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EcoSal Plus

Domain 3:

Metabolism

Regulation of Glutamine Synthetase Activity

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  • Author: Earl R. Stadtman1
  • Editor: Valley Stewart2
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Laboratory of Biochemistry, National Heart, Lung, and Blood Institute, National Institutes of Health, Building 50, Room 2140, Bethesda, MD 20892-8012.; 2: University of California, Davis, Davis, CA
  • Received 03 March 2004 Accepted 27 May 2004 Published 09 September 2004
  • Address correspondence to Earl R. Stadtman erstadtman@nih.gov
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  • Abstract:

    Detailed studies of the glutamine synthetase (GS) in and other bacteria have shown that the activity of this enzyme is regulated by at least five different mechanisms: (i) cumulative feedback inhibition by multiple end products of glutamine metabolism, (ii) interconversion between taut and relaxed protein configurations in response to binding and dissociation of divalent cations at one of its two metal binding sites, (iii) dynamic interconversion of the enzyme between covalently modified (adenylylated) and unmodified forms by a novel bicyclic cascade system, (iv) repression and derepression of glutamine synthetase formation by cyclic phosphorylation and dephosphorylation of an RNA factor that governs transcription activities, and (v) regulation of glutamine synthetase turnover by the coupling of site specific metal ion-catalyzed oxidation with proteolytic degradation of the enzyme. Glutamine synthetase activity in is subject to inhibition by seven different end products of glutamine metabolism, namely, by tryptophan, histidine, carbamyl-phosphate, CTP, AMP, glucose-6-phosphate, and NAD, and also by serine, alanine, and glycine. The cascade theory predicts that the steady-state level of glutamine synthetase adenylylation and therefore its catalytic activity is determined by the combined effects of all metabolites that affect the kinetic parameters of one or more of the enzymes in the cascade. Furthermore, under conditions where the supplies of ATP and glutamate are not limiting and the production of glutamine exceeds the demand, GS is no longer needed, then it will be converted to the catalytically inactive adenylylated form that is not under protection of ATP and glutamate.

  • Citation: Stadtman E. 2004. Regulation of Glutamine Synthetase Activity, EcoSal Plus 2004; doi:10.1128/ecosalplus.3.6.1.6

Key Concept Ranking

Amino Acids
0.41031516
Reactive Oxygen Species
0.38484573
RNA Polymerase
0.33898306
Protein Kinase
0.31411135
0.41031516

