View source for Glutamine synthetase

{{stack begin}}
{{enzyme
| Name = glutamate—ammonia ligase
| EC_number = 6.3.1.2
| CAS_number = 9023-70-5
| IUBMB_EC_number = 6/3/1/2
| GO_code = 0004356 
| image = MN MN ADP PPQ.png
| width = 
| caption = Active site between two monomers of glutamine synthetase from ''[[Salmonella typhimurium]]''. Cation binding sites are yellow and orange; [[adenosine diphosphate|ADP]] is pink; [[DL-Phosphinothricin|phosphinothricin]] is blue.<ref name="pmid11329256">{{PDB|1FPY}}; {{cite journal |vauthors=Gill HS, Eisenberg D | title = The crystal structure of phosphinothricin in the active site of glutamine synthetase illuminates the mechanism of enzymatic inhibition | journal = Biochemistry | volume = 40 | issue = 7 | pages = 1903–12 |date=February 2001 | pmid = 11329256 | doi = 10.1021/bi002438h | url = | issn = }}</ref>
}}
{{Pfam_box
| Symbol = Gln-synt_N
| Name = Glutamine synthetase,<br />beta-Grasp domain
| image =
| width = 150
| caption = Crystallographic structure of glutamine synthetase from ''[[salmonella typhimurium]]''.<ref name="pmid11329256"/>
| Pfam = PF03951
| InterPro = IPR008147
| SMART = 
| PROSITE = PDOC00162
| SCOP = 2gls
| TCDB = 
| OPM family = 
| OPM protein = 
| PDB = {{PDB2|1f1h}}, {{PDB2|1f52}}, {{PDB2|1fpy}}, {{PDB2|1hto}}, {{PDB2|1lgr}}, {{PDB2|2bvc}}, {{PDB2|2gls}}, {{PDB2|2qc8}}, {{PDB2|2ojw}}
}}
{{Pfam_box
| Symbol = Gln-synt_C
| Name = Glutamine synthetase,<br />catalytic domain
| image = PDB 2gls EBI.jpg
| width = 
| caption = 12-subunit enzyme glutamine synthetase from ''[[Salmonella typhimurium]]''.<ref name="pmid2572586">{{PDB|2GLS}}; {{cite journal |vauthors=Yamashita MM, Almassy RJ, Janson CA, Cascio D, Eisenberg D | title = Refined atomic model of glutamine synthetase at 3.5 A resolution | journal = J. Biol. Chem. | volume = 264 | issue = 30 | pages = 17681–90 |date=October 1989 | pmid = 2572586 | doi = | url = | issn = }}</ref>
| Pfam = PF00120
| Pfam_clan = CL0286
| InterPro = IPR008146
| SMART = 
| PROSITE = PDOC00162
| SCOP = 2gls
| TCDB = 
| OPM family = 
| OPM protein = 
| PDB = {{PDB2|1f1h}}, {{PDB2|1f52}}, {{PDB2|1fpy}}, {{PDB2|1hto}}, {{PDB2|1lgr}}, {{PDB2|2bvc}}, {{PDB2|2gls}}, {{PDB2|2qc8}}, {{PDB2|2ojw}}
}}
{{infobox protein
| Name = glutamate-ammonia ligase (glutamine synthetase)
| caption = 
| image = 
| width = 
| HGNCid = 4341
| Symbol = GLUL
| AltSymbols = GLNS
| EntrezGene = 2752
| OMIM = 138290
| RefSeq = NM_002065
| UniProt = P15104
| PDB = 2qc8
| ECnumber = 6.3.1.2
| Chromosome = 1
| Arm = q
| Band = 31
| LocusSupplementaryData = 
}}
{{stack end}}

