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{{DISPLAYTITLE:''gamma''-Glutamylcysteine}} |
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{{DISPLAYTITLE:γ-<small>L</small>-Glutamyl-<small>L</small>-cysteine}} |
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{{chembox |
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{{chembox |
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| Name = γ-{{sm|l}}-Glutamyl-{{sm|l}}-cysteine |
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| verifiedrevid = 415503417 |
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| verifiedrevid = 443832022 |
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|Name=γ-Glutamylcysteine |
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|ImageFile=gamma-Glutamylcysteine.svg |
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| ImageFile = gamma-Glutamylcysteine.svg |
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| ImageFile_Ref = {{chemboximage|correct|??}} |
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|ImageSize=200px |
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| ImageName = Stereo, skeletal formula of ''gamma''-glutamylcysteine ((2''S'')-2-amino, -) |
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|IUPACName=2-amino-5--5-oxopentanoic acid |
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| IUPACName = γ-Glutamylcysteine |
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|OtherNames= |
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| SystematicName = (2''S'')-2-Amino-5-{amino}-5-oxopentanoic acid |
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| OtherNames = ''gamma''-Glutamylcysteine |
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|Section1={{Chembox Identifiers |
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|Section1={{Chembox Identifiers |
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| CASNo = 636-58-8 |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| CASNo_Ref = {{cascite|correct|??}} |
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| CASNo_Comment = |
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| PubChem = 123938 |
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| ChemSpiderID = 110467 |
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| ChemSpiderID = 110467 |
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| KEGG_Ref = {{keggcite|correct|kegg}} |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| DrugBank = DB03408 |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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| KEGG = C00669 |
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| KEGG = C00669 |
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| KEGG_Ref = {{keggcite|correct|kegg}} |
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| InChI = 1/C8H14N2O5S/c9-4(7(12)13)1-2-6(11)10-5(3-16)8(14)15/h4-5,16H,1-3,9H2,(H,10,11)(H,12,13)(H,14,15)/t4-,5-/m0/s1 |
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| MeSHName = gamma-glutamylcysteine |
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| InChIKey = RITKHVBHSGLULN-WHFBIAKZBB |
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| ChEBI = 17515 |
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| ChEMBL_Ref = {{ebicite|correct|EBI}} |
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| ChEBI_Ref = {{ebicite|correct|EBI}} |
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| ChEMBL = 460831 |
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| ChEMBL = 460831 |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| ChEMBL_Ref = {{ebicite|correct|EBI}} |
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| Beilstein = 1729154 |
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| 3DMet = B01305 |
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| SMILES = C(CC(=O)N(CS)C(=O)O)(C(=O)O)N |
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| StdInChI = 1S/C8H14N2O5S/c9-4(7(12)13)1-2-6(11)10-5(3-16)8(14)15/h4-5,16H,1-3,9H2,(H,10,11)(H,12,13)(H,14,15)/t4-,5-/m0/s1 |
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| StdInChI = 1S/C8H14N2O5S/c9-4(7(12)13)1-2-6(11)10-5(3-16)8(14)15/h4-5,16H,1-3,9H2,(H,10,11)(H,12,13)(H,14,15)/t4-,5-/m0/s1 |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey = RITKHVBHSGLULN-WHFBIAKZSA-N |