References

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2. Almassy RJ, Janson CA, Hamlin R, Xong N-H, Eisenberg D. 1986. Novel subunit interactions in the structure of glutamine synthetase. Nature 323:304–309. [PubMed][CrossRef]
3. Yamashita MM, Almassy RJ, Janson CA, Cascio D, Eisenberg D. 1989. Refined atomic model of glutamine synthetase at 3.5 Å resolution. J Biol Chem 264:17681–17690.
4. Colombo G, Villafranca JJ. 1986 Amino acid sequence of Escherichia coli glutamine synthetase deduced from the DNA nucleotide sequence. J Biol Chem 261:10587–10591.[PubMed]
5. Lei M, Aebi U, Heidner EG, Eisenberg D. 1979. Limited proteolysis of glutamine synthetase is inhibited by glutamate and by feedback inhibitors. J Biol Chem 254:3129–3124.[PubMed]
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7. Denton MD, Ginsburg A. 1969. Conformational changes in glutamine synthetase from Escherichia coli. I. The binding of Mn2+ in relation to some aspects of the enzyme structure and activity. Biochemistry 8:1714–1725. [PubMed][CrossRef]
8. Shapiro BM, Stadtman ER. 1969. Regulation of glutamine synthetase. IX. Reactivity of sulfhydryl groups of the enzyme from Escherichia coli. J Biol Chem 242:5069–5079.
9. Hunt JB, Ginsburg A. 1975. Metal ion requirement by glutamine synthetase of Escherichia coli in catalysis of γ-glutamyl transfer. Arch Biochem Biophys 166:102–124. [CrossRef]
10. Hunt JB, Smyrniotis P, Ginsburg A, Stadtman ER. 1975. Metal ion requirement by glutamine synthetase. Arch Biochem Biophys 166:102–124. [PubMed][CrossRef]
11. Valentine RC, Shapiro BM, Stadtman ER. 1968. Regulation of glutamine synthetase. XII. Electron microscopy of the enzyme from Escherichia coli. Biochemistry 7:2143–2152. [PubMed][CrossRef]
12. Woolfolk CA, Stadtman ER. 1967. Regulation of glutamine synthetase. III. Cumulative feedback inhibition of glutamine synthetase from Escherichia coli. Arch Biochem Biophys 122:174–189. [CrossRef]
13. Woolfolk CA, Stadtman ER. 1964. Cumulative feedback inhibition in the multiple end product regulation of glutamine synthetase in Escherichia coli. Biochem Biophys Res Commun 17:313–319. [CrossRef]
14. Liaw S-H, Pan C, Eisenberg D. 1993. Feedback inhibition of fully unadenylylated glutamine synthetase from Salmonella typhimurium by glycine, alanine and serine. Proc Natl Acad Sci USA 90:4996–5000. [PubMed][CrossRef]
15. Liaw S-H, Jun G, Eisenberg D. 1994. Interactions of nucleotides with fully unadenylylated glutamine synthetase from Salmonella typhimurium. Biochemistry 33:11184–11188. [PubMed][CrossRef]
16. Woolfolk CA, Stadtman ER. 1967. Regulation of glutamine synthetase. IV. Reversible dissociation and inactivation of glutamine synthetase from Escherichia coli by concerted action of EDTA and urea. Arch Biochem Biophys 122:174–189. [PubMed][CrossRef]
17. Rivett AJ, Roseman JE, Oliver CN, Levine RL, Stadtman ER. 1985. Covalent modification of proteins by mixed-function oxidation: recognition by intracellular proteases, p 317–328. In Khairallah EA, Bond JS, and Bird JW (ed), Intracellular Protein Catabolism. Alan R. Liss, New York, N.Y.
18. Stadtman ER, Shapiro BM, Kingdon HS, Woolfolk CA, Hubbard JS. 1968. Cellular regulation of glutamine synthetase in Escherichia coli. Adv Enzyme Regul 6:257–289. [PubMed][CrossRef]
19. Fisher MT. 1992. Promotion of the in vitro renaturation of dodecameric glutamine synthetase from Escherichia coli in the presence of GroEL Chaperonin and ATP. Biochemistry 31:3955–3963. [PubMed][CrossRef]
20. Adler SP, Purich D, Stadtman ER. 1975. Cascade control of Escherichia coli glutamine synthetase. Purification and properties of the PII regulatory protein and the uridylyltransferase-uridylyl removing enzyme. J Biol Chem 250:6264–6272.[PubMed]
21. Brown MS, Segal A, Stadtman ER. 1971. Modulation of glutamine synthetase adenylylation and deadenylylation is mediated by nucleotide transformation of the PII regulatory protein. Proc Natl Acad Sci USA 68:2949–2953. [PubMed][CrossRef]
22. Kingdon HS, Shapiro BM, Stadtman ER. 1967. Regulation of glutamine synthetase. VIII. ATP:glutamine synthetase adenylyltransferase, an enzyme that catalyzes alterations in the regulatory properties of glutamine synthetase. Proc Natl Acad Sci USA 58:1703–1710. [PubMed][CrossRef]
23. Stadtman ER. 1993. Oxidation of free amino acids and amino acid residues in proteins by radiolysis and by metal catalyzed reactions. Annu Rev Biochem 62:797–821. [PubMed][CrossRef]
24. Rhee SG, Chock PB, Stadtman ER. 1985. Nucleotideylation involved in the regulation of glutamine synthetase in E. coli, p 273–297. In Freedman R and Hawkins HC (ed), The Enzymology of Posttranslation Modification of Proteins, vol. II. Academic Press, New York, N.Y.
25. Shapiro BM, Stadtman ER. 1968. 5′-adenylyl-O-tyrosine. The novel phosphodiester residue of adenylylated glutamine synthetase from Escherichia coli. J Biol Chem 243:3769–3771.[PubMed]
26. Shapiro BM, Stadtman ER. 1968. Glutamine synthetase deadenylylating enzyme. Biochem Biophys Res Commun 30:32–37. [PubMed][CrossRef]
27. Chock PB, Stadtman ER. 1977. Superiority of interconvertible enzyme cascades in metabolic regulation: analysis of multicyclic systems. Proc Natl Acad Sci USA 74:2761–2765. [PubMed][CrossRef]
28. Stadtman ER, Chock PB. 1977. Superiority of interconvertible enzyme cascades in metabolic regulation. Analysis of multicyclic systems. Proc Natl Acad Sci USA 74:2766–2770. [CrossRef]
29. Engleman EG, Francis SH. 1978. Cascade control of E. coli glutamine synthetase II Metabolite regulation of the enzymes in the cascade. Arch Biochem Biophys 191:602–612. [PubMed][CrossRef]
30. Rhee SG, Chock PB, Stadtman ER. 1989. Regulation of Escherichia coli glutamine synthetase. Adv Enzymol Relat Areas Mol Biol 62:37–91. [CrossRef]
31. Stadtman ER, Chock PB. 1978. Interconvertible enzyme cascades in metabolic regulation. Curr Top Cell Regul 13:53–94.[PubMed]
32. Stadtman ER, Chock PB, Rhee SG. 1980. Role of enzyme-catalyzed covalent modifications in regulation of glutamine synthetase, p 57–68. In Mildner P and Ries B (ed), Enzyme Regulation and Mechanism of Action, vol. 60. Pergamon Press, New York, N.Y.
33. Magasanik B. 1982. Genetic control of nitrogen assimilation in bacteria. Annu Rev Genet 16:135–168. [PubMed][CrossRef]
34. Ninfa AJ, Magasanik B. 1986. Covalent modification of the glnG product NRI by the glnL product, NRII. Proc Natl Acad Sci USA 83:5909–5913. [PubMed][CrossRef]
35. Weiss V, Magasanik B. 1988. Phosphorylation of nitrogen regulator I NRI of Escherichia coli. Proc Natl Acad Sci USA 85:8919–8923. [PubMed][CrossRef]
36. Keener J, Kustu S. 1988. Protein kinase and phosphoprotein phosphatase activities of nitrogen regulatory proteins NTRB and NTRC of enteric bacteria: roles of the conserved N-terminal domain of NTRC. Proc Natl Acad Sci USA 85:4976–4980. [PubMed][CrossRef]
37. Keener J, Wong P, Popham D, Wallis J, Kustu S. 1967. A sigma factor and auxiliary proteins required for nitrogen-regulated transcription in enteric bacteria, p 159–175. In Reznikoff WS, Burgess RR, Dahlberg JE, Gross CA, Record MT, Jr, and Wickens MP (ed), RNA Polymerase and Regulation of Transcription. Elsevier Science Publishers, New York, N.Y.
38. Kustu S, Sei K, Keener J. 1986. Nitrogen regulation of enteric bacteria, p 139–154. In Higgins IR Booth and CF (ed), Regulation of Gene Expression. Cambridge Universitiy Press, Cambridge, Mass.
39. Fucci L, Coon CN, Oliver MJ, Stadtman ER. 1983. Inactivation of key enzymes by mixed-function oxidation reactions: possible implication in protein turnover and ageing. Proc Natl Acad Sci USA 80:1521–1525. [PubMed][CrossRef]
40. Eisenberg D, Gill HS, Pfluegl GMU, Rotstein SH. 2000. Structure-function relationships of glutamine synthetases. Biochim Biophys Acta 1477:122–145.[PubMed]
41. Lewisch SA, Levine RL. 1995. Determination of 2-oxo-histidine by amino acid analysis. Anal Biochem 231:127–134. [CrossRef]
42. Climent I, Levine RL. 1991. Oxidation of the active site of glutamine synthetase: conversion of arginine-344 to γ-glutamyl semialdehyde. Arch Biochem Biophys 289:371–375. [PubMed][CrossRef]
43. Rivett AJ. 1985. Preferential degradation of the oxidatively modified form of glutamine synthetase by intracellular mammalian proteases. J Biol Chem 260:300–305.[PubMed]
44. Roseman JE, Levine RL. 1987. Purification of a protease from Escherichia coli with specificity for oxidized glutamine synthetase. J Biol Chem 262:2101–2110.[PubMed]
45. Oliver CN, Levine RL, Stadtman ER. 1982. Regulation of glutamine synthetase degradation, p 233–294. In Ornston LN and Sligar SG (ed), Experiences in Biochemical Perception. Academic Press, New York, N.Y.
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/content/journal/ecosalplus/10.1128/ecosalplus.3.6.1.6
2004-09-09
2017-12-15

