2 glyceraldehyde-3-phosphate dehydrogenase and its involvement as an adhesin | journal = Veterinary Microbiology | volume = 102 | issue = 1–2 | pages = 87–94 | date = August 2004 | pmid = 15288930 | doi = 10.1016/j.vetmic.2004.05.008 }}</ref><ref>{{cite journal | vauthors = Barbosa MS, Báo SN, Andreotti PF, de Faria FP, Felipe MS, dos Santos Feitosa L, Mendes-Giannini MJ, Soares CM | title = Glyceraldehyde-3-phosphate dehydrogenase of Paracoccidioides brasiliensis is a cell surface protein involved in fungal adhesion to extracellular matrix proteins and interaction with cells | journal = Infection and Immunity | volume = 74 | issue = 1 | pages = 382–389 | date = January 2006 | pmid = 16368993 | pmc = 1346668 | doi = 10.1128/IAI.74.1.382-389.2006 }}</ref> GAPDH is found to be surface bound contributing in adhesion and also in competitive exclusion of harmful pathogens.<ref>{{cite journal | vauthors = Ramiah K, van Reenen CA, Dicks LM | title = Surface-bound proteins of Lactobacillus plantarum 423 that contribute to adhesion of Caco-2 cells and their role in competitive exclusion and displacement of Clostridium sporogenes and Enterococcus faecalis | journal = Research in Microbiology | volume = 159 | issue = 6 | pages = 470–475 | date = 2008-07-01 | pmid = 18619532 | doi = 10.1016/j.resmic.2008.06.002 | doi-access = free }}</ref> GAPDH from ''[[Candida albicans]]'' is found to cell-wall associated and binds to [[Fibronectin]] and [[Laminin]].<ref>{{cite journal | vauthors = Gozalbo D, Gil-Navarro I, Azorín I, Renau-Piqueras J, Martínez JP, Gil ML | title = The cell wall-associated glyceraldehyde-3-phosphate dehydrogenase of Candida albicans is also a fibronectin and laminin binding protein | journal = Infection and Immunity | volume = 66 | issue = 5 | pages = 2052–2059 | date = May 1998 | pmid = 9573088 | pmc = 108162 | doi = 10.1128/IAI.66.5.2052-2059.1998 }}</ref> GAPDH from [[probiotic]]s species are known to bind human colonic [[mucin]] and ECM, resulting in enhanced colonization of probiotics in the human gut.<ref>{{cite journal | vauthors = Deng Z, Dai T, Zhang W, Zhu J, Luo XM, Fu D, Liu J, Wang H | title = Glyceraldehyde-3-Phosphate Dehydrogenase Increases the Adhesion of ''Lactobacillus reuteri'' to Host Mucin to Enhance Probiotic Effects | journal = International Journal of Molecular Sciences | volume = 21 | issue = 24 | pages = 9756 | date = December 2020 | pmid = 33371288 | doi = 10.3390/ijms21249756 | pmc = 7766874 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Kinoshita H, Uchida H, Kawai Y, Kawasaki T, Wakahara N, Matsuo H, Watanabe M, Kitazawa H, Ohnuma S, Miura K, Horii A, Saito T | title = Cell surface Lactobacillus plantarum LA 318 glyceraldehyde-3-phosphate dehydrogenase (GAPDH) adheres to human colonic mucin | journal = Journal of Applied Microbiology | volume = 104 | issue = 6 | pages = 1667–1674 | date = June 2008 | pmid = 18194256 | doi = 10.1111/j.1365-2672.2007.03679.x | s2cid = 22346488 }}</ref><ref>{{cite journal | vauthors = Kinoshita H, Wakahara N, Watanabe M, Kawasaki T, Matsuo H, Kawai Y, Kitazawa H, Ohnuma S, Miura K, Horii A, Saito T | title = Cell surface glyceraldehyde-3-phosphate dehydrogenase (GAPDH) of Lactobacillus plantarum LA 318 recognizes human A and B blood group antigens | journal = Research in Microbiology | volume = 159 | issue = 9–10 | pages = 685–691 | date = 2008-11-01 | pmid = 18790050 | doi = 10.1016/j.resmic.2008.07.005 | doi-access = free }}</ref> Patel D. et al., showed that ''[[Lactobacillus acidophilus]]'' GAPDH binds with mucin, acting in adhesion.<ref>{{cite journal | vauthors = Patel DK, Shah KR, Pappachan A, Gupta S, Singh DD | title = Cloning, expression and characterization of a mucin-binding GAPDH from Lactobacillus acidophilus | journal = International Journal of Biological Macromolecules | volume = 91 | pages = 338–346 | date = October 2016 | pmid = 27180300 | doi = 10.1016/j.ijbiomac.2016.04.041 }}</ref>