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| StdInChIKey = RITKHVBHSGLULN-WHFBIAKZSA-N |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| CASNo=636-58-8 |
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}} |
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| PubChem = 123938 |
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| ChEBI = 17515 |
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| SMILES = O=C(O)(NC(=O)CC(C(=O)O)N)CS |
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| MeSHName=Gamma-glutamylcysteine |
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}} |
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|Section2={{Chembox Properties |
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|Section2={{Chembox Properties |
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| C=8 | H=14 | N=2 | O=5 | S=1 |
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| Formula=C<sub>8</sub>H<sub>14</sub>N<sub>2</sub>O<sub>5</sub>S |
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| Appearance = White, opaque crystals |
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| MolarMass=250.27216 |
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| LogP = −1.168 |
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| Appearance= |
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| pKa = 2.214 |
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| Density= |
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| pKb = 11.783 |
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| MeltingPt= |
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| BoilingPt= |
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|Section3={{Chembox Related |
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| Solubility= |
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| OtherFunction_label = alkanoic acids |
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}} |
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| OtherFunction = {{unbulleted list|]|]|]|]}} |
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|Section3={{Chembox Hazards |
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}} |
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| MainHazards= |
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| FlashPt= |
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| Autoignition= |
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'''γ-<small>L</small>-Glutamyl-<small>L</small>-cysteine''', also known as '''γ-glutamylcysteine''' ('''GGC'''), is a ] found in ]s, ]s, ], some ], and ]. It has a relatively unusual γ-bond between the constituent ]s, ] and ] and is a key intermediate in the γ-glutamyl cycle first described by Meister in the 1970s.<ref>{{Cite journal|last1=Orlowski|first1=M.|last2=Meister|first2=A.|date=1970-11-01|title=The ''Gamma''-Glutamyl Cycle: A Possible Transport System for Amino Acids|journal=Proceedings of the National Academy of Sciences|volume=67|issue=3|pages=1248–1255|doi=10.1073/pnas.67.3.1248|pmid=5274454|pmc=283344|bibcode=1970PNAS...67.1248O|issn=0027-8424|doi-access=free}}</ref><ref name=":0">{{Cite journal|last1=Meister|first1=A|last2=Anderson|first2=M E|date=1983|title=Glutathione|journal=Annual Review of Biochemistry|volume=52|issue=1|pages=711–760|doi=10.1146/annurev.bi.52.070183.003431|pmid=6137189|issn=0066-4154}}</ref> It is the most immediate precursor to the ] ].<ref name=":1">{{Cite journal|last1=Anderson|first1=M. E.|last2=Meister|first2=A.|date=1983-02-01|title=Transport and direct utilization of ''gamma''-glutamylcyst(e)ine for glutathione synthesis.|journal=Proceedings of the National Academy of Sciences|volume=80|issue=3|pages=707–711|doi=10.1073/pnas.80.3.707|pmid=6572362|pmc=393448|bibcode=1983PNAS...80..707A|issn=0027-8424|doi-access=free}}</ref> |
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'''γ-Glutamylcysteine''' is a precursor of ]. It is formed by ] and used by ] to form glutathione. |
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== Biosynthesis == |
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{{Amino acid metabolism intermediates}} |
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GGC is synthesized from <small>L</small>-glutamic acid and <small>L</small>-cysteine in the ] of virtually all ] in an ] (ATP)-requiring reaction ] by the ] ] (GCL, EC 6.3.2.2; formerly γ-glutamylcysteine synthetase). The production of GGC is the ] step in glutathione synthesis. |