'''Glutamine synthetase''' (GS) ({{EC number|6.3.1.2}})<ref name="pmid2900091">{{cite journal |vauthors=Eisenberg D, Almassy RJ, Janson CA, Chapman MS, Suh SW, Cascio D, Smith WW | title = Some evolutionary relationships of the primary biological catalysts glutamine synthetase and RuBisCO | journal = Cold Spring Harb. Symp. Quant. Biol. | volume = 52 | issue = | pages = 483–90 | year = 1987 | pmid = 2900091 | doi = 10.1101/sqb.1987.052.01.055| url = | issn = }}</ref> is an [[enzyme]] that plays an essential role in the [[metabolism]] of [[nitrogen]] by catalyzing the condensation of [[glutamate]] and [[ammonia]] to form [[glutamine]]:

Glutamate + [[Adenosine triphosphate|ATP]] + NH<sub>3</sub> → Glutamine + [[Adenosine diphosphate|ADP]] + phosphate 
[[File:GS reacction.PNG|center|alt=Glutamine Synthetase reaction. |Glutamine Synthetase Catalyzed Reaction.]]

Glutamine Synthetase uses ammonia produced by nitrate reduction, [[amino acid]] degradation, and [[photorespiration]].<ref name="pmid8563633">{{cite journal |vauthors=Liaw SH, Kuo I, Eisenberg D | title = Discovery of the ammonium substrate site on glutamine synthetase, a third cation binding site | journal = Protein Sci. | volume = 4 | issue = 11 | pages = 2358–65 |date=Nov 1995 | pmid = 8563633 | pmc = 2143006 | doi = 10.1002/pro.5560041114| url = | issn = }}</ref> The amide group of glutamate is a nitrogen source for the synthesis of glutamine pathway [[metabolites]].<ref name="pmid8099447">{{cite journal |vauthors=Liaw SH, Pan C, Eisenberg D | title = Feedback inhibition of fully unadenylylated glutamine synthetase from Salmonella typhimurium by glycine, alanine, and serine | journal = Proc. Natl. Acad. Sci. USA | volume = 90 | issue = 11 | pages = 4996–5000 |date=Jun 1993 | pmid = 8099447 | pmc = 46640 | doi = 10.1073/pnas.90.11.4996| url = | issn = }}</ref>

Other reactions may take place via GS. Competition between [[ammonium]] ion and water, their binding affinities, and the concentration of ammonium ion, influences glutamine synthesis and glutamine hydrolysis. Glutamine is formed if an ammonium ion attacks the acyl-phosphate intermediate, while glutamate is remade if water attacks the intermediate.<ref name="pmid10708854">{{cite journal |vauthors=Eisenberg D, Gill HS, Pfluegl GM, Rotstein SH | title = Structure-function relationships of glutamine synthetases | journal = Biochim Biophys Acta | volume = 1477 | issue = 1–2 | pages = 122–45 |date=Mar 2000 | pmid = 10708854 | pmc =  | doi = 10.1016/S0167-4838(99)00270-8| url = | issn = }}</ref><ref name="pmid7904828">{{cite journal |vauthors=Liaw SH, Eisenberg D | title = Structural model for the reaction mechanism of glutamine synthetase, based on five crystal structures of enzyme-substrate complexes | journal = Biochemistry | volume = 33 | issue = 3 | pages = 675–81 |date=Jan 1994 | pmid = 7904828 | pmc = | doi = 10.1021/bi00169a007| url = | issn = }}</ref>  Ammonium ion binds more strongly than water to GS due to electrostatic forces between a cation and a negatively charged pocket.<ref name="pmid8563633"/> Another possible reaction is upon NH<sub>2</sub>OH binding to GS, rather than NH<sub>4</sub>+, yields γ-glutamylhydroxamate.<ref name="pmid10708854"/><ref name="pmid7904828"/>

== Structure ==

[[File:Gs1.png|thumb|left | alt=GS Dodecamer |Glutamine Synthetase – 12 subunits.<ref name="pmid11329256"/>]]