=== Transcription and apoptosis ===

GAPDH can itself activate [[transcription (genetics)|transcription]]. The ''OCA-S'' transcriptional coactivator complex contains GAPDH and [[lactate dehydrogenase]], two proteins previously only thought to be involved in [[metabolism]]. GAPDH moves between the [[cytosol]] and the [[Cell nucleus|nucleus]] and may thus link the metabolic state to gene transcription.<ref name="Zheng_2033">{{cite journal | vauthors = 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 = 255–266 | date = July 2003 | pmid = 12887926 | doi = 10.1016/S0092-8674(03)00552-X | s2cid = 5543647 | doi-access = free }}</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="Hara_2005">{{cite journal | vauthors = Hara MR, Agrawal N, Kim SF, Cascio MB, Fujimuro M, Ozeki Y, Takahashi M, Cheah JH, Tankou SK, Hester LD, Ferris CD, Hayward SD, Snyder SH, Sawa A | title = S-nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following Siah1 binding | journal = Nature Cell Biology | volume = 7 | issue = 7 | pages = 665–674 | date = July 2005 | pmid = 15951807 | doi = 10.1038/ncb1268 | s2cid = 1922911 }}</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="Hara_2006">{{cite journal | vauthors = Hara MR, Thomas B, Cascio MB, Bae BI, Hester LD, Dawson VL, Dawson TM, Sawa A, Snyder SH | title = Neuroprotection by pharmacologic blockade of the GAPDH death cascade | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 10 | pages = 3887–3889 | date = March 2006 | pmid = 16505364 | pmc = 1450161 | doi = 10.1073/pnas.0511321103 | doi-access = free | bibcode = 2006PNAS..103.3887H }}</ref>

=== Metabolic switch ===

GAPDH acts as a reversible metabolic switch under oxidative stress.<ref name="Agarwal_2012">{{cite journal | vauthors = Agarwal AR, Zhao L, Sancheti H, Sundar IK, Rahman I, Cadenas E | title = Short-term cigarette smoke exposure induces reversible changes in energy metabolism and cellular redox status independent of inflammatory responses in mouse lungs | journal = American Journal of Physiology. Lung Cellular and Molecular Physiology | volume = 303 | issue = 10 | pages = L889–L898 | date = November 2012 | pmid = 23064950 | doi = 10.1152/ajplung.00219.2012 }}</ref> When cells are exposed to [[oxidant]]s, they need excessive amounts of the antioxidant cofactor [[NADPH]]. In the cytosol, NADPH is reduced from NADP+ by several enzymes, three of them catalyze the first steps of the [[pentose phosphate pathway]]. Oxidant-treatments cause an inactivation of GAPDH. This inactivation re-routes temporally the metabolic flux from glycolysis to the pentose phosphate pathway, allowing the cell to generate more NADPH.<ref name="Ralser_2007">{{cite journal | vauthors = Ralser M, Wamelink MM, Kowald A, Gerisch B, Heeren G, Struys EA, Klipp E, Jakobs C, Breitenbach M, Lehrach H, Krobitsch S | title = Dynamic rerouting of the carbohydrate flux is key to counteracting oxidative stress | journal = Journal of Biology | volume = 6 | issue = 4 | pages = 10 | date = December 2007 | pmid = 18154684 | pmc = 2373902 | doi = 10.1186/jbiol61 | doi-access = free }}</ref> Under stress conditions, NADPH is needed by some antioxidant-systems including [[glutaredoxin]] and [[thioredoxin]] as well as being essential for the recycling of [[gluthathione]].