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=== Occurrence === |
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{{DEFAULTSORT:Glutamylcysteine, gamma-}} |
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GGC occurs in human ] in the range of 1 to 5 μM<ref name=":0" /><ref name=":1" /> and intracellularly at 5 to 10 μM.<ref>{{Cite journal|last=Mårtensson|first=Johannes|date=1987|title=Method for determination of free and total glutathione and γ-glutamylcysteine concentrations in human leukocytes and plasma|journal=Journal of Chromatography B: Biomedical Sciences and Applications|volume=420|issue=1|pages=152–157|doi=10.1016/0378-4347(87)80166-4|pmid=3667817|issn=0378-4347}}</ref> The intracellular concentration is generally low because GGC is rapidly ] with a ] to form glutathione. This second and final ] step in glutathione ] is catalysed by the activity of the ATP dependent ] enzyme. |
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=== Importance === |
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GGC is essential to ]ian life. Mice that have had the glutamate-cysteine ligase (GCL) ] ] do not develop beyond the embryo stage and die before birth.<ref>{{Cite journal|last1=Dalton|first1=Timothy P.|last2=Chen|first2=Ying|last3=Schneider|first3=Scott N.|last4=Nebert|first4=Daniel W.|author4-link=Daniel W. Nebert|last5=Shertzer|first5=Howard G.|date=2004|title=Genetically altered mice to evaluate glutathione homeostasis in health and disease|journal=Free Radical Biology and Medicine|volume=37|issue=10|pages=1511–1526|doi=10.1016/j.freeradbiomed.2004.06.040|pmid=15477003|issn=0891-5849}}</ref> This is because GGC is vital for the biosynthesis of glutathione. Since the production of cellular GGC in humans slows down with age, as well as during the progression of many ], it has been postulated that supplementation with GGC could offer health benefits. Such GGC supplementation may also be of benefit in situations where glutathione has been ] lowered below optimum, such as following strenuous exercise, during trauma or episodes of poisoning. |
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Several review articles have been published exploring the therapeutic potential of GGC to replenish glutathione in age-related<ref>{{Cite journal|last1=Ferguson|first1=Gavin|last2=Bridge|first2=Wallace|date=2016|title=Glutamate cysteine ligase and the age-related decline in cellular glutathione: The therapeutic potential of γ-glutamylcysteine|journal=Archives of Biochemistry and Biophysics|volume=593|pages=12–23|doi=10.1016/j.abb.2016.01.017|pmid=26845022|issn=0003-9861}}</ref> and chronic disease states such as ].<ref>{{Cite journal|last1=Braidy|first1=Nady|last2=Zarka|first2=Martin|last3=Welch|first3=Jeffrey|last4=Bridge|first4=Wallace|date=2015-04-27|title=Therapeutic Approaches to Modulating Glutathione Levels as a Pharmacological Strategy in Alzheimer's Disease|journal=Current Alzheimer Research|volume=12|issue=4|pages=298–313|doi=10.2174/1567205012666150302160308|pmid=25731620|issn=1567-2050}}</ref> |
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{{organic-compound-stub}} |
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GGC is also capable of being a powerful antioxidant in its own right.<ref>{{Cite journal|last1=Quintana-Cabrera|first1=Ruben|last2=Bolaños|first2=Juan|date=2013-01-29|title=Glutathione and γ-glutamylcysteine in the antioxidant and survival functions of mitochondria|journal=Biochemical Society Transactions|volume=41|issue=1|pages=106–110|doi=10.1042/bst20120252|pmid=23356267|issn=0300-5127}}</ref><ref>{{Cite journal|last1=Quintana Cabrera|first1=Rubén|last2=Fernández Fernández|first2=Seila|last3=Bobo Jiménez|first3=Veronica|last4=Escobar|first4=Javier|last5=Sastre|first5=Juan|last6=Almeida|first6=Ángeles|last7=Bolaños|first7=Juan P.|date=2012|title=γ-Glutamylcysteine detoxifies reactive oxygen species by acting as glutathione peroxidase-1 cofactor|journal=Nature Communications|volume=3|issue=1|pages=718|doi=10.1038/ncomms1722|pmid=22395609|pmc=3316877|bibcode=2012NatCo...3..718Q|issn=2041-1723|doi-access=free}}</ref><ref>{{Cite journal|last1=Nakamura|first1=Yukiko K.|last2=Dubick|first2=Michael A.|last3=Omaye|first3=Stanley T.|date=2012|title=γ-Glutamylcysteine inhibits oxidative stress in human endothelial cells|journal=Life Sciences|volume=90|issue=3–4|pages=116–121|doi=10.1016/j.lfs.2011.10.016|pmid=22075492|issn=0024-3205}}</ref> |
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=== Availability === |
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GGC synthesis for commercial use is exceedingly difficult and, until recently, no commercially viable process for large scale production had been developed. The major drawback preventing the commercial success of chemical synthesis of GGC is the number of steps involved due to the three reactive groups on <small>L</small>-glutamic acid and <small>L</small>-cysteine molecules, which must be masked to achieve the correct ]. Similarly, there have been numerous attempts at biological production of GGC by ] over the years and none have been successfully commercialised.<ref>{{Cite patent|title=Microorganism and method for overproduction of ''gamma''-glutamylcysteine and derivatives of this dipeptide by fermentation|pubdate=2014-11-20|country=US|number=2014342399|assign=Wacker Chemie AG|inventor1-last=Thoen |inventor1-first=Marcel|inventor2-last=Schloesser |inventor2-first=Thomas |
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}}</ref><ref>{{Cite patent|title=Candida utilis containing ''gamma''-glutamylcysteine|pubdate=2004-12-22|country=EP|number=1489173|assign=Ajinomoto KK|inventor1-last=Nishiuchi |inventor1-first=Hiroaki|inventor2-last=Nishimura |inventor2-first=Yasushi|inventor3-last=Kuroda |inventor3-first=Motonaka}}</ref><ref>{{Cite patent|title=''gamma''-Glutamylcysteine-producing yeast and method of screening the same|gdate=2002-11-21|country=EP|number=1452585|pubdate=2004-09-01|assign=Ajinomoto KK|inventor1-last=Nishiuchi |inventor1-first=Hiroaki|inventor2-last=Suehiro |inventor2-first=Mariko|inventor3-last=Sugimoto |inventor3-first=Reiko|inventor4= NISHIMURA YASUSHI; KURODA MOTONAKA}}</ref><ref>{{Cite patent|title=Method for producing γ-glutamylcysteine|gdate=2003-12-11|country=US|number=7410790|pubdate=2008-08-12|assign=Ajinomoto KK|inventor1-last=Suehiro |inventor1-first=Mariko|inventor2-last=Nishiuchi |inventor2-first=Hiroaki|inventor3-last=Nishimura |inventor3-first=Yasushi}}</ref> |
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Towards the end of 2019, a biocatalytic process was successfully commercialized. GGC is now available as a supplement in the US under the trademarked name of Glyteine and Continual-G. |
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== Bioavailability and supplementation == |
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A human ] in healthy, non-fasting adults demonstrated that orally administered GGC can significantly increase ] GSH levels indicating systemic bioavailability, validating the therapeutic potential of GGC.<ref name=":2">{{Cite journal|last1=Zarka|first1=Martin Hani|last2=Bridge|first2=Wallace John|date=2017|title=Oral administration of γ-glutamylcysteine increases intracellular glutathione levels above homeostasis in a randomised human trial pilot study|journal=Redox Biology|volume=11|pages=631–636|doi=10.1016/j.redox.2017.01.014|pmid=28131081|pmc=5284489|issn=2213-2317|doi-access=free}}</ref> |
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Animal model studies with GGC have supported a potential therapeutic role for GGC in both the reduction of ] induced damage in tissues, including the brain<ref>{{Cite journal|last1=Le|first1=Truc M.|last2=Jiang|first2=Haiyan|last3=Cunningham|first3=Gary R.|last4=Magarik|first4=Jordan A.|last5=Barge|first5=William S.|last6=Cato|first6=Marilyn C.|last7=Farina|first7=Marcelo|last8=Rocha|first8=Joao B.T.|last9=Milatovic|first9=Dejan|last10=Lee|first10=Eunsook|last11=Aschner|first11=Michael|date=2011|title=γ-Glutamylcysteine ameliorates oxidative injury in neurons and astrocytes in vitro and increases brain glutathione in vivo|journal=NeuroToxicology|volume=32|issue=5|pages=518–525|doi=10.1016/j.neuro.2010.11.008|pmid=21159318|issn=0161-813X|pmc=3079792}}</ref> and as a treatment for ].<ref name=":3">{{Cite journal|last1=Yang|first1=Yang|last2=Li|first2=Ling|last3=Hang|first3=Qiyun|last4=Fang|first4=Yuan|last5=Dong|first5=Xiaoliang|last6=Cao|first6=Peng|last7=Yin|first7=Zhimin|last8=Luo|first8=Lan|date=2019|title=γ-glutamylcysteine exhibits anti-inflammatory effects by increasing cellular glutathione level|journal=Redox Biology|volume=20|pages=157–166|doi=10.1016/j.redox.2018.09.019|pmid=30326393|pmc=6197438|issn=2213-2317|doi-access=free}}</ref> |