Glutamine Synthetase can be composed of 8, 10, or 12 identical subunits separated into two face-to-face rings.<ref name="pmid10708854"/><ref name="Berg_2007">{{cite book |vauthors=Stryer L, Berg JM, Tymoczko JL | title = Biochemistry | edition = 6th | language = | publisher = W.H. Freeman | location = San Francisco | year = 2007 | origyear = | pages = 679–706 | quote = | isbn = 0-7167-8724-5 | oclc = | doi = | url = | accessdate = }}</ref><ref name="url_PDB_MOFT_GS">{{cite web | url = http://www.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb30_1.html | title = Glutamine Synthetase | author = Goodsell DS | date = June 2002 | work = Molecule of the month | publisher = RCSB Protein Data Bank | accessdate = 2010-05-08 }}</ref><ref name="pmid18005987">{{cite journal |vauthors=Krajewski WW, Collins R, Holmberg-Schiavone L, Jones TA, Karlberg T, Mowbray SL | title = Crystal structures of mammalian glutamine synthetases illustrate substrate-induced conformational changes and provide opportunities for drug and herbicide design | journal = J Mol Biol | volume = 375 | issue = 1 | pages = 317–28 |date=Jan 2008 | pmid = 18005987 | pmc =  | doi = 10.1016/j.jmb.2007.10.029| url = | issn = }}</ref> Bacterial GS are dodecamers with 12 active sites between each [[monomer]].<ref name="pmid10708854"/> Each active site creates a ‘tunnel’ which is the site of three distinct substrate binding sites: [[nucleotide]], ammonium ion, and amino acid.<ref name="pmid8563633"/><ref name="pmid10708854"/><ref name="pmid18005987"/><ref name="pmid4906326">{{cite journal |vauthors=Ginsburg A, Yeh J, Hennig SB, Denton MD | title = Some effects of adenylylation on the biosynthetic properties of the glutamine synthetase from Escherichia coli | journal = Biochemistry | volume = 9 | issue = 3 | pages = 633–49 |date=Feb 1970 | pmid = 4906326 | pmc =  | doi = 10.1021/bi00805a025| url = | issn = }}</ref> ATP binds to the top of the bifunnel that opens to the external surface of GS.<ref name="pmid8563633"/> Glutamate binds at the bottom of the active site.<ref name="pmid7904828"/>  The middle of the bifunnel contains two sites in which divalent [[cations]] bind (Mn+2 or Mg+2). One cation binding site is involved in phosphoryl transfer of ATP to glutamate, while the second stabilizes active GS and helps with the binding of glutamate.<ref name="pmid10708854"/> 
 
[[Hydrogen bonding]] and [[hydrophobic]] interactions hold the two rings of GS together. Each subunit possesses a C-terminus and an N-terminus in its sequence. The C-terminus (helical thong) stabilizes the GS structure by inserting into the hydrophobic region of the subunit across in the other ring. The N-terminus is exposed to the solvent. In addition, the central channel is formed via six four-stranded β-sheets composed of anti-parallel loops from the twelve subunits.<ref name="pmid10708854"/>

== Mechanism ==

GS catalyzes the ATP-dependent condensation of glutamate with ammonia to yield glutamine.<ref name="pmid8563633"/> The hydrolysis of ATP drives<ref name="Berg_2007"/>  the first step of a two-part, concerted mechanism.<ref name="pmid8563633"/><ref name="pmid10708854"/> ATP phosphorylates glutamate to form ADP and an acyl-phosphate intermediate, γ-glutamyl phosphate, which reacts with ammonia, forming glutamine and inorganic phosphate. ADP and P<sub>i</sub> do not dissociate until ammonia binds and glutamine is released.<ref name="pmid10708854"/>