=== ER-to-Golgi transport ===

GAPDH also appears to be involved in the [[Vesicle (biology)#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="Tisdale_2007">{{cite journal | vauthors = 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 = 733–741 | date = June 2007 | pmid = 17488287 | pmc = 3775588 | doi = 10.1111/j.1600-0854.2007.00569.x }}</ref>

=== Additional functions ===

GAPDH, like many other enzymes, has multiple functions. In addition to catalysing the 6th step of [[glycolysis]], recent evidence implicates GAPDH in other cellular processes. GAPDH has been described to exhibit higher order multifunctionality in the context of maintaining cellular iron homeostasis,<ref>{{cite journal | vauthors = Boradia VM, Raje M, Raje CI | title = Protein moonlighting in iron metabolism: glyceraldehyde-3-phosphate dehydrogenase (GAPDH) | journal = Biochemical Society Transactions | volume = 42 | issue = 6 | pages = 1796–1801 | date = December 2014 | pmid = 25399609 | doi = 10.1042/BST20140220 }}</ref> specifically as a [[chaperone (protein)|chaperone protein]] for labile heme within cells.<ref>{{cite journal | vauthors = Sweeny EA, Singh AB, Chakravarti R, Martinez-Guzman O, Saini A, Haque MM, Garee G, Dans PD, Hannibal L, Reddi AR, Stuehr DJ | title = Glyceraldehyde-3-phosphate dehydrogenase is a chaperone that allocates labile heme in cells | journal = The Journal of Biological Chemistry | volume = 293 | issue = 37 | pages = 14557–14568 | date = September 2018 | pmid = 30012884 | pmc = 6139559 | doi = 10.1074/jbc.RA118.004169 | doi-access = free }}</ref> This came as a surprise to researchers but it makes evolutionary sense to re-use and adapt existing proteins instead of evolving a novel protein from scratch.

== Use as loading control ==

Because the GAPDH gene is often stably and constitutively expressed at high levels in most tissues and cells, it is considered a [[housekeeping gene]]. For this reason, GAPDH is commonly used by biological researchers as a [[Western blot normalization|loading control]] for [[western blot]] and as a control for [[qPCR]]. However, researchers have reported different regulation of GAPDH under specific conditions.<ref name="Barber_2005">{{cite journal | vauthors = Barber RD, Harmer DW, Coleman RA, Clark BJ | title = GAPDH as a housekeeping gene: analysis of GAPDH mRNA expression in a panel of 72 human tissues | journal = Physiological Genomics | volume = 21 | issue = 3 | pages = 389–395 | date = May 2005 | pmid = 15769908 | doi = 10.1152/physiolgenomics.00025.2005 | citeseerx = 10.1.1.459.7039 }}</ref> For example, the transcription factor [[MZF1|MZF-1]] has been shown to regulate the GAPDH gene.<ref>{{cite journal | vauthors = Piszczatowski RT, Rafferty BJ, Rozado A, Tobak S, Lents NH | title = The glyceraldehyde 3-phosphate dehydrogenase gene (GAPDH) is regulated by myeloid zinc finger 1 (MZF-1) and is induced by calcitriol | journal = Biochemical and Biophysical Research Communications | volume = 451 | issue = 1 | pages = 137–141 | date = August 2014 | pmid = 25065746 | doi = 10.1016/j.bbrc.2014.07.082 }}</ref> Hypoxia also strongly upregulates GAPDH.<ref>{{cite journal | vauthors = Saygin D, Tabib T, Bittar HE, Valenzi E, Sembrat J, Chan SY, Rojas M, Lafyatis R | title = Transcriptional profiling of lung cell populations in idiopathic pulmonary arterial hypertension | journal = Pulmonary Circulation | volume = 10 | issue = 1 | pages = 239–243 | year = 2008 | pmid = 32166015 | doi = 10.1007/s11684-008-0045-7 | pmc = 7052475 | s2cid = 85327763 }}</ref> Therefore, the use of GAPDH as loading control has to be considered carefully.

