Glutamine synthetase

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glutamate—ammonia ligase
MN MN ADP PPQ.png
Active site between two monomers of glutamine synthetase from Salmonella typhimurium . Cation binding sites are yellow and orange; ADP is pink; phosphinothricin is blue. [1]
Identifiers
EC no. 6.3.1.2
CAS no. 9023-70-5
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / QuickGO
Search
PMC articles
PubMed articles
NCBI proteins
Glutamine synthetase,
beta-Grasp domain
Identifiers
SymbolGln-synt_N
Pfam PF03951
InterPro IPR008147
PROSITE PDOC00162
SCOP2 2gls / SCOPe / SUPFAM
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
PDB 1f1h ​, 1f52 ​, 1fpy ​, 1hto ​, 1lgr ​, 2bvc ​, 2gls ​, 2qc8 ​, 2ojw ​
Glutamine synthetase,
catalytic domain
PDB 2gls EBI.jpg
12-subunit enzyme glutamine synthetase from Salmonella typhimurium . [2]
Identifiers
SymbolGln-synt_C
Pfam PF00120
Pfam clan CL0286
InterPro IPR008146
PROSITE PDOC00162
SCOP2 2gls / SCOPe / SUPFAM
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
PDB 1f1h ​, 1f52 ​, 1fpy ​, 1hto ​, 1lgr ​, 2bvc ​, 2gls ​, 2qc8 ​, 2ojw ​
glutamate-ammonia ligase (glutamine synthetase)
Identifiers
SymbolGLUL
Alt. symbolsGLNS
NCBI gene 2752
HGNC 4341
OMIM 138290
PDB 2qc8
RefSeq NM_002065
UniProt P15104
Other data
EC number 6.3.1.2
Locus Chr. 1 q31
Search for
Structures Swiss-model
Domains InterPro

Glutamine synthetase (GS) (EC 6.3.1.2) [3] is an enzyme that plays an essential role in the metabolism of nitrogen by catalyzing the condensation of glutamate and ammonia to form glutamine:

Contents

Glutamate + ATP + NH3 → Glutamine + ADP + phosphate

Glutamine synthetase catalyzed reaction Glutamine synthetase reaction.svg
Glutamine synthetase catalyzed reaction

Glutamine synthetase uses ammonia produced by nitrate reduction, amino acid degradation, and photorespiration. [4] The amide group of glutamate is a nitrogen source for the synthesis of glutamine pathway metabolites. [5]

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. [6] [7] Ammonium ion binds more strongly than water to GS due to electrostatic forces between a cation and a negatively charged pocket. [4] Another possible reaction is upon NH2OH binding to GS, rather than NH4+, yields γ-glutamylhydroxamate. [6] [7]

Structure

Glutamine synthetase, 12 subunits Gs1.png
Glutamine synthetase, 12 subunits

Glutamine synthetase can be composed of 8, 10, or 12 identical subunits separated into two face-to-face rings. [6] [8] [9] [10] Bacterial GS are dodecamers with 12 active sites between each monomer. [6] Each active site creates a ‘tunnel’ which is the site of three distinct substrate binding sites: nucleotide, ammonium ion, and amino acid. [4] [6] [10] [11] ATP binds to the top of the bifunnel that opens to the external surface of GS. [4] Glutamate binds at the bottom of the active site. [7] 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. [6]

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. [6]

Mechanism

GS catalyzes the ATP-dependent condensation of glutamate with ammonia to yield glutamine. [4] The hydrolysis of ATP drives [8] the first step of a two-part, concerted mechanism. [4] [6] 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 Pi do not dissociate until ammonia binds and glutamine is released. [6]

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. [5] [7] 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. [7] In the second step, deprotonation of ammonium allows ammonia to attack the intermediate from its nearby site to form glutamine. [12] Phosphate leaves through the top of the active site, while glutamine leaves through the bottom (between two rings). [13] [7]

Two views of glutamine synthetase PDB ID: 1FPY 030-GlutamineSynthetase-1fpy-twoviews.tiff
Two views of glutamine synthetase PDB ID: 1FPY

Biological function

GS is present predominantly in the brain, kidneys, and liver. [4] [10] 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. [4] [14] GS, in the brain, is found primarily in astrocytes. [15] Astrocytes protect neurons against excitotoxicity by taking up excess ammonia and glutamate. [14] In hyperammonemic environments (high levels of ammonia), astroglial swelling occurs. [14] [16] [17] 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. [14] 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. [16]

Classes

There seem to be three different classes of GS: [18] [19] [20]

Plants have two or more isozymes of GSII, one of the isozymes is translocated into the chloroplast. Another form is cytosolic. The cytosolic GS gene translation is regulated by its 5' untranslated region (UTR), while its 3' UTR plays role in transcript turnover. [23]