ATP binds first to the top of the active site near a cation binding site, while glutamate binds near the second cation binding site at the bottom of the active site.<ref name="pmid8099447"/><ref name="pmid7904828"/> The presence of ADP causes a conformational shift in GS that stabilizes the γ-glutamyl phosphate moiety.  Ammonium binds strongly to GS only if the acyl-phosphate intermediate is present. Ammonium, rather than ammonia, binds to GS because the binding site is polar and exposed to solvent.<ref name="pmid7904828"/>  In the second step, deprotonation of ammonium allows ammonia to attack the intermediate from its nearby site to form glutamine.<ref name="pmid235885">{{cite journal |vauthors=Hunt JB, Smyrniotis PZ, Ginsburg A, Stadtman ER | title = Metal ion requirement by glutamine synthetase of Escherichia coli in catalysis of gamma-glutamyl transfer | journal = Arch Biochem Biophys | volume = 166 | issue = 1 | pages = 102–24 |date=Jan 1975 | pmid = 235885 | pmc = | doi = 10.1016/0003-9861(75)90370-7 | url = | issn = }}</ref> Phosphate leaves through the top of the active site, while glutamine leave through the bottom (between two rings).{{cite web |url= http://www.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb30_1.html |title= Glutamine Synthetase |author= Goodsell, DS |date= June 2002 |work= |publisher= RCSB Protein Data Bank |accessdate=8 May 2010}}<ref name="pmid7904828"/>

[[File:30-GlutamineSynthetase-1fpy-twoviews.tif|thumb|right|Two views of Glutamine Synthetase PDB ID: 1FPY]]

== Biological Function ==

GS is present predominantly in the brain, kidneys, and liver.<ref name="pmid8563633"/><ref name="pmid18005987"/> GS in the brain participates in the metabolic regulation of glutamate, the detoxification of brain ammonia, the assimilation of ammonia, recyclization of [[neurotransmitters]], and termination of neurotransmitter signals.<ref name="pmid8563633"/><ref name="pmid12020613">{{cite journal |vauthors=Suarez I, Bodega G, Fernandez B | title = Glutamine synthetase in brain: effect of ammonia | journal = Neurochem Int. | volume = 41 | issue = 2–3 | pages = 123–42 |date=Aug–Sep 2002 | pmid = 12020613 | pmc = | doi = 10.1016/S0197-0186(02)00033-5| url = | issn = }}</ref>  GS, in the brain, is found primarily in [[astrocytes]].<ref>[http://www.neurologyindia.com/article.asp?issn=0028-3886;year=2013;volume=61;issue=4;spage=383;epage=388;aulast=Venkatesh Venkatesh K, Srikanth L, Vengamma B, Chandrasekhar C, Sanjeevkumar A, Mouleshwara Prasad BC, Sarma PV. In vitro differentiation of cultured human CD34+ cells into astrocytes. Neurol India 2013;61:383-8]</ref> Astrocytes protect neurons against excitotoxicity by taking up excess ammonia and glutamate.<ref name="pmid12020613"/> In hyperammonemic environments (high levels of ammonia), astroglial swelling occurs.<ref name="pmid12020613"/><ref name="pmid9053810">{{cite journal  |vauthors=Willard-Mack CL, Koehler RC, Hirata T, etal |title=Inhibition of glutamine synthetase reduces ammonia-induced astrocyte swelling in rat |journal=Neuroscience |volume=71 |issue=2 |pages=589–99 |date=March 1996 |pmid=9053810 |doi=10.1016/0306-4522(95)00462-9 |url=}}</ref><ref name="pmid15708485">{{cite journal |vauthors=Tanigami H, Rebel A, Martin LJ, Chen TY, Brusilow SW, Traystman RJ, Koehler RC | title = Effect of glutamine synthetase inhibition on astrocyte swelling and altered astroglial protein expression during hyperammonemia in rats | journal = Neuroscience | volume = 131 | issue = 2 | pages = 437–49 | year = 2005 | month = | pmid = 15708485 | pmc = 1819407 | doi = 10.1016/j.neuroscience.2004.10.045| url = | issn = }}</ref> Different perspectives have approached the problem of astroglial swelling. One study shows that morphological changes occur that increase GS expression in glutamatergic areas or other adaptations that alleviates high levels of glutamate and ammonia.<ref name="pmid12020613"/> Another perspective is that astrocyte swelling is due to glutamine accumulation. To prevent increased levels of cortical glutamate and cortical water content, a study has been conducted to prevent GS activity in rats by the use of MSO.<ref name="pmid9053810"/>

