Summary: Eukaryotic glutathione synthase
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Glutathione synthetase Edit Wikipedia article
|Locus||Chr. 20 q11.2|
|Eukaryotic glutathione synthase|
Human glutathione synthetase
|Eukaryotic glutathione synthase, ATP binding domain|
Human glutathione synthetase
|Prokaryotic glutathione synthetase, N-terminal domain|
Structure of escherichia coli glutathione synthetase at ph 7.5
|Prokaryotic glutathione synthetase, ATP-grasp domain|
Structure of escherichia coli glutathione synthetase at ph 7.5
Glutathione synthetase (GSS) (EC 126.96.36.199) is the second enzyme in the glutathione (GSH) biosynthesis pathway. It catalyses the condensation of gamma-glutamylcysteine and glycine, to form glutathione. Glutathione synthetase is also a potent antioxidant. It is found in a large number of species including bacteria, yeast, mammals, and plants.
In humans, defects in GSS are inherited in an autosomal recessive way and are the cause of severe metabolic acidosis, 5-oxoprolinuria, increased rate of haemolysis, and defective function of the central nervous system. Deficiencies in GSS can cause a spectrum of deleterious symptoms in plants and human beings alike.
In eukaryotes, this is a homodimeric enzyme. The substrate-binding domain has a 3-layer alpha/beta/alpha structure. This enzyme utilizes and stabilizes an acylphosphate intermediate to later perform a favorable nucleophilic attack of glycine.
Human and yeast glutathione synthetases are homodimers, meaning they are composed of two identical subunits of itself non-covalently bound to each other. On the other hand, E. coli glutathione synthetase is a homotetramer. Nevertheless, they are part of the ATP-grasp superfamily, which consists of 21 enzymes that contain an ATP-grasp fold. Each subunit interacts with each other through alpha helix and beta sheet hydrogen bonding interactions and contains two domains. One domain facilitates the ATP-grasp mechanism and the other is the catalytic active site for γ-glutamylcysteine. The ATP-grasp fold is conserved within the ATP-grasp superfamily and is characterized by two alpha helices and beta sheets that hold onto the ATP molecule between them. The domain containing the active site exhibits interesting properties of specificity. In contrast to γ-glutamylcysteine synthetase, glutathione synthetase accepts a large variety of glutamyl-modified analogs of γ-glutamylcysteine, but is much more specific for cysteine-modified analogs of γ-glutamylcysteine. Crystalline structures have shown glutathione synthetase bound to GSH, ADP, two magnesium ions, and a sulfate ion. Two magnesium ions function to stabilize the acylphosphate intermediate, facilitate binding of ATP, and activate removal of phosphate group from ATP. Sulfate ion serves as a replacement for inorganic phosphate once the acylphosphate intermediate is formed inside the active site.
The biosynthetic mechanisms for synthetases use energy from nucleoside triphosphates, whereas synthases do not. Glutathione synthetase stays true to this rule, in that it uses the energy generated by ATP. Initially, the carboxylate group on γ-glutamylcysteine is converted into an acyl phosphate by the transfer of an inorganic phosphate group of ATP to generate an acyl phosphate intermediate. Then the amino group of glycine participates in a nucleophilic attack, displacing the phosphate group and forming GSH. After the final GSH product is made, it can be used by glutathione peroxidase to neutralize reactive oxygen species (ROS) such as H2O2 or Glutathione S-transferases in the detoxification of xenobiotics.
Glutathione synthetase is important for a variety of biological functions in multiple organisms. In Arabidopsis thaliana, low levels of glutathione synthetase have resulted in increased vulnerability to stressors such as heavy metals, toxic organic chemicals, and oxidative stress. The presence of a thiol functional group allows its product GSH to serve both as an effective oxidizing and reducing agent in numerous biological scenarios. Thiols can easily accept a pair of electrons and become oxidized to disulfides, and the disulfides can be readily reduced to regenerate thiols. Additionally, the thiol side chain of cysteines serve as potent nucleophiles and react with oxidants and electrophilic species that would otherwise cause damage to the cell. Interactions with certain metals also stabilize thiolate intermediates.
In humans, glutathione synthetase functions in a similar manner. Its product GSH participates in cellular pathways involved in homeostasis and cellular maintenance. For instance, glutathione peroxidases catalyze the oxidation of GSH to glutathione disulfide (GSSG) by reducing free radicals and reactive oxygen species such as hydrogen peroxide. Glutathione S-transferase uses GSH to clean up various metabolites, xenobiotics, and electrophiles to mercapturates for excretion. Because of its antioxidant role, GSS mostly produce GSH inside the cytoplasm of liver cells and imported to mitochondria where detoxification occurs.]] GSH is also essential for the activation of the immune system to generate robust defense mechanisms against invading pathogens. GSH is capable of preventing infection from the influenza virus.
Patients with mutations in the GSS gene develop glutathione synthetase (GSS) deficiency, an autosomal recessive disorder. Patients develop a wide range of symptoms depending on the severity of the mutations. Mildly affected patients experience a compensated haemolytic anaemia because mutations affect stability of the enzyme. Moderately and severely affected individuals have enzymes with dysfunctional catalytic sites, rendering it unable to participate in detoxification reactions. Physiological symptoms include metabolic acidosis, neurological defects, and increased susceptibility to pathogenic infections.
Treatment of individuals with glutathione synthetase deficiency generally involve therapeutic treatments to address mild to severe symptoms and conditions. In order to treat metabolic acidosis, severely affected patients are given large amounts of bicarbonate and antioxidants such as vitamin E and vitamin C. In mild cases, ascorbate and N-acetylcysteine have been shown to increase glutathione levels and increase erythrocyte production. It is important to note that because glutathione synthetase deficiency is so rare, it is poorly understood. The disease also appears on a spectrum, so it is even more difficult to generalize among the few cases that occur.
- Gogos A, Shapiro L (Dec 2002). "Large conformational changes in the catalytic cycle of glutathione synthase". Structure. 10 (12): 1669–76. PMID 12467574. doi:10.1016/S0969-2126(02)00906-1.
- Njålsson R, Norgren S (2005). "Physiological and pathological aspects of GSH metabolism.". Acta Paediatr. 94 (2): 132–7. PMID 15981742. doi:10.1080/08035250410025285.
- Li H, Xu H, Graham DE, White RH (Aug 2003). "Glutathione synthetase homologs encode alpha-L-glutamate ligases for methanogenic coenzyme F420 and tetrahydrosarcinapterin biosyntheses". Proceedings of the National Academy of Sciences of the United States of America. 100 (17): 9785–90. PMC . PMID 12909715. doi:10.1073/pnas.1733391100.
- Njålsson R (Sep 2005). "Glutathione synthetase deficiency". Cellular and Molecular Life Sciences. 62 (17): 1938–45. PMID 15990954. doi:10.1007/s00018-005-5163-7.
- O'Neill M. "Glutathione Synthetase Deficiency". Online Mendelian Inheritance in Man.
- Polekhina G, Board PG, Gali RR, Rossjohn J, Parker MW (Jun 1999). "Molecular basis of glutathione synthetase deficiency and a rare gene permutation event". The EMBO Journal. 18 (12): 3204–13. PMC . PMID 10369661. doi:10.1093/emboj/18.12.3204.
- Banerjee R (2007). "Antioxidant Molecules and Redox Factors". Redox Biochemistry. Hoboken, N.J.: Wiley. p. 16. ISBN 978-0-471-78624-5.
- Fawaz MV, Topper ME, Firestine SM (Dec 2011). "The ATP-grasp enzymes". Bioorganic Chemistry. 39 (5-6): 185–91. PMC . PMID 21920581. doi:10.1016/j.bioorg.2011.08.004.
- Fyfe PK, Alphey MS, Hunter WN (Apr 2010). "Structure of Trypanosoma brucei glutathione synthetase: domain and loop alterations in the catalytic cycle of a highly conserved enzyme". Molecular and Biochemical Parasitology. 170 (2): 93–9. PMC . PMID 20045436. doi:10.1016/j.molbiopara.2009.12.011.
- Galperin MY, Koonin EV (1997). "A diverse superfamily of enzymes with ATP-dependent carboxylate-amine/thiol ligase activity". Protein Science. 6 (12): 2639–43. PMC . PMID 9416615. doi:10.1002/pro.5560061218.
- Meister A (1978). "Current Status of the γ-Glutamyl Cycle". In Wendel A, Sies H. Functions of Glutathione in Liver and Kidney. Berlin, Heidelberg: Springer Berlin Heidelberg. p. 49. ISBN 978-3-642-67132-6.
- Hara T, Kato H, Katsube Y, Oda J (Sep 1996). "A pseudo-michaelis quaternary complex in the reverse reaction of a ligase: structure of Escherichia coli B glutathione synthetase complexed with ADP, glutathione, and sulfate at 2.0 A resolution". Biochemistry. 35 (37): 11967–74. PMID 8810901. doi:10.1021/bi9605245.
- "Synthases and Ligases". IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN), and Nomenclature Commission of IUB (NC-IUB), Newsletter. 1984.
- Herrera K, Cahoon RE, Kumaran S, Jez J (Jun 2007). "Reaction mechanism of glutathione synthetase from Arabidopsis thaliana: site-directed mutagenesis of active site residues". The Journal of Biological Chemistry. 282 (23): 17157–65. PMID 17452339. doi:10.1074/jbc.M700804200.
- Moyer AM, Sun Z, Batzler AJ, Li L, Schaid DJ, Yang P, Weinshilboum RM (Mar 2010). "Glutathione pathway genetic polymorphisms and lung cancer survival after platinum-based chemotherapy". Cancer Epidemiology, Biomarkers & Prevention. 19 (3): 811–21. PMC . PMID 20200426. doi:10.1158/1055-9965.EPI-09-0871.
- Xiang C, Werner BL, Christensen EM, Oliver DJ (Jun 2001). "The biological functions of glutathione revisited in arabidopsis transgenic plants with altered glutathione levels". Plant Physiology. 126 (2): 564–74. PMC . PMID 11402187. doi:10.1104/pp.126.2.564.
- Conte ML, Carroll KS (14 February 2013). "The Chemistry of Thiol Oxidation and Detection" (PDF). Oxidative Stress and Redox Regulation. pp. 1–42. doi:10.1007/978-94-007-5787-5_1.
- Suzuki N, Higuchi T, Nagano T (Aug 2002). "Multiple active intermediates in oxidation reaction catalyzed by synthetic heme-thiolate complex relevant to cytochrome p450". Journal of the American Chemical Society. 124 (32): 9622–8. PMID 12167058. doi:10.1021/ja0115013.
- Fang YZ, Yang S, Wu G (Oct 2002). "Free radicals, antioxidants, and nutrition". Nutrition. 18 (10): 872–9. PMID 12361782. doi:10.1016/S0899-9007(02)00916-4.
- Ribas V, García-Ruiz C, Fernández-Checa JC (Jul 2014). "Glutathione and mitochondria". Frontiers in Pharmacology. 5: 151. PMC . PMID 25024695. doi:10.3389/fphar.2014.00151.
- Townsend DM, Tew KD, Tapiero H (2003). "The importance of glutathione in human disease". Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie. 57 (3-4): 145–55. PMID 12818476. doi:10.1016/S0753-3322(03)00043-X.
- Cai J, Chen Y, Seth S, Furukawa S, Compans RW, Jones DP (Apr 2003). "Inhibition of influenza infection by glutathione". Free Radical Biology & Medicine. 34 (7): 928–36. PMID 12654482. doi:10.1016/S0891-5849(03)00023-6.
- Ristoff E, Mayatepek E, Larsson A (Jul 2001). "Long-term clinical outcome in patients with glutathione synthetase deficiency". The Journal of Pediatrics. 139 (1): 79–84. PMID 11445798. doi:10.1067/mpd.2001.114480.
- Kraut JA, Madias NE (May 2010). "Metabolic acidosis: pathophysiology, diagnosis and management". Nature Reviews. Nephrology. 6 (5): 274–85. PMID 20308999. doi:10.1038/nrneph.2010.33.
- Jain A, Buist NR, Kennaway NG, Powell BR, Auld PA, Mårtensson J (Feb 1994). "Effect of ascorbate or N-acetylcysteine treatment in a patient with hereditary glutathione synthetase deficiency". The Journal of Pediatrics. 124 (2): 229–33. PMID 8301428. doi:10.1016/S0022-3476(94)70309-4.
- Ristoff E, Larsson A (2007). "Inborn errors in the metabolism of glutathione". Orphanet Journal of Rare Diseases. 2: 16. PMC . PMID 17397529. doi:10.1186/1750-1172-2-16.
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.
Eukaryotic glutathione synthase Provide feedback
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Internal database links
|Similarity to PfamA using HHSearch:||GSH_synth_ATP|
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR004887
This entry represents the substrate-binding domain of glutathione synthetase (EC) (GSS), a homodimeric enzyme that catalyses the conversion of gamma-L-glutamyl-L-cysteine and glycine to phosphate and glutathione in the presence of ATP. This is the second step in glutathione biosynthesis, the first step being catalysed by gamma-glutamylcysteine synthetase [PUBMED:15981742]. In humans, defects in GSS are inherited in an autosomal recessive way and are the cause of severe metabolic acidosis, 5-oxoprolinuria, and increased rate of haemolysis and defective function of the central nervous system. The substrate-binding domain has a 3-layer alpha/beta/alpha structure [PUBMED:10369661].
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function||ATP binding (GO:0005524)|
|glutathione synthase activity (GO:0004363)|
|Biological process||glutathione biosynthetic process (GO:0006750)|
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This superfamily is characterised by bein g the copies of the domain that precedes the ATP-grasp domain common to all superfamily members, and it can contain a substrate-binding function.
The clan contains the following 11 members:Biotin_carb_N Dala_Dala_lig_N DUF1246 GARS_N GSH-S_N GSH_synth_ATP GSH_synthase Ins134_P3_kin_N PPIP5K2_N Rimk_N Synapsin
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|Seed source:||Pfam-B_2922 (release 6.5)|
|Number in seed:||225|
|Number in full:||1447|
|Average length of the domain:||106.20 aa|
|Average identity of full alignment:||37 %|
|Average coverage of the sequence by the domain:||21.37 %|
|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:||15|
|Download:||download the raw HMM for this family|
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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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The tree shows the occurrence of this domain across different species. More...
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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.
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There is 1 interaction 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 GSH_synthase domain has been found. There are 21 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.
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