== Cellular distribution ==

All steps of glycolysis take place in the [[cytosol]] and so does the reaction catalysed by GAPDH. In [[red blood cells]], 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="Campanella_2005">{{cite journal | vauthors = Campanella ME, Chu H, Low PS | title = Assembly and regulation of a glycolytic enzyme complex on the human erythrocyte membrane | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 7 | pages = 2402–2407 | date = February 2005 | pmid = 15701694 | pmc = 549020 | doi = 10.1073/pnas.0409741102 | doi-access = free | bibcode = 2005PNAS..102.2402C }}</ref> Bringing several glycolytic enzymes close to each other is expected to greatly increase the overall speed of glucose breakdown. Recent studies have also revealed that GAPDH is expressed in an iron dependent fashion on the exterior of the cell membrane a where it plays a role in maintenance of cellular iron homeostasis.<ref name="Sirover_2014">{{cite journal | vauthors = Sirover MA | title = Structural analysis of glyceraldehyde-3-phosphate dehydrogenase functional diversity | journal = The International Journal of Biochemistry & Cell Biology | volume = 57 | pages = 20–26 | date = December 2014 | pmid = 25286305 | pmc = 4268148 | doi = 10.1016/j.biocel.2014.09.026 }}</ref><ref name="Kumar_2012">{{cite journal | vauthors = Kumar S, Sheokand N, Mhadeshwar MA, Raje CI, Raje M | title = Characterization of glyceraldehyde-3-phosphate dehydrogenase as a novel transferrin receptor | journal = The International Journal of Biochemistry & Cell Biology | volume = 44 | issue = 1 | pages = 189–199 | date = January 2012 | pmid = 22062951 | doi = 10.1016/j.biocel.2011.10.016 }}</ref>

== Clinical significance ==

=== Cancer ===

GAPDH is overexpressed in multiple human cancers, such as cutaneous [[melanoma]], and its expression is positively correlated with tumor progression.<ref name=pmid25550585>{{cite journal | vauthors = Ramos D, Pellín-Carcelén A, Agustí J, Murgui A, Jordá E, Pellín A, Monteagudo C | title = Deregulation of glyceraldehyde-3-phosphate dehydrogenase expression during tumor progression of human cutaneous melanoma | journal = Anticancer Research | volume = 35 | issue = 1 | pages = 439–444 | date = January 2015 | pmid = 25550585 }}</ref><ref name=pmid23620736>{{cite journal | vauthors = Wang D, Moothart DR, Lowy DR, Qian X | title = The expression of glyceraldehyde-3-phosphate dehydrogenase associated cell cycle (GACC) genes correlates with cancer stage and poor survival in patients with solid tumors | journal = PLOS ONE | volume = 8 | issue = 4 | pages = e61262 | date = 2013 | pmid = 23620736 | pmc = 3631177 | doi = 10.1371/journal.pone.0061262 | doi-access = free | bibcode = 2013PLoSO...861262W }}</ref> Its glycolytic and antiapoptotic functions contribute to proliferation and protection of tumor cells, promoting [[tumorigenesis]]. Notably, GAPDH protects against [[telomere]] shortening induced by [[chemotherapeutic]] drugs that stimulate the [[sphingolipid]] [[ceramide]]. Meanwhile, conditions like [[oxidative stress]] impair GAPDH function, leading to cellular aging and death.<ref name="Nicholls_2012"/> Moreover, depletion of GAPDH has managed to induce [[senescence]] in tumor cells, thus presenting a novel therapeutic strategy for controlling tumor growth.<ref name=pmid21749859>{{cite journal | vauthors = Phadke M, Krynetskaia N, Mishra A, Krynetskiy E | title = Accelerated cellular senescence phenotype of GAPDH-depleted human lung carcinoma cells | journal = Biochemical and Biophysical Research Communications | volume = 411 | issue = 2 | pages = 409–415 | date = July 2011 | pmid = 21749859 | pmc = 3154080 | doi = 10.1016/j.bbrc.2011.06.165 }}</ref>

=== Neurodegeneration ===

GAPDH has been implicated in several neurodegenerative diseases and disorders, largely through interactions with other proteins specific to that disease or disorder. These interactions may affect not only energy metabolism but also other GAPDH functions.<ref name=pmid20727968/> For example, GAPDH interactions with [[beta-amyloid]] precursor protein (betaAPP) could interfere with its function regarding the [[cytoskeleton]] or membrane transport, while interactions with [[huntingtin]] could interfere with its function regarding apoptosis, nuclear [[tRNA]] transport, [[DNA replication]], and [[DNA repair]]. In addition, nuclear translocation of GAPDH has been reported in [[Parkinson's disease]] (PD), and several anti-apoptotic PD drugs, such as [[rasagiline]], function by preventing the nuclear translocation of GAPDH. 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.<ref name=pmid12428732>{{cite journal | vauthors = Mazzola JL, Sirover MA | title = Alteration of intracellular structure and function of glyceraldehyde-3-phosphate dehydrogenase: a common phenotype of neurodegenerative disorders? | journal = Neurotoxicology | volume = 23 | issue = 4–5 | pages = 603–609 | date = October 2002 | pmid = 12428732 | doi = 10.1016/s0161-813x(02)00062-1 }}</ref> The [[Single-nucleotide polymorphism|SNP]] rs3741916 in the [[5']] [[Untranslated region|UTR]] of the ''GAPDH'' gene may be associated with late onset [[Alzheimer's disease]].<ref name=pmid20864222>{{cite journal | vauthors = Allen M, Cox C, Belbin O, Ma L, Bisceglio GD, Wilcox SL, Howell CC, Hunter TA, Culley O, Walker LP, Carrasquillo MM, Dickson DW, Petersen RC, Graff-Radford NR, Younkin SG, Ertekin-Taner N | title = Association and heterogeneity at the GAPDH locus in Alzheimer's disease | journal = Neurobiology of Aging | volume = 33 | issue = 1 | pages = 203.e25–203.e33 | date = January 2012 | pmid = 20864222 | pmc = 3017231 | doi = 10.1016/j.neurobiolaging.2010.08.002 }}</ref>