== Classes ==

There seem to be three different classes of GS:<ref name="pmid8096645">{{cite journal |vauthors=Kumada Y, Benson DR, Hillemann D, Hosted TJ, Rochefort DA, Thompson CJ, Wohlleben W, Tateno Y | title = Evolution of the glutamine synthetase gene, one of the oldest existing and functioning genes | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 90 | issue = 7 | pages = 3009–13 |date=April 1993 | pmid = 8096645 | pmc = 46226 | doi = 10.1073/pnas.90.7.3009| url = | issn = }}</ref><ref name="pmid2575672">{{cite journal |vauthors=Shatters RG, Kahn ML | title = Glutamine synthetase II in Rhizobium: reexamination of the proposed horizontal transfer of DNA from eukaryotes to prokaryotes | journal = J. Mol. Evol. | volume = 29 | issue = 5 | pages = 422–8 |date=November 1989 | pmid = 2575672 | doi = 10.1007/BF02602912| url = | issn = }}</ref><ref name="pmid7916055">{{cite journal |vauthors=Brown JR, Masuchi Y, Robb FT, Doolittle WF | title = Evolutionary relationships of bacterial and archaeal glutamine synthetase genes | journal = J. Mol. Evol. | volume = 38 | issue = 6 | pages = 566–76 |date=June 1994 | pmid = 7916055 | doi = 10.1007/BF00175876| url = | issn = }}</ref>

* Class I enzymes (GSI) are specific to [[prokaryote]]s, and are oligomers of 12 identical [[Protein subunit|subunits]].<ref name="url160.114.99.91">{{cite web| url =http://160.114.99.91/astrojan/protein/pictures/glnsd.jpg| title =GSI structure| date =| format =| work =| publisher =| pages =| language =| archiveurl =https://web.archive.org/web/20081217043028/http://160.114.99.91/astrojan/protein/pictures/glnsd.jpg| archivedate =2008-12-17| quote =| accessdate =2009-03-31| deadurl =yes| df =}}</ref> The activity of GSI-type enzyme is controlled by the adenylation of a [[tyrosine]] residue. The adenylated enzyme is inactive.<ref>[http://www.ebi.ac.uk/interpro/DisplayIproEntry?ac=IPR001637 InterPro:IPR001637 Glutamine synthetase class-I, adenylation site]</ref> 
* Class II enzymes (GSII) are found in [[eukaryotes]] and in bacteria belonging to the [[Rhizobiaceae]], [[Frankiaceae]], and [[Streptomycetaceae]] families (these bacteria have also a class-I GS). GSII are [[decamer]] of identical subunits.<ref name="pmid18005987"/>{{PDB|2OJW}}.

Plants have two or more isozymes of GSII, one of the isozymes is translocated into the [[chloroplast]]. Another form is [[cytosol]]ic. The cytosolic GS gene translation is regulated by its [[Five prime untranslated region|5' untranslated region]] (UTR), while its [[Three prime untranslated region|3' UTR]] plays role in transcript turnover.<ref>{{Cite journal|last=Ortega|first=Jose Luis|last2=Wilson|first2=Olivia L.|last3=Sengupta-Gopalan|first3=Champa|date=2012-12-01|title=The 5' untranslated region of the soybean cytosolic glutamine synthetase β(1) gene contains prokaryotic translation initiation signals and acts as a translational enhancer in plants|journal=Molecular genetics and genomics: MGG|volume=287|issue=11–12|pages=881–893|doi=10.1007/s00438-012-0724-6|issn=1617-4623|pmc=3881598|pmid=23080263}}</ref>

* Class III enzymes (GSIII) have, currently, only been found in ''[[Bacteroides fragilis]]'' and in ''[[Butyrivibrio fibrisolvens]]''. It is a double-ringed dodecamer of identical chains.<ref name="pmid16879836">{{cite journal |vauthors=van Rooyen JM, Abratt VR, Sewell BT | title = Three-dimensional structure of a type III glutamine synthetase by single-particle reconstruction
 | journal = J. Mol. Biol. | volume = 361 | issue = 4 | pages = 796–810 |date=August 2006 | pmid = 16879836 | doi=10.1016/j.jmb.2006.06.026  | url = | issn = }}</ref> It is much larger (about 700 amino acids) than the GSI (450 to 470 amino acids) or GSII (350 to 420 amino acids) enzymes.

While the three classes of GS's are clearly structurally related, the sequence similarities are not so extensive.

== Regulation & Inhibition ==
Regulation of GS only occurs in prokaryotes.<ref name=":0" /> GS is subject to reversible covalent modification. Tyr<sup>397</sup> of all 12 subunits can undergo [[adenylylation]] or deadenylylation by adenylyl transferase (AT), a bifunctional regulatory enzyme.<ref name=":0">{{Cite book|title=Biochemistry (6th Edition)|last=Garrett, Grisham|first=|publisher=Cengage Learning|year=2017|isbn=978-1-305-57720-6|location=United States of America|pages=886–889}}</ref> Adenylylation is a [[post-translational modification]] <nowiki/>involving the covalent attachment of [[Adenosine monophosphate|AMP]] to a protein side chain. Each adenylylation requires an [[Adenosine triphosphate|ATP]] and complete inhibition of GS requires 12 ATP. Deadenylylation by AT involves phosphorolytic removal of the Tyr-linked adenylyl groups as [[Adenosine diphosphate|ADP]]. AT activity is influenced by the regulatory protein that is associated with it: P<sub>II</sub>, a 44-kD [[Protein trimer|trimer]].<ref name=":0" /> P<sub>II</sub> also undergoes post-translational modification by [[(protein-PII) uridylyltransferase|uridylyl transferase]], thus P<sub>II</sub> has two forms. The state of P<sub>II</sub> dictates the activity of adenylyl transferase. If P<sub>II</sub> is not uridylylated, then it will take on the P<sub>IIA</sub> form. The AT:P<sub>IIA</sub> complex will deactivate GS by adenylylation. If P<sub>II</sub> is uridylylated, then it will take on the P<sub>IID</sub> form. The AT:P<sub>IID</sub> complex will activate GS by deadenylylation.<ref name=":0" /> The AT:P<sub>IIA</sub> and AT:P<sub>IID</sub> complexes are [[Allosteric regulation|allosterically regulated]] in a reciprocal fashion by [[Alpha-Ketoglutaric acid|α-ketoglutarate]] (α-KG) and [[glutamine]] (Gln). Gln will activate AT:P<sub>IIA</sub> activity and inhibits AT:P<sub>IID</sub>, leading to adenylylation and subsequent deactivation of GS. Furthermore, Gln favors the conversion of P<sub>IID</sub> to P<sub>IIA</sub>. The effects of α-KG on the complexes are opposite.<ref name=":0" /> In the majority of gram-negative bacteria, GS can be modified by adenylylation (some cyanobacteria and green algae or exceptions).<ref>{{cite journal |vauthors=Ivanovsky RN, Khatipov EA | title = Evidence of covalent modification of glutamine synthetase in the purple sulfur bacterium | journal = FEMS Microbiology Letters | doi=10.1111/j.1574-6968.1994.tb07153.x | year = 1994 | volume = 122 |issue=1–2| pages = 115–119 }}</ref>
[[File:Regulation of glutamine synthetase through covalent modification.jpg|alt=|left|thumb|Glutamine Synthetase activity influenced by its regulatory protein, which is designated P<sub>II</sub>.]]
Inhibition of GS has largely focused on amino site ligands.<ref name="pmid10708854"/> Other inhibitors are the result of glutamine metabolism: tryptophan, histidine, carbamoyl phosphate, glucosamine-6-phosphate, cytidine triphosphate (CTP), and adenosine monophosphate (AMP).<ref name="pmid8099447"/><ref name="Berg_2007"/><ref name="pmid2871863">{{cite journal |vauthors=Krishnan IS, Singhal RK, Dua RD | title = Purification and characterization of glutamine synthetase from Clostridium pasteurianum | journal = Biochemistry | volume =  25| issue = 7 | pages = 1589–99 |date=Apr 1986 | pmid = 2871863 | pmc = | doi = 10.1021/bi00355a021| url = | issn = }}</ref> Other inhibitors/regulators are glycine and alanine. Alanine, glycine, and serine bind to the glutamate substrate site. GDP, AMP, ADP bind to the ATP site.<ref name="pmid10708854"/> L-serine, L-alanine, and glycine bind to the site for L-glutamate in unadenylated GS. The four amino acids bind to the site by their common atoms, “the main chain” of amino acids.<ref name="pmid8099447"/> Glutamate is another product of glutamine metabolism; however, glutamate is a substrate for GS inhibiting it to act as a regulator to GS.2 Each inhibitor can reduce the activity of the enzyme; once all final glutamine metabolites are bound to GS, the activity of GS is almost completely inhibited.<ref name="Berg_2007"/> Many inhibitory input signals allows for fine tuning of GS  by reflecting nitrogen levels in the organism.

