Please note: this site relies heavily on the use of javascript. Without a javascript-enabled browser, this site will not function correctly. Please enable javascript and reload the page, or switch to a different browser.
467  structures 3132  species 5  interactions 5852  sequences 35  architectures

Family: Gp_dh_N (PF00044)

Summary: Glyceraldehyde 3-phosphate dehydrogenase, NAD binding domain

Pfam includes annotations and additional family information from a range of different sources. These sources can be accessed via the tabs below.

This is the Wikipedia entry entitled "Glyceraldehyde 3-phosphate dehydrogenase". More...

Glyceraldehyde 3-phosphate dehydrogenase Edit Wikipedia article

GAPDH
GAPDH with labels.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases GAPDH, GAPD, G3PD, HEL-S-162eP, glyceraldehyde-3-phosphate dehydrogenase
External IDs OMIM: 138400 MGI: 5434255 HomoloGene: 107053 GeneCards: GAPDH
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_002046
NM_001256799
NM_001289745
NM_001289746

XM_001476707

RefSeq (protein)

NP_001243728.1
NP_001276674.1
NP_001276675.1
NP_002037.2

NP_001276655.1
NP_032110.1

Location (UCSC) Chr 12: 6.53 – 6.54 Mb Chr 6: 125.16 – 125.17 Mb
PubMed search [1] [2]
Wikidata
View/Edit Human View/Edit Mouse
Glyceraldehyde 3-phosphate dehydrogenase, NAD binding domain
PDB 1cer EBI.jpg
determinants of enzyme thermostability observed in the molecular structure of thermus aquaticus d-glyceraldehyde-3-phosphate dehydrogenase at 2.5 angstroms resolution
Identifiers
Symbol Gp_dh_N
Pfam PF00044
Pfam clan CL0063
InterPro IPR020828
PROSITE PDOC00069
SCOP 1gd1
SUPERFAMILY 1gd1
Glyceraldehyde 3-phosphate dehydrogenase, C-terminal domain
PDB 2czc EBI.jpg
crystal structure of glyceraldehyde-3-phosphate dehydrogenase from pyrococcus horikoshii ot3
Identifiers
Symbol Gp_dh_C
Pfam PF02800
Pfam clan CL0139
InterPro IPR020829
PROSITE PDOC00069
SCOP 1gd1
SUPERFAMILY 1gd1

Glyceraldehyde 3-phosphate dehydrogenase (abbreviated as GAPDH or less commonly as G3PDH) (EC 1.2.1.12) is an enzyme of ~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,[3] ER to Golgi vesicle shuttling, and fast axonal, or axoplasmic transport.[4] In sperm, a testis-specific isoenzyme GAPDHS is expressed.

Structure

Under normal cellular conditions, cytoplasmic 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.[5][6] Nuclear GAPDH has increased isoelectric point (pI) of pH 8.3–8.7.[6] Of note, the cysteine residue C152 in the enzyme's active site is required for the induction of apoptosis by oxidative stress.[6] Notably, post-translational modifications of cytoplasmic GAPDH contribute to its functions outside of glycolysis.[5]

Interestingly, GAPDH is encoded by a single gene that produces a single mRNA transcript with no known splice variants, though an isoform does exist as a separate gene that is expressed only in spermatozoa.[6]

Reaction

glyceraldehyde 3-phosphate glyceraldehyde phosphate dehydrogenase D-glycerate 1,3-bisphosphate
D-glyceraldehyde-3-phosphate wpmp.png   D-glycerate 1,3-bisphosphate.svg
NAD+ +Pi NADH + H+
Biochem reaction arrow reversible YYYY horiz med.png
NAD+ +Pi 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 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 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 high, and the reaction, therefore, too slow and equilibrium too unfavorable 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.

Regulation

This protein may use the morpheein model of allosteric regulation.[7]

Function

Metabolic

As its name indicates, glyceraldehyde 3-phosphate dehydrogenase (GAPDH) catalyses the conversion of glyceraldehyde 3-phosphate to D-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.

Transcription and apoptosis

GAPDH can itself activate 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 nucleus and may thus link the metabolic state to gene transcription.[8]

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 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 degradation, thus initiating controlled cell shutdown.[9] 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.[10]

Metabolic switch

GAPDH acts as reversible metabolic switch under oxidative stress.[11] When cells are exposed to oxidants, 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.[12] 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 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 rab2 to the vesicular-tubular clusters of the ER where it helps to form COP 1 vesicles. GAPDH is activated via tyrosine phosphorylation by Src.[13]

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.[14] 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 loading control for western blot and as a control for qPCR. However, researchers have reported different regulation of GAPDH under specific conditions.[15] For example, the transcription factor MZF-1 has been shown to regulate the GAPDH gene.[16] 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.[17] 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.[18][19]

Clinical significance

Cancer

GAPDH is overexpressed in multiple human cancers, such as cutaneous melanoma, and its expression is positively correlated with tumor progression.[20][21] 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.[6] Moreover, depletion of GAPDH has managed to induce senescence in tumor cells, thus presenting a novel therapeutic strategy for controlling tumor growth.[22]

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.[5] 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.[23] The SNP rs3741916 in the 5' UTR of the GAPDH gene may be associated with late onset Alzheimer's disease.[24]

Interactions

Protein binding partners

GAPDH participates in a number of biological functions through its protein–protein interactions with:

Nucleic acid binding partners

GAPDH binds to single-stranded RNA and DNA and a number of nucleic acid binding partners have been identified:[6]

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

[[File:
GlycolysisGluconeogenesis_WP534 go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to Entrez go to article go to article go to article go to article go to article go to WikiPathways go to article go to Entrez go to article
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
GlycolysisGluconeogenesis_WP534 go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to Entrez go to article go to article go to article go to article go to article go to WikiPathways go to article go to Entrez go to article
|{{{bSize}}}px|alt=Glycolysis and Gluconeogenesis edit]]
Glycolysis and Gluconeogenesis edit
  1. ^ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534". 

References

  1. ^ "Human PubMed Reference:". 
  2. ^ "Mouse PubMed Reference:". 
  3. ^ Tarze A, Deniaud A, Le Bras M, Maillier E, Molle D, Larochette N, Zamzami N, Jan G, Kroemer G, Brenner C (April 2007). "GAPDH, a novel regulator of the pro-apoptotic mitochondrial membrane permeabilization". Oncogene. 26 (18): 2606–20. doi:10.1038/sj.onc.1210074. PMID 17072346. 
  4. ^ Zala D, Hinckelmann MV, Yu H, Lyra da Cunha MM, Liot G, Cordelières FP, Marco S, Saudou F (January 2013). "Vesicular glycolysis provides on-board energy for fast axonal transport". Cell. 152 (3): 479–91. doi:10.1016/j.cell.2012.12.029. PMID 23374344. 
  5. ^ a b c d e f g Tristan C, Shahani N, Sedlak TW, Sawa A (February 2011). "The diverse functions of GAPDH: views from different subcellular compartments". Cellular Signalling. 23 (2): 317–23. doi:10.1016/j.cellsig.2010.08.003. PMID 20727968. 
  6. ^ a b c d e f g h i j k l m n o p q r s Nicholls C, Li H, Liu JP (August 2012). "GAPDH: a common enzyme with uncommon functions". Clinical and Experimental Pharmacology & Physiology. 39 (8): 674–9. doi:10.1111/j.1440-1681.2011.05599.x. PMID 21895736. 
  7. ^ Selwood T, Jaffe EK (March 2012). "Dynamic dissociating homo-oligomers and the control of protein function". Archives of Biochemistry and Biophysics. 519 (2): 131–43. doi:10.1016/j.abb.2011.11.020. PMC 3298769Freely accessible. PMID 22182754. 
  8. ^ Zheng L, Roeder RG, Luo Y (July 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. doi:10.1016/S0092-8674(03)00552-X. PMID 12887926. 
  9. ^ 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 (July 2005). "S-nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following Siah1 binding". Nature Cell Biology. 7 (7): 665–74. doi:10.1038/ncb1268. PMID 15951807. 
  10. ^ Hara MR, Thomas B, Cascio MB, Bae BI, Hester LD, Dawson VL, Dawson TM, Sawa A, Snyder SH (March 2006). "Neuroprotection by pharmacologic blockade of the GAPDH death cascade". Proceedings of the National Academy of Sciences of the United States of America. 103 (10): 3887–9. doi:10.1073/pnas.0511321103. PMC 1450161Freely accessible. PMID 16505364. 
  11. ^ Agarwal AR, Zhao L, Sancheti H, Sundar IK, Rahman I, Cadenas E (November 2012). "Short-term cigarette smoke exposure induces reversible changes in energy metabolism and cellular redox status independent of inflammatory responses in mouse lungs". American Journal of Physiology. Lung Cellular and Molecular Physiology. 303 (10): L889–98. doi:10.1152/ajplung.00219.2012. PMID 23064950. 
  12. ^ Ralser M, Wamelink MM, Kowald A, Gerisch B, Heeren G, Struys EA, Klipp E, Jakobs C, Breitenbach M, Lehrach H, Krobitsch S (2007). "Dynamic rerouting of the carbohydrate flux is key to counteracting oxidative stress". Journal of Biology. 6 (4): 10. doi:10.1186/jbiol61. PMC 2373902Freely accessible. PMID 18154684. 
  13. ^ Tisdale EJ, Artalejo CR (June 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. 
  14. ^ Boradia VM, Raje M, Raje CI (December 2014). "Protein moonlighting in iron metabolism: glyceraldehyde-3-phosphate dehydrogenase (GAPDH)". Biochemical Society Transactions. 42 (6): 1796–801. doi:10.1042/BST20140220. PMID 25399609. 
  15. ^ Barber RD, Harmer DW, Coleman RA, Clark BJ (May 2005). "GAPDH as a housekeeping gene: analysis of GAPDH mRNA expression in a panel of 72 human tissues". Physiological Genomics. 21 (3): 389–95. doi:10.1152/physiolgenomics.00025.2005. PMID 15769908. 
  16. ^ Piszczatowski RT, Rafferty BJ, Rozado A, Tobak S, Lents NH (August 2014). "The glyceraldehyde 3-phosphate dehydrogenase gene (GAPDH) is regulated by myeloid zinc finger 1 (MZF-1) and is induced by calcitriol". Biochemical and Biophysical Research Communications. 451 (1): 137–41. doi:10.1016/j.bbrc.2014.07.082. PMID 25065746. 
  17. ^ Campanella ME, Chu H, Low PS (February 2005). "Assembly and regulation of a glycolytic enzyme complex on the human erythrocyte membrane". Proceedings of the National Academy of Sciences of the United States of America. 102 (7): 2402–7. doi:10.1073/pnas.0409741102. PMC 549020Freely accessible. PMID 15701694. 
  18. ^ Sirover MA (December 2014). "Structural analysis of glyceraldehyde-3-phosphate dehydrogenase functional diversity". The International Journal of Biochemistry & Cell Biology. 57: 20–6. doi:10.1016/j.biocel.2014.09.026. PMID 25286305. 
  19. ^ a b Kumar S, Sheokand N, Mhadeshwar MA, Raje CI, Raje M (January 2012). "Characterization of glyceraldehyde-3-phosphate dehydrogenase as a novel transferrin receptor". The International Journal of Biochemistry & Cell Biology. 44 (1): 189–99. doi:10.1016/j.biocel.2011.10.016. PMID 22062951. 
  20. ^ Ramos D, Pellín-Carcelén A, Agustí J, Murgui A, Jordá E, Pellín A, Monteagudo C (January 2015). "Deregulation of glyceraldehyde-3-phosphate dehydrogenase expression during tumor progression of human cutaneous melanoma". Anticancer Research. 35 (1): 439–44. PMID 25550585. 
  21. ^ Wang D, Moothart DR, Lowy DR, Qian X (2013). "The expression of glyceraldehyde-3-phosphate dehydrogenase associated cell cycle (GACC) genes correlates with cancer stage and poor survival in patients with solid tumors". PLOS ONE. 8 (4): e61262. doi:10.1371/journal.pone.0061262. PMC 3631177Freely accessible. PMID 23620736. 
  22. ^ Phadke M, Krynetskaia N, Mishra A, Krynetskiy E (July 2011). "Accelerated cellular senescence phenotype of GAPDH-depleted human lung carcinoma cells". Biochemical and Biophysical Research Communications. 411 (2): 409–15. doi:10.1016/j.bbrc.2011.06.165. PMID 21749859. 
  23. ^ a b c Mazzola JL, Sirover MA (October 2002). "Alteration of intracellular structure and function of glyceraldehyde-3-phosphate dehydrogenase: a common phenotype of neurodegenerative disorders?". Neurotoxicology. 23 (4–5): 603–9. doi:10.1016/s0161-813x(02)00062-1. PMID 12428732. 
  24. ^ 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 (January 2012). "Association and heterogeneity at the GAPDH locus in Alzheimer's disease". Neurobiology of Aging. 33 (1): 203.e25–33. doi:10.1016/j.neurobiolaging.2010.08.002. PMID 20864222. 
  25. ^ Raje CI, Kumar S, Harle A, Nanda JS, Raje M (February 2007). "The macrophage cell surface glyceraldehyde-3-phosphate dehydrogenase is a novel transferrin receptor". The Journal of Biological Chemistry. 282 (5): 3252–61. doi:10.1074/jbc.M608328200. PMID 17121833. 
  26. ^ Secreted multifunctional Glyceraldehyde-3-phosphate dehydrogenase sequesters lactoferrin and iron into cells via a non-canonical pathway. Anoop S. Chauhan, Pooja Rawat, Himanshu Malhotra, Navdeep Sheokand, Manoj Kumar, Anil Patidar, Surbhi Chaudhary, Priyanka Jakhar, Chaaya I. Raje and Manoj Raje Scientific Reports 5, 18465; doi:10.1038/srep18465 (2015)

Further reading

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

Glyceraldehyde 3-phosphate dehydrogenase, NAD binding domain Provide feedback

GAPDH is a tetrameric NAD-binding enzyme involved in glycolysis and glyconeogenesis. N-terminal domain is a Rossmann NAD(P) binding fold.

Literature references

  1. Kim H, Feil IK, Verlinde CL, Petra PH, Hol WG; , Biochemistry 1995;34:14975-14986.: Crystal structure of glycosomal glyceraldehyde-3-phosphate dehydrogenase from Leishmania mexicana: implications for structure-based drug design and a new position for the inorganic phosphate binding site. PUBMED:7578111 EPMC:7578111


Internal database links

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR020828

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) plays an important role in glycolysis and gluconeogenesis [PUBMED:2716055] by reversibly catalysing the oxidation and phosphorylation of D-glyceraldehyde-3-phosphate to 1,3-diphospho-glycerate. The enzyme exists as a tetramer of identical subunits, each containing 2 conserved functional domains: an NAD-binding domain, and a highly conserved catalytic domain [PUBMED:6303388]. The enzyme has been found to bind to actin and tropomyosin, and may thus have a role in cytoskeleton assembly. Alternatively, the cytoskeleton may provide a framework for precise positioning of the glycolytic enzymes, thus permitting efficient passage of metabolites from enzyme to enzyme [PUBMED:6303388].