== Interactions ==

=== Protein binding partners ===

GAPDH participates in a number of biological functions through its [[protein–protein interactions]] with:
{{div col|colwidth=33em}}
* [[tubulin]] to facilitate microtubule bundling;<ref name=pmid20727968/>
* [[actin]] to facilitate actin polymerization;<ref name=pmid20727968/>
* [[VDAC1]] to induce [[mitochondria]]l [[membrane permeability|membrane permeabilization]] (MMP) and apoptosis;<ref name=pmid20727968/>
* Inositol 1,4,5-trisphosphate receptor to regulate intracellular [[Ca2+]] [[signal transduction|signaling]];<ref name=pmid20727968/>
* [[Oct-1]] to form the [[coactivator]] [[protein complex|complex]] OCA-S, which is required for [[histone H2B]] synthesis during [[S phase]] of the [[cell cycle]];<ref name="Nicholls_2012"/>
* [[p22 (protein)|p22]] to aid [[microtubule]] organization;<ref name="Nicholls_2012"/>
* Rab2 to facilitate [[endoplasmic reticulum]] (ER)–[[golgi apparatus|golgi]] transport;<ref name="Nicholls_2012"/> 
* [[Transferrin]] on the surface of diverse cells and in extracellular fluid;<ref name="Nicholls_2012"/><ref name="Kumar_2012"/><ref>{{cite journal | vauthors = Raje CI, Kumar S, Harle A, Nanda JS, Raje M | title = The macrophage cell surface glyceraldehyde-3-phosphate dehydrogenase is a novel transferrin receptor | journal = The Journal of Biological Chemistry | volume = 282 | issue = 5 | pages = 3252–3261 | date = February 2007 | pmid = 17121833 | doi = 10.1074/jbc.M608328200 | doi-access = free }}</ref>
* [[Lactate dehydrogenase]];<ref name="Nicholls_2012"/>
* Lactoferrin;<ref name="Chauhan_2015">{{cite journal | vauthors = Chauhan AS, Rawat P, Malhotra H, Sheokand N, Kumar M, Patidar A, Chaudhary S, Jakhar P, Raje CI, Raje M | title = Secreted multifunctional Glyceraldehyde-3-phosphate dehydrogenase sequesters lactoferrin and iron into cells via a non-canonical pathway | journal = Scientific Reports | volume = 5 | issue =  | pages = 18465 | date = December 2015 | pmid = 26672975 | pmc = 4682080 | doi = 10.1038/srep18465 | bibcode = 2015NatSR...518465C }}</ref>
* Apurinic/apyrimidinic endonuclease ([[APEX1|APE1]]), thus converting oxidized APE1 to its reduced form, to restart its [[endonuclease]] activity;<ref name="Nicholls_2012"/>
* [[Promyelocytic leukemia protein|Promyelocytic leukaemia protein]] (PML) in an [[RNA]]-dependent fashion;<ref name="Nicholls_2012"/>
* [[Rheb]] to sequester the [[GTPase]] during low glucose conditions;<ref name="Nicholls_2012"/>
* Siah1 to form a complex that translocates to the nucleus, where it [[ubiquitin]]ates and degrades nuclear proteins during nitrosative stress conditions;<ref name="Nicholls_2012"/>
* GAPDH's competitor of Siah protein enhances life (GOSPEL) to block GAPDH interaction with Siah1 and, thus, cell death in response to oxidative stress;<ref name="Nicholls_2012"/> 
* p300/[[CREB-binding protein|CREB binding protein]] (CBP), which [[acetylate]]s GAPDH and, in turn, enhances the acetylation of additional apoptotic targets;<ref name="Nicholls_2012"/>
* skeletal muscle-specific Ca2+/calmodulin-dependent protein kinase;<ref name="Nicholls_2012"/>
* [[Akt]];<ref name="Nicholls_2012"/>
* [[Beta-amyloid]] precursor protein (betaAPP);<ref name=pmid12428732/>
* [[Huntingtin]].<ref name=pmid12428732/>
* [[GAPDH]] can self-associate into homotypic oligomers/aggregates
{{Div col end}}