Feedback regulation distinguishes the difference between two eukaryotic types of GS: brain and non-brain tissues. Non-brain GS responds to end-product feedback inhibition, while brain GS does not.<ref name="pmid10708854"/>  High concentrations of glutamine-dependent metabolites should inhibit GS activity, while low concentrations should activate GS activity.<ref name="pmid10708854"/>

[[File:Methionine Sulfoximine.PNG|thumb|right | alt=MSO. |Methionine Sulfoximine acting as an inhibitor to the glutamate binding site.]]

Inhibitors:
* Methionine Sulfoximine (MSO): MSO is an inhibitor that binds to the glutamate site. Bound to GS, MSO is phosphorylated by ATP  that results in an irreversible, non-covalent inhibition of GS. The S-isomer configuration is more inhibitory.<ref name="pmid10708854"/> Glutamate entry is blocked into the active site by a stabilization of the flexible loop in the active site by MSO.<ref name="pmid7904828"/>
* [[Phosphinothricin]]<ref name="pmid11329256"/>(PPT, Glufosinate): Phosphinothricin is an inhibitor that binds to the glutamate site. Glufosinate is used as an herbicide. Glufosinate treated plants die due to a buildup of ammonia and a cessation of photosynthesis.<ref name="pmid18005987"/>
* Many synthetic inhibitors are available today.<ref name="pmid10708854"/>
Research on ''[[Escherichia coli|E. coli]]'' revealed that GS is regulated through gene expression. The gene that encodes the GS subunit is designated ''[[GlnA RNA motif|GlnA]]''. Transcription of GlnA is dependent on ''NR<sub>I</sub>'' (a specific [[Enhancer (genetics)|transcriptional enhancer]]). Active transcription occurs if NR<sub>I</sub> is in its phosphorylated form, designated ''NR<sub>I</sub>-P''. Phosphorylation of NR<sub>I</sub> is catalyzed by NR<sub>II</sub>, a protein [[kinase]]. If NR<sub>II</sub> is complexed with P<sub>IIA</sub> then it will function as a [[phosphatase]] and NR<sub>I</sub>-P is converted back to NR<sub>I</sub>. In this case, transcription of GlnA ceases.<ref name=":0" />

== References ==
{{Reflist|30em}}

== External links ==
*[http://www.ebi.ac.uk/interpro/DisplayIproEntry?ac=IPR008147 InterPro entry]
*[http://pdbbeta.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb30_1.html RCSB PDB molecule of the month]

{{Amino acid metabolism enzymes}}
{{Ligases CO CS and CN}}
{{Enzymes}}
{{Glutamate metabolism and transport modulators}}
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{{DEFAULTSORT:Glutamine Synthetase}}
[[Category:EC 6.3.1|2]]
[[Category:Glutamate (neurotransmitter)]]