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

Regulation and inhibition

GS is subject to reversible covalent modification. Tyr397 of all 12 subunits can undergo adenylylation or deadenylylation by adenylyl transferase (AT), a bifunctional regulatory enzyme. [25] Adenylylation is a post-translational modification involving the covalent attachment of AMP to a protein side chain. Each adenylylation requires an ATP and complete inhibition of GS requires 12 ATP. Deadenylylation by AT involves phosphorolytic removal of the Tyr-linked adenylyl groups as ADP. AT activity is influenced by the regulatory protein that is associated with it: PII, a 44-kD trimer. [25] PII also undergoes post-translational modification by uridylyl transferase, thus PII has two forms. The state of PII dictates the activity of adenylyl transferase. If PII is not uridylylated, then it will take on the PIIA form. The AT:PIIA complex will deactivate GS by adenylylation. If PII is uridylylated, then it will take on the PIID form. The AT:PIID complex will activate GS by deadenylylation. [25] The AT:PIIA and AT:PIID complexes are allosterically regulated in a reciprocal fashion by α-ketoglutarate (α-KG) and glutamine (Gln). Gln will activate AT:PIIA activity and inhibits AT:PIID, leading to adenylylation and subsequent deactivation of GS. Furthermore, Gln favors the conversion of PIID to PIIA. The effects of α-KG on the complexes are opposite. [25] In the majority of gram-negative bacteria, GS can be modified by adenylylation (some cyanobacteria and green algae or exceptions). [26]

Inhibition of GS has largely focused on amino site ligands. [6] Other inhibitors are the result of glutamine metabolism: tryptophan, histidine, carbamoyl phosphate, glucosamine-6-phosphate, cytidine triphosphate (CTP), and adenosine monophosphate (AMP). [5] [8] [27] 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. [6] 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. [5] 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. [8] 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. [6] High concentrations of glutamine-dependent metabolites should inhibit GS activity, while low concentrations should activate GS activity. [6]

Methionine sulfoximine acting as an inhibitor to the glutamate binding site Methionine Sulfoximine.PNG
Methionine sulfoximine acting as an inhibitor to the glutamate binding site

Inhibitors:

Research on E. coli revealed that GS is regulated through gene expression. The gene that encodes the GS subunit is designated glnA . Transcription of glnA is dependent on NRI (a specific transcriptional enhancer). Active transcription occurs if NRI is in its phosphorylated form, designated NRI-P. Phosphorylation of NRI is catalyzed by NRII, a protein kinase. If NRII is complexed with PIIA then it will function as a phosphatase and NRI-P is converted back to NRI. In this case, transcription of glnA ceases. [25]

GS is subject to completely different regulatory mechanisms in cyanobacteria. [28] Instead of the common NtrC-NtrB two component system, [29] [30] cyanobacteria harbour the transcriptional regulator NtcA which is restricted to this clade and controls expression of GS and a multitude of genes involved in nitrogen metabolism. [31] [32] Moreover, GS in cyanobacteria is not covalently modified to raise sensitivity for feedback inhibition. [30] Instead, GS in Cyanobacteria is inhibited by small proteins, termed GS inactivating factors (IFs) whose transcription is negatively regulated by NtcA. [33] [34] These inactivating factors are furthermore regulated by different Non-coding RNAs: The sRNA NsiR4 interacts with the 5'UTR of the mRNA of the GS inactivating factor IF7 (gifA mRNA) and reduces its expression. NsiR4 expression is under positive control of the nitrogen control transcription factor NtcA. [35] In addition, expression of the GS inactivating factor IF17 is controlled by a glutamine-binding riboswitch. [36]

Related Research Articles

<span class="mw-page-title-main">Glutamate dehydrogenase</span> Hexameric enzyme

Glutamate dehydrogenase is an enzyme observed in both prokaryotes and eukaryotic mitochondria. The aforementioned reaction also yields ammonia, which in eukaryotes is canonically processed as a substrate in the urea cycle. Typically, the α-ketoglutarate to glutamate reaction does not occur in mammals, as glutamate dehydrogenase equilibrium favours the production of ammonia and α-ketoglutarate. Glutamate dehydrogenase also has a very low affinity for ammonia, and therefore toxic levels of ammonia would have to be present in the body for the reverse reaction to proceed. In the brain, the NAD+/NADH ratio in brain mitochondria encourages oxidative deamination. In bacteria, the ammonia is assimilated to amino acids via glutamate and aminotransferases. In plants, the enzyme can work in either direction depending on environment and stress. Transgenic plants expressing microbial GLDHs are improved in tolerance to herbicide, water deficit, and pathogen infections. They are more nutritionally valuable.