=== Nucleic acid binding partners ===

GAPDH binds to single-stranded RNA <ref>{{cite journal | vauthors = White MR, Khan MM, Deredge D, Ross CR, Quintyn R, Zucconi BE, Wysocki VH, Wintrode PL, Wilson GM, Garcin ED | title = A dimer interface mutation in glyceraldehyde-3-phosphate dehydrogenase regulates its binding to AU-rich RNA | journal = The Journal of Biological Chemistry | volume = 290 | issue = 3 | pages = 1770–1785 | date = January 2015 | pmid = 25451934 | pmc = 4340419 | doi = 10.1074/jbc.M114.618165 | doi-access = free }}</ref> and DNA and a number of nucleic acid binding partners have been identified:<ref name="Nicholls_2012"/>
{{div col|colwidth=33em}}
* [[tRNA]],
* [[Hepatitis A]] viral RNA,
* [[Hepatitis B]] viral RNA,
* [[Hepatitis C]] viral RNA,
* HPIV3,
* [[lymphokine]] mRNA,
* [[IFN-γ]] mRNA,
* [[JEV]] mRNA, and
* [[telomere|telomeric]] DNA.
{{Div col end}}

===Inhibitors===
* [[Desmethylselegiline]]<ref name="GerlachReichmannRiederer2012">{{cite journal | vauthors = Gerlach M, Reichmann H, Riederer P | title=A critical review of evidence for preclinical differences between rasagiline and selegiline | journal=Basal Ganglia | volume=2 | issue=4 | date=2012 | doi=10.1016/j.baga.2012.04.032 | pages=S9–S15 }}</ref>
* [[Koningic acid]]
* [[Rasagiline]]<ref name="GerlachReichmannRiederer2012" />
* [[Selegiline]]<ref name="GerlachReichmannRiederer2012" />

== Interactive pathway map ==

{{GlycolysisGluconeogenesis_WP534|highlight=Glyceraldehyde_3-phosphate_dehydrogenase}}

== References ==
{{reflist}}

== Further reading ==
{{refbegin|30em}}
* {{cite book | vauthors = Voet D, Voet JG | title = Biochemistry | publisher = Wiley | location = New York | year = 2010 | isbn = 978-0-470-57095-1 }}
* {{cite book | vauthors = Stryer L, Berg JM, Tymoczko JL | title = Biochemistry, Fifth Edition & Lecture Notebook | publisher = W. H. Freeman | location = San Francisco | year = 2002 | isbn = 978-0-7167-9804-0 }}
* [https://www.ncbi.nlm.nih.gov/books/bv.fcgi?highlight=glyceraldehyde+3+phosphate+dehydrogenase&rid=mcb.figgrp.4342 diagram of the GAPDH reaction mechanism] from Lodish MCB at NCBI bookshelf
* [https://www.ncbi.nlm.nih.gov/books/bv.fcgi?highlight=glyceraldehyde+3+phosphate+dehydrogenase&rid=mboc4.figgrp.297 similar diagram] from Alberts The Cell at NCBI bookshelf
{{refend}}

== External links ==
*[https://www.ebi.ac.uk/pdbe/pdbe-kb/proteins/P04406 PDBe-KB] provides an overview of all the structure information available in the PDB for Human Glyceraldehyde-3-phosphate dehydrogenase

{{PDB_Gallery|geneid=2597}}
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{{Glycolysis enzymes}}
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{{DEFAULTSORT:Glyceraldehyde 3-Phosphate Dehydrogenase}}
[[Category:EC 1.2.1]]
[[Category:Glycolysis enzymes]]
[[Category:Glycolysis]]