Abstract:

Detailed studies of the glutamine synthetase (GS) in and other bacteria have shown that the activity of this enzyme is regulated by at least five different mechanisms: (i) cumulative feedback inhibition by multiple end products of glutamine metabolism, (ii) interconversion between taut and relaxed protein configurations in response to binding and dissociation of divalent cations at one of its two metal binding sites, (iii) dynamic interconversion of the enzyme between covalently modified (adenylylated) and unmodified forms by a novel bicyclic cascade system, (iv) repression and derepression of glutamine synthetase formation by cyclic phosphorylation and dephosphorylation of an RNA factor that governs transcription activities, and (v) regulation of glutamine synthetase turnover by the coupling of site specific metal ion-catalyzed oxidation with proteolytic degradation of the enzyme. Glutamine synthetase activity in is subject to inhibition by seven different end products of glutamine metabolism, namely, by tryptophan, histidine, carbamyl-phosphate, CTP, AMP, glucose-6-phosphate, and NAD, and also by serine, alanine, and glycine. The cascade theory predicts that the steady-state level of glutamine synthetase adenylylation and therefore its catalytic activity is determined by the combined effects of all metabolites that affect the kinetic parameters of one or more of the enzymes in the cascade. Furthermore, under conditions where the supplies of ATP and glutamate are not limiting and the production of glutamine exceeds the demand, GS is no longer needed, then it will be converted to the catalytically inactive adenylylated form that is not under protection of ATP and glutamate.

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Figures

Image of Figure 1
Figure 1

Three characteristic orientations are shown. When the molecule is resting on a face, the subunits appear as a hexagonal ring (Top). Molecules viewed from the side appear as two layers of subunits seen as four spots when viewed exactly down a diameter between subunits (Middle) or, in general, as two layers of subunits (Bottom). