Summary: Glucose-6-phosphate dehydrogenase, NAD binding domain
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Glucose-6-phosphate dehydrogenase Edit Wikipedia article
|Glucose-6-phosphate dehydrogenase, NAD binding domain|
glucose 6-phosphate dehydrogenase from leuconostoc mesenteroides
|PDB structures||RCSB PDB PDBe PDBsum|
|Gene Ontology||AmiGO / QuickGO|
- D-glucose 6-phosphate + NADP+ ⇌ 6-phospho-D-glucono-1,5-lactone + NADPH + H+
This enzyme participates in the pentose phosphate pathway (see image), a metabolic pathway that supplies reducing energy to cells (such as erythrocytes) by maintaining the level of the co-enzyme nicotinamide adenine dinucleotide phosphate (NADPH). The NADPH in turn maintains the level of glutathione in these cells that helps protect the red blood cells against oxidative damage from compounds like hydrogen peroxide. Of greater quantitative importance is the production of NADPH for tissues involved in biosynthesis of fatty acids or isoprenoids, such as the liver, mammary glands, adipose tissue, and the adrenal glands. G6PD reduces NADP+ to NADPH while oxidizing glucose-6-phosphate.
G6PD is widely distributed in many species from bacteria to humans. Multiple sequence alignment of over 100 known G6PDs from different organisms reveal sequence identity ranging from 30% to 94%. Human G6PD has over 30% identity in amino acid sequence to G6PD sequences from other species. Humans also have two isoforms of a single gene coding for G6PD. Moreover, 150 different human G6PD mutants have been documented. These mutations are mainly missense mutations that result in amino acid substitutions, and while some of them result in G6PD deficiency, others do not seem to result in any noticeable functional differences. Some scientists have proposed that some of the genetic variation in human G6PD resulted from generations of adaptation to malarial infection.
Other species experience a variation in G6PD as well. In higher plants, several isoforms of G6PDH have been reported, which are localized in the cytosol, the plastidic stroma, and peroxisomes. A modified F420-dependent (as opposed to NADP+-dependent) G6PD is found in Mycobacterium tuberculosis, and is of interest for treating tuberculosis. The bacterial G6PD found in Leuconostoc mesenteroides was shown to be reactive toward 4-Hydroxynonenal, in addition to G6P.
G6PD is generally found as a dimer of two identical monomers (see main thumbnail). Depending on conditions, such as pH, these dimers can themselves dimerize to form tetramers. Each monomer in the complex has a substrate binding site that binds to G6P, and a catalytic coenzyme binding site that binds to NADP+/NADPH using the Rossman fold. For some higher organisms, such as humans, G6PD contains an additional NADP+ binding site, called the NADP+ structural site, that does not seem to participate directly in the reaction catalyzed by G6PD. The evolutionary purpose of the NADP+ structural site is unknown. As for size, each monomer is approximately 500 amino acids long (514 amino acids for humans).
Functional and structural conservation between human G6PD and Leuconostoc mesenteroides G6PD points to 3 widely conserved regions on the enzyme: a 9 residue peptide in the substrate binding site, RIDHYLGKE (residues 198-206 on human G6PD), a nucleotide-binding fingerprint, GxxGDLA (residues 38-44 on human G6PD), and a partially conserved sequence EKPxG near the substrate binding site (residues 170-174 on human G6PD), where we have use "x" to denote a variable amino acid. The crystal structure of G6PD reveals an extensive network of electrostatic interactions and hydrogen bonding involving G6P, 3 water molecules, 3 lysines, 1 arginine, 2 histidines, 2 glutamic acids, and other polar amino acids.
The proline at position 172 is thought to play a crucial role in positioning Lys171 correctly with respect to the substrate, G6P. In the two crystal structures of normal human G6P, Pro172 is seen exclusively in the cis confirmation, while in the crystal structure of one disease causing mutant (variant Canton R459L), Pro172 is seen almost exclusively in the trans confirmation.
With access to crystal structures, some scientists have tried to model the structures of other mutants. For example, in German ancestry, where enzymopathy due to G6PD deficiency is rare, mutation sites on G6PD have been shown to lie near the NADP+ binding site, the G6P binding site, and near the interface between the two monomers. Thus, mutations in these critical areas are possible without completely disrupting the function of G6PD. In fact, it has been shown that most disease causing mutations of G6PD occur near the NADP+ structural site.