Biosynthesis, i.e., chemical synthesis occurring in biological contexts, is a term most often referring to multi-step, enzyme-catalyzed processes where chemical substances absorbed as nutrients serve as enzyme substrates, with conversion by the living organism either into simpler or more complex products. Examples of biosynthetic pathways include those for the production of amino acids, lipid membrane components, and nucleotides, but also for the production of all classes of biological macromolecules, and of acetyl-coenzyme A, adenosine triphosphate, nicotinamide adenine dinucleotide and other key intermediate and transactional molecules needed for metabolism. Thus, in biosynthesis, any of an array of compounds, from simple to complex, are converted into other compounds, and so it includes both the catabolism and anabolism of complex molecules. Biosynthetic processes are often represented via charts of metabolic pathways. A particular biosynthetic pathway may be located within a single cellular organelle, while others involve enzymes that are located across an array of cellular organelles and structures.

<span class="mw-page-title-main">Glutamate dehydrogenase 1</span> Enzyme

GLUD1 is a mitochondrial matrix enzyme, one of the family of glutamate dehydrogenases that are ubiquitous in life, with a key role in nitrogen and glutamate (Glu) metabolism and energy homeostasis. This dehydrogenase is expressed at high levels in liver, brain, pancreas and kidney, but not in muscle. In the pancreatic cells, GLUD1 is thought to be involved in insulin secretion mechanisms. In nervous tissue, where glutamate is present in concentrations higher than in the other tissues, GLUD1 appears to function in both the synthesis and the catabolism of glutamate and perhaps in ammonia detoxification.

<span class="mw-page-title-main">Succinyl coenzyme A synthetase</span> Class of enzymes

Succinyl coenzyme A synthetase is an enzyme that catalyzes the reversible reaction of succinyl-CoA to succinate. The enzyme facilitates the coupling of this reaction to the formation of a nucleoside triphosphate molecule from an inorganic phosphate molecule and a nucleoside diphosphate molecule. It plays a key role as one of the catalysts involved in the citric acid cycle, a central pathway in cellular metabolism, and it is located within the mitochondrial matrix of a cell.

Carbamoyl phosphate synthetase I is a ligase enzyme located in the mitochondria involved in the production of urea. Carbamoyl phosphate synthetase I transfers an ammonia molecule to a molecule of bicarbonate that has been phosphorylated by a molecule of ATP. The resulting carbamate is then phosphorylated with another molecule of ATP. The resulting molecule of carbamoyl phosphate leaves the enzyme.

<span class="mw-page-title-main">Amino acid synthesis</span> The set of biochemical processes by which amino acids are produced

Amino acid biosynthesis is the set of biochemical processes by which the amino acids are produced. The substrates for these processes are various compounds in the organism's diet or growth media. Not all organisms are able to synthesize all amino acids. For example, humans can synthesize 11 of the 20 standard amino acids. These 11 are called the non-essential amino acids.

<span class="mw-page-title-main">CAD protein</span> Protein-coding gene in the species Homo sapiens

CAD protein is a trifunctional multi-domain enzyme involved in the first three steps of pyrimidine biosynthesis. De-novo synthesis starts with cytosolic carbamoylphosphate synthetase II which uses glutamine, carbon dioxide and ATP. This enzyme is inhibited by uridine triphosphate.

<span class="mw-page-title-main">CTP synthetase</span> Enzyme

CTP synthase is an enzyme involved in pyrimidine biosynthesis that interconverts UTP and CTP.

<span class="mw-page-title-main">Glutaminase</span> A mitochondrial enzyme that catalyzes the breakdown of glutamine

Glutaminase is an amidohydrolase enzyme that generates glutamate from glutamine. Glutaminase has tissue-specific isoenzymes. Glutaminase has an important role in glial cells.

<span class="mw-page-title-main">Carbamoyl phosphate synthetase</span> Class of enzymes

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<span class="mw-page-title-main">GMP synthase</span> Protein domain

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<span class="mw-page-title-main">Amidophosphoribosyltransferase</span> Mammalian protein found in Homo sapiens

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<span class="mw-page-title-main">Ribose-phosphate diphosphokinase</span> Class of enzymes

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<span class="mw-page-title-main">Adenylylation</span> Biological process

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<span class="mw-page-title-main">Glutamine—tRNA ligase</span>

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<span class="mw-page-title-main">Glutamine riboswitch</span> Glutamine-binding RNA structure

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<span class="mw-page-title-main">Pii nitrogen regulatory proteins</span> Protein family

The PII family comprises a group of widely distributed signal transduction proteins found in nearly all Bacteria and also present in Archaea and in the chloroplasts of Algae and plants. PII form barrel-like homotrimers with a flexible loop, namely T-loop, emerging from each subunit. PII proteins have extraordinary sensory properties; they can exist in a vast range of structural status accordingly to the levels of ATP, ADP and 2-oxogluratate. These metabolites interact allosterically with PII in three conserved binding sites located in the lateral cavity between each PII subunit. ATP and ADP bind competitively to the nucleotide binding whereas the 2-oxoglutarate only interacts with PII in the presence of MgATP.

The glnALG operon is an operon that regulates the nitrogen content of a cell. It codes for the structural gene glnA the two regulatory genes glnL and glnG. glnA encodes glutamine synthetase, an enzyme which catalyzes the conversion of glutamate and ammonia to glutamine, thereby controlling the nitrogen level in the cell. glnG encodes NRI which regulates the expression of the glnALG operon at three promoters, which are glnAp1, glnAp2 located upstream of glnA) and glnLp. glnL encodes NRII which regulates the activity of NRI. No significant homology is found in Eukaryotes.

Carbamoyl phosphate synthetase III is one of the three isoforms of the carbamoyl phosphate synthetase, an enzyme that catalyzes the active production of carbamoyl phosphate in many organisms.

References

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  2. ↑ PDB: 2GLS ​; Yamashita MM, Almassy RJ, Janson CA, Cascio D, Eisenberg D (October 1989). "Refined atomic model of glutamine synthetase at 3.5 A resolution". J. Biol. Chem. 264 (30): 17681–90. doi:10.2210/pdb2gls/pdb. PMID   2572586.
  3. ↑ Eisenberg D, Almassy RJ, Janson CA, Chapman MS, Suh SW, Cascio D, Smith WW (1987). "Some evolutionary relationships of the primary biological catalysts glutamine synthetase and RuBisCO". Cold Spring Harb. Symp. Quant. Biol. 52: 483–90. doi:10.1101/sqb.1987.052.01.055. PMID   2900091.
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  16. 1 2 Willard-Mack CL, Koehler RC, Hirata T, et al. (March 1996). "Inhibition of glutamine synthetase reduces ammonia-induced astrocyte swelling in rat". Neuroscience. 71 (2): 589–99. doi:10.1016/0306-4522(95)00462-9. PMID   9053810. S2CID   31674240.
  17. ↑ Tanigami H, Rebel A, Martin LJ, Chen TY, Brusilow SW, Traystman RJ, Koehler RC (2005). "Effect of glutamine synthetase inhibition on astrocyte swelling and altered astroglial protein expression during hyperammonemia in rats". Neuroscience. 131 (2): 437–49. doi:10.1016/j.neuroscience.2004.10.045. PMC   1819407 . PMID   15708485.
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  22. ↑ InterPro:IPR001637 Glutamine synthetase class-I, adenylation site
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  24. ↑ van Rooyen JM, Abratt VR, Sewell BT (August 2006). "Three-dimensional structure of a type III glutamine synthetase by single-particle reconstruction". J. Mol. Biol. 361 (4): 796–810. doi:10.1016/j.jmb.2006.06.026. hdl: 11394/1617 . PMID   16879836.
  25. 1 2 3 4 5 Garrett, Grisham (2017). Biochemistry (6th ed.). United States of America: Cengage Learning. pp. 886–889. ISBN   978-1-305-57720-6.
  26. ↑ Ivanovsky RN, Khatipov EA (1994). "Evidence of covalent modification of glutamine synthetase in the purple sulfur bacterium". FEMS Microbiology Letters. 122 (1–2): 115–119. doi: 10.1111/j.1574-6968.1994.tb07153.x .
  27. ↑ Krishnan IS, Singhal RK, Dua RD (Apr 1986). "Purification and characterization of glutamine synthetase from Clostridium pasteurianum". Biochemistry. 25 (7): 1589–99. doi:10.1021/bi00355a021. PMID   2871863.
  28. ↑ Bolay P, Muro-Pastor M, Florencio F, Klähn S (27 October 2018). "The Distinctive Regulation of Cyanobacterial Glutamine Synthetase". Life. 8 (4): 52. Bibcode:2018Life....8...52B. doi: 10.3390/life8040052 . PMC   6316151 . PMID   30373240.
  29. ↑ Merrick MJ, Edwards RA (December 1995). "Nitrogen control in bacteria". Microbiological Reviews. 59 (4): 604–22. doi:10.1128/MR.59.4.604-622.1995. PMC   239390 . PMID   8531888.
  30. 1 2 Fisher R, Tuli R, Haselkorn R (June 1981). "A cloned cyanobacterial gene for glutamine synthetase functions in Escherichia coli, but the enzyme is not adenylylated". Proceedings of the National Academy of Sciences of the United States of America. 78 (6): 3393–7. Bibcode:1981PNAS...78.3393F. doi: 10.1073/pnas.78.6.3393 . PMC   319574 . PMID   6115380.
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