GAPDH displays diverse non-glycolytic functions as well, its role depending upon its subcellular location. For instance, the translocation of GAPDH to the nucleus acts as a signalling mechanism for programmed cell death, or apoptosis [PUBMED:10740219]. The accumulation of GAPDH within the nucleus is involved in the induction of apoptosis, where GAPDH functions in the activation of transcription. The presence of GAPDH is associated with the synthesis of pro-apoptotic proteins like BAX, c-JUN and GAPDH itself.

GAPDH has been implicated in certain neurological diseases: GAPDH is able to bind to the gene products from neurodegenerative disorders such as Huntington's disease, Alzheimer's disease, Parkinson's disease and Machado-Joseph disease through stretches encoded by their CAG repeats. Abnormal neuronal apoptosis is associated with these diseases. Propargylamines such as deprenyl increase neuronal survival by interfering with apoptosis signalling pathways via their binding to GAPDH, which decreases the synthesis of pro-apoptotic proteins [PUBMED:12721812].

This entry represents the N-terminal domain which is a Rossmann NAD(P) binding fold.

Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

Loading domain graphics...

Pfam Clan

This family is a member of clan NADP_Rossmann (CL0063), which has the following description:

A class of redox enzymes are two domain proteins. One domain, termed the catalytic domain, confers substrate specificity and the precise reaction of the enzyme. The other domain, which is common to this class of redox enzymes, is a Rossmann-fold domain. The Rossmann domain binds nicotinamide adenine dinucleotide (NAD+) and it is this cofactor that reversibly accepts a hydride ion, which is lost or gained by the substrate in the redox reaction. Rossmann domains have an alpha/beta fold, which has a central beta sheet, with approximately five alpha helices found surrounding the beta sheet.The strands forming the beta sheet are found in the following characteristic order 654123. The inter sheet crossover of the stands in the sheet form the NAD+ binding site [1]. In some more distantly relate Rossmann domains the NAD+ cofactor is replaced by the functionally similar cofactor FAD.

The clan contains the following 184 members:

2-Hacid_dh_C 3Beta_HSD 3HCDH_N adh_short adh_short_C2 ADH_zinc_N ADH_zinc_N_2 AdoHcyase_NAD AdoMet_MTase AlaDh_PNT_C Amino_oxidase ApbA AviRa B12-binding Bac_GDH Bin3 Bmt2 CheR CMAS CmcI CoA_binding CoA_binding_2 CoA_binding_3 Cons_hypoth95 DAO DapB_N DFP DNA_methylase DOT1 DREV DUF1442 DUF166 DUF1776 DUF2431 DUF268 DUF364 DUF43 DUF5129 DUF5130 DUF938 DXP_redisom_C DXP_reductoisom Eco57I ELFV_dehydrog Eno-Rase_FAD_bd Eno-Rase_NADH_b Enoyl_reductase Epimerase F420_oxidored FAD_binding_2 FAD_binding_3 FAD_oxidored Fibrillarin FMO-like FmrO FtsJ G6PD_N GCD14 GDI GDP_Man_Dehyd GFO_IDH_MocA GIDA GidB GLF Glu_dehyd_C Glyco_hydro_4 GMC_oxred_N Gp_dh_N GRAS GRDA HI0933_like HIM1 IlvN K_oxygenase KR LCM Ldh_1_N Lycopene_cycl Malic_M Mannitol_dh MCRA Met_10 Methyltr_RsmB-F Methyltrans_Mon Methyltrans_SAM Methyltransf_10 Methyltransf_11 Methyltransf_12 Methyltransf_15 Methyltransf_16 Methyltransf_17 Methyltransf_18 Methyltransf_19 Methyltransf_2 Methyltransf_20 Methyltransf_21 Methyltransf_22 Methyltransf_23 Methyltransf_24 Methyltransf_25 Methyltransf_28 Methyltransf_29 Methyltransf_3 Methyltransf_30 Methyltransf_31 Methyltransf_32 Methyltransf_34 Methyltransf_4 Methyltransf_5 Methyltransf_7 Methyltransf_8 Methyltransf_9 Methyltransf_PK MethyltransfD12 MetW Mg-por_mtran_C MOLO1 Mqo MT-A70 MTS Mur_ligase N2227 N6-adenineMlase N6_Mtase N6_N4_Mtase NAD_binding_10 NAD_binding_2 NAD_binding_3 NAD_binding_4 NAD_binding_5 NAD_binding_7 NAD_binding_8 NAD_binding_9 NAD_Gly3P_dh_N NAS NmrA NNMT_PNMT_TEMT NodS NSP13 OCD_Mu_crystall PARP_regulatory PCMT PDH Polysacc_synt_2 Pox_MCEL Prenylcys_lyase PrmA PRMT5 Pyr_redox Pyr_redox_2 Pyr_redox_3 RmlD_sub_bind Rossmann-like rRNA_methylase RrnaAD Rsm22 RsmJ Sacchrp_dh_NADP SAM_MT SAMBD SE Semialdhyde_dh Shikimate_DH Spermine_synth TehB THF_DHG_CYH_C Thi4 ThiF TPM_phosphatase TPMT TrkA_N TRM TRM13 TrmK tRNA_U5-meth_tr Trp_halogenase TylF Ubie_methyltran UDPG_MGDP_dh_N UPF0020 UPF0146 V_cholerae_RfbT XdhC_C YjeF_N

Alignments

We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the UniProtKB sequence database, the NCBI sequence database, and our metagenomics sequence database. More...

View options

We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

  Seed
(80)
Full
(5852)
Representative proteomes UniProt
(26344)
NCBI
(28747)
Meta
(2977)
RP15
(1427)
RP35
(4034)
RP55
(6863)
RP75
(10566)
Jalview View  View  View  View  View  View  View  View  View 
HTML View                 
PP/heatmap 1                

1Cannot generate PP/Heatmap alignments for seeds; no PP data available

Key: ✓ available, x not generated, not available.

Format an alignment

  Seed
(80)
Full
(5852)
Representative proteomes UniProt
(26344)
NCBI
(28747)
Meta
(2977)
RP15
(1427)
RP35
(4034)
RP55
(6863)
RP75
(10566)
Alignment:
Format:
Order:
Sequence:
Gaps:
Download/view:

Download options

We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.

  Seed
(80)
Full
(5852)
Representative proteomes UniProt
(26344)
NCBI
(28747)
Meta
(2977)
RP15
(1427)
RP35
(4034)
RP55
(6863)
RP75
(10566)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download   Download   Download  
Gzipped Download   Download   Download   Download   Download   Download   Download   Download   Download  

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...

Trees

This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

Note: You can also download the data file for the tree.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Overington
Previous IDs: gpdh;
Type: Domain
Author: Eddy SR, Griffiths-Jones SR
Number in seed: 80
Number in full: 5852
Average length of the domain: 101.60 aa
Average identity of full alignment: 41 %
Average coverage of the sequence by the domain: 29.48 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 17690987 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 23.4 23.4
Trusted cut-off 23.4 23.4
Noise cut-off 23.3 23.3
Model length: 101
Family (HMM) version: 22
Download: download the raw HMM for this family

Species distribution

Sunburst controls

Hide

Weight segments by...


Change the size of the sunburst

Small
Large

Colour assignments

Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence

Selections

Align selected sequences to HMM

Generate a FASTA-format file

Clear selection

This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

Loading sunburst data...

Tree controls

Hide

The tree shows the occurrence of this domain across different species. More...

Loading...

Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.

Interactions

There are 5 interactions for this family. More...

Gp_dh_C CP12 Gp_dh_C CP12 Gp_dh_N

Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Gp_dh_N domain has been found. There are 467 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

Loading structure mapping...