NADP+ structural site
The NADP+ structural site is located greater than 20Å away from the substrate binding site and the catalytic coenzyme NADP+ binding site. Its purpose in the enzyme catalyzed reaction has been unclear for many years. For some time, it was thought that NADP+ binding to the structural site was necessary for dimerization of the enzyme monomers. However, this was shown to be incorrect. On the other hand, it was shown that the presence of NADP+ at the structural site promotes the dimerization of dimers to form enzyme tetramers. It was also thought that the tetramer state was necessary for catalytic activity; however, this too was shown to be false. The NADP+ structural site is quite different from the NADP+ catalytic coenzyme binding site, and contains the nucleotide-binding fingerprint.
The structural site bound to NADP+ possesses favorable interactions that keep it tightly bound. In particular, there is a strong network of hydrogen bonding with electrostatic charges being diffused across multiple atoms through hydrogen bonding with 4 water molecules (see figure). Moreover, there is an extremely strong set of hydrophobic stacking interactions that result in overlapping π systems.
The structural site has been shown to be important for maintaining the long term stability of the enzyme. More than 40 severe class I mutations involve mutations near the structural site, thus affecting the long term stability of these enzymes in the body, ultimately resulting in G6PD deficiency. For example, two severe class I mutations, G488S and G488V, drastically increase the dissociation constant between NADP+ and the structural site by a factor of 7 to 13. With the proximity of residue 488 to Arg487, it is thought that a mutation at position 488 could affect the positioning of Arg487 relative to NADP+, and thus disrupt binding.
G6PD converts G6P into 6-phosphoglucono-δ-lactone and is the rate-limiting enzyme of the pentose phosphate pathway. Thus, regulation of G6PD has downstream consequences for the activity of the rest of the pentose phosphate pathway.
Glucose-6-phosphate dehydrogenase is stimulated by its substrate G6P. The usual ratio of NADPH/NADP+ in the cytosol of tissues engaged in biosyntheses is about 100/1. Increased utilization of NADPH for fatty acid biosynthesis will dramatically increase the level of NADP+, thus stimulating G6PD to produce more NADPH. Yeast G6PD is inhibited by long chain fatty acids according to two older publications and might be product inhibition in fatty acid synthesis which requires NADPH.
G6PD is negatively regulated by acetylation on lysine 403 (Lys403), an evolutionarily conserved residue. The K403 acetylated G6PD is incapable of forming active dimers and displays a complete loss of activity. Mechanistically, acetylating Lys304 sterically hinders the NADP+ from entering the NADP+ structural site, which reduces the stability of the enzyme. Cells sense extracellular oxidative stimuli to decrease G6PD acetylation in a SIRT2-dependent manner. The SIRT2-mediated deacetylation and activation of G6PD stimulates pentose phosphate pathway to supply cytosolic NADPH to counteract oxidative damage and protect mouse erythrocytes.
Regulation can also occur through genetic pathways. The isoform, G6PDH, is regulated by transcription and posttranscription factors. Moreover, G6PD is one of a number of glycolytic enzymes activated by the transcription factor hypoxia-inducible factor 1 (HIF1).
G6PD is remarkable for its genetic diversity. Many variants of G6PD, mostly produced from missense mutations, have been described with wide-ranging levels of enzyme activity and associated clinical symptoms. Two transcript variants encoding different isoforms have been found for this gene.
Glucose-6-phosphate dehydrogenase deficiency is very common worldwide, and causes acute hemolytic anemia in the presence of simple infection, ingestion of fava beans, or reaction with certain medicines, antibiotics, antipyretics, and antimalarials.
Cell growth and proliferation are affected by G6PD. G6PD inhibitors are under investigation to treat cancers and other conditions. In vitro cell proliferation assay indicates that G6PD inhibitors, DHEA (dehydroepiandrosterone) and ANAD (6-aminonicotinamide), effectively decrease the growth of AML cell lines. G6PD is hypomethylated at K403 in acute myeloid leukemia, SIRT2 activates G6PD to enhance NADPH production and promote leukemia cell proliferation.
- Thomas D, Cherest H, Surdin-Kerjan Y (March 1991). "Identification of the structural gene for glucose-6-phosphate dehydrogenase in yeast. Inactivation leads to a nutritional requirement for organic sulfur". The EMBO Journal. 10 (3): 547–53. PMC . PMID 2001672.
- Aster J, Kumar V, Robbins SL, Abbas AK, Fausto N, Cotran RS (2010). Robbins and Cotran Pathologic Basis of Disease. Saunders/Elsevier. pp. Kindle Locations 33340–33341. ISBN 1-4160-3121-9.
- Cappellini MD, Fiorelli G (January 2008). "Glucose-6-phosphate dehydrogenase deficiency". Lancet. 371 (9606): 64–74. doi:10.1016/S0140-6736(08)60073-2. PMID 18177777.
- Kotaka M, Gover S, Vandeputte-Rutten L, Au SW, Lam VM, Adams MJ (May 2005). "Structural studies of glucose-6-phosphate and NADP+ binding to human glucose-6-phosphate dehydrogenase". Acta Crystallographica D. 61 (Pt 5): 495–504. doi:10.1107/S0907444905002350. PMID 15858258.
- Au SW, Gover S, Lam VM, Adams MJ (March 2000). "Human glucose-6-phosphate dehydrogenase: the crystal structure reveals a structural NADP(+) molecule and provides insights into enzyme deficiency". Structure. 8 (3): 293–303. doi:10.1016/S0969-2126(00)00104-0. PMID 10745013.
- "G6PD glucose-6-phosphate dehydrogenase [ Homo sapiens (human) ]". NCBI. Retrieved 13 December 2015.
- Kiani F, Schwarzl S, Fischer S, Efferth T (July 2007). "Three-dimensional modeling of glucose-6-phosphate dehydrogenase-deficient variants from German ancestry". PLOS One. 2 (7): e625. doi:10.1371/journal.pone.0000625. PMC . PMID 17637841.
- Luzzatto L, Bienzle U (June 1979). "The malaria/G.-6-P.D. hypothesis". Lancet. 1 (8127): 1183–4. doi:10.1016/S0140-6736(79)91857-9. PMID 86896.
- Corpas FJ, Barroso JB, Sandalio LM, Distefano S, Palma JM, Lupiáñez JA, Del Río LA (March 1998). "A dehydrogenase-mediated recycling system of NADPH in plant peroxisomes". The Biochemical Journal. 330 ( Pt 2) (Pt 2): 777–84. doi:10.1042/bj3300777. PMC . PMID 9480890.
- Bashiri G, Squire CJ, Moreland NJ, Baker EN (June 2008). "Crystal structures of F420-dependent glucose-6-phosphate dehydrogenase FGD1 involved in the activation of the anti-tuberculosis drug candidate PA-824 reveal the basis of coenzyme and substrate binding". The Journal of Biological Chemistry. 283 (25): 17531–41. doi:10.1074/jbc.M801854200. PMID 18434308.
- Szweda LI, Uchida K, Tsai L, Stadtman ER (February 1993). "Inactivation of glucose-6-phosphate dehydrogenase by 4-hydroxy-2-nonenal. Selective modification of an active-site lysine". The Journal of Biological Chemistry. 268 (5): 3342–7. PMID 8429010.
- Wang XT, Chan TF, Lam VM, Engel PC (August 2008). "What is the role of the second "structural" NADP+-binding site in human glucose 6-phosphate dehydrogenase?". Protein Science. 17 (8): 1403–11. doi:10.1110/ps.035352.108. PMC . PMID 18493020.
- Eger-Neufeldt I, Teinzer A, Weiss L, Wieland O (March 1965). "Inhibition of glucose-6-phosphate dehydrogenase by long chain acyl-coenzyme A". Biochemical and Biophysical Research Communications. 19 (1): 43–48. doi:10.1016/0006-291X(65)90116-6.
- Kawaguchi A, Bloch K (September 1974). "Inhibition of glucose 6-phosphate dehydrogenase by palmitoyl coenzyme A". The Journal of Biological Chemistry. 249 (18): 5793–800. PMID 4153382.
- Wang YP, Zhou LS, Zhao YZ, Wang SW, Chen LL, Liu LX, Ling ZQ, Hu FJ, Sun YP, Zhang JY, Yang C, Yang Y, Xiong Y, Guan KL, Ye D (June 2014). "Regulation of G6PD acetylation by SIRT2 and KAT9 modulates NADPH homeostasis and cell survival during oxidative stress". The EMBO Journal. 33 (12): 1304–20. doi:10.1002/embj.201387224. PMC . PMID 24769394.
- Kletzien RF, Harris PK, Foellmi LA (February 1994). "Glucose-6-phosphate dehydrogenase: a "housekeeping" enzyme subject to tissue-specific regulation by hormones, nutrients, and oxidant stress". FASEB Journal. 8 (2): 174–81. PMID 8119488.
- de Lartigue J (2012-06-12). "Cancer Research Moves Beyond the Original Hallmarks of Cancer". OncLive.
- "Entrez Gene: G6PD glucose-6-phosphate dehydrogenase".
- Tian WN, Braunstein LD, Pang J, Stuhlmeier KM, Xi QC, Tian X, Stanton RC (April 1998). "Importance of glucose-6-phosphate dehydrogenase activity for cell growth". The Journal of Biological Chemistry. 273 (17): 10609–17. doi:10.1074/jbc.273.17.10609. PMID 9553122.
- Xu SN, Wang TS, Li X, Wang YP (September 2016). "SIRT2 activates G6PD to enhance NADPH production and promote leukaemia cell proliferation". Scientific Reports. 6: 32734. doi:10.1038/srep32734. PMC . PMID 27586085.
- Vulliamy T, Beutler E, Luzzatto L (1993). "Variants of glucose-6-phosphate dehydrogenase are due to missense mutations spread throughout the coding region of the gene". Human Mutation. 2 (3): 159–67. doi:10.1002/humu.1380020302. PMID 8364584.
- Mason PJ (September 1996). "New insights into G6PD deficiency". British Journal of Haematology. 94 (4): 585–91. PMID 8826878.
- Wajcman H, Galactéros F (August 2004). "[Glucose 6-phosphate dehydrogenase deficiency: a protection against malaria and a risk for hemolytic accidents]". Comptes Rendus Biologies (in French). 327 (8): 711–20. doi:10.1016/j.crvi.2004.07.010. PMID 15506519.
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Glucose-6-phosphate dehydrogenase, NAD binding domain Provide feedback
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External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR022674
Glucose-6-phosphate dehydrogenase (EC) (G6PDH) is a ubiquitous protein, present in bacteria and all eukaryotic cell types [PUBMED:2838391]. The enzyme catalyses the the first step in the pentose pathway, i.e. the conversion of glucose-6-phosphate to gluconolactone 6-phosphate in the presence of NADP, producing NADPH. The ubiquitous expression of the enzyme gives it a major role in the production of NADPH for the many NADPH-mediated reductive processes in all cells [PUBMED:3393536]. Deficiency of G6PDH is a common genetic abnormality affecting millions of people worldwide. Many sequence variants, most caused by single point mutations, are known, exhibiting a wide variety of phenotypes [PUBMED:3393536].This entry represents the NAD-binding domain of glucose-6-phosphate dehydrogenase.
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function||NADP binding (GO:0050661)|
|glucose-6-phosphate dehydrogenase activity (GO:0004345)|
|Biological process||glucose metabolic process (GO:0006006)|
|oxidation-reduction process (GO:0055114)|
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
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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 . In some more distantly relate Rossmann domains the NAD+ cofactor is replaced by the functionally similar cofactor FAD.
The clan contains the following 204 members:2-Hacid_dh_C 3Beta_HSD 3HCDH_N 3HCDH_RFF 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 CbiJ CheR CMAS CmcI CoA_binding CoA_binding_2 CoA_binding_3 Cons_hypoth95 DAO DapB_N DFP DNA_methylase DOT1 DRE2_N DREV DUF1188 DUF1442 DUF1611_N DUF166 DUF1776 DUF2431 DUF268 DUF2855 DUF3410 DUF364 DUF43 DUF5129 DUF5130 DUF938 DXP_reductoisom DXPR_C 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 Glyco_tran_WecB GMC_oxred_N Gp_dh_N GRAS GRDA HI0933_like HIM1 IlvN ISPD_C K_oxygenase KR LCM Ldh_1_N LpxI_N Lycopene_cycl Malic_M Mannitol_dh MCRA Met_10 Methyltr_RsmB-F Methyltr_RsmF_N Methyltrans_Mon Methyltrans_SAM Methyltransf_10 Methyltransf_11 Methyltransf_12 Methyltransf_14 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_33 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 NSP11 NSP16 OCD_Mu_crystall Orbi_VP4 PALP PARP_regulatory PCMT PDH PglD_N Polysacc_syn_2C Polysacc_synt_2 Pox_MCEL Pox_mRNA-cap Prenylcys_lyase PrmA PRMT5 Pyr_redox Pyr_redox_2 Pyr_redox_3 Reovirus_L2 RmlD_sub_bind Rossmann-like rRNA_methylase RrnaAD Rsm22 RsmJ Sacchrp_dh_NADP SAM_MT 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 Urocanase V_cholerae_RfbT XdhC_C YjeF_N
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...
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Key: available, not generated, — not available.
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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.
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|Author:||Finn RD , Griffiths-Jones SR|
|Number in seed:||558|
|Number in full:||8708|
|Average length of the domain:||176.10 aa|
|Average identity of full alignment:||36 %|
|Average coverage of the sequence by the domain:||35.06 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 45638612 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||22|
|Download:||download the raw HMM for this family|
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The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
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Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
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Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
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The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
You can use the tree controls to manipulate how the interactive tree is displayed:
- show/hide the summary boxes
- highlight species that are represented in the seed alignment
- expand/collapse the tree or expand it to a given depth
- select a sub-tree or a set of species within the tree and view them graphically or as an alignment
- save a plain text representation of the tree
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.
There are 3 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
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 G6PD_N domain has been found. There are 46 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 sequence.
Loading structure mapping...