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In contrast, supplementation with glutathione is incapable of increasing cellular glutathione since the GSH concentration found in the extracellular environment is much lower than that found intracellularly by about a thousand-fold. This large difference means that there is an insurmountable ] that prohibits extracellular glutathione from entering cells. Although currently unproven, GGC may be the pathway intermediate of glutathione transportation in multicellular organisms.<ref>{{Cite journal|last1=Wu|first1=Guoyao|last2=Fang|first2=Yun-Zhong|last3=Yang|first3=Sheng|last4=Lupton|first4=Joanne R.|last5=Turner|first5=Nancy D.|date=2004-03-01|title=Glutathione Metabolism and Its Implications for Health|journal=The Journal of Nutrition|volume=134|issue=3|pages=489–492|doi=10.1093/jn/134.3.489|pmid=14988435|issn=0022-3166|doi-access=free}}</ref><ref>{{Cite journal|last1=Stark|first1=Avishay-Abraham|last2=Porat|first2=Noga|last3=Volohonsky|first3=Gloria|last4=Komlosh|first4=Arthur|last5=Bluvshtein|first5=Evgenia|last6=Tubi|first6=Chen|last7=Steinberg|first7=Pablo|date=2003|title=The role of γ-glutamyl transpeptidase in the biosynthesis of glutathione|journal=BioFactors|volume=17|issue=1–4|pages=139–149|doi=10.1002/biof.5520170114|pmid=12897436|s2cid=86244588|issn=0951-6433}}</ref> |
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== Safety == |
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Safety assessment of GGC sodium salt in rats has shown that orally administered (]) GGC was not acutely toxic at the limit single dosage of 2000 mg/kg (monitored over 14 days) and demonstrated no adverse effects following repeated daily doses of 1000 mg/kg over 90 days.<ref>{{Cite journal|last1=Chandler|first1=S.D.|last2=Zarka|first2=M.H.|last3=Vinaya Babu|first3=S.N.|last4=Suhas|first4=Y.S.|last5=Raghunatha Reddy|first5=K.R.|last6=Bridge|first6=W.J.|date=2012|title=Safety assessment of ''gamma''-glutamylcysteine sodium salt|journal=Regulatory Toxicology and Pharmacology|volume=64|issue=1|pages=17–25|doi=10.1016/j.yrtph.2012.05.008|pmid=22698997|issn=0273-2300}}</ref> |
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== History == |
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In 1983, pioneers of glutathione research, Mary E. Anderson and ], were the first to report on the ability of GGC to augment cellular GSH levels in a rat model. Intact GGC, which was synthesised in their own laboratory, was shown to be taken up by cells, bypassing the rate-limiting step of the GCL enzyme to be converted to glutathione. Control experiments with combinations of the constituent amino acids that make up GGC, including <small>L</small>-glutamic acid and <small>L</small>-cysteine, were ineffective. Since this initial work, only a few studies using GGC were performed due to the fact that there was no commercial source of GGC on the market. Subsequently, GGC has become commercially available and studies investigating its efficacy have commenced.<ref name=":2" /><ref name=":3" /><ref>{{Cite journal|last1=Braidy|first1=Nady|last2=Zarka|first2=Martin|last3=Jugder|first3=Bat-Erdene|last4=Welch|first4=Jeffrey|last5=Jayasena|first5=Tharusha|last6=Chan|first6=Daniel K. Y.|last7=Sachdev|first7=Perminder|last8=Bridge|first8=Wallace|date=2019-08-08|title=The Precursor to Glutathione (GSH), γ-Glutamylcysteine (GGC), Can Ameliorate Oxidative Damage and Neuroinflammation Induced by Aβ40 Oligomers in Human Astrocytes|journal=Frontiers in Aging Neuroscience|volume=11|page=177|doi=10.3389/fnagi.2019.00177|pmid=31440155|pmc=6694290|issn=1663-4365|doi-access=free}}</ref> |
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== References == |
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{{Reflist}} |
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{{amino acid metabolism intermediates}} |
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{{DEFAULTSORT:Glutamyl-L-cysteine, gamma-L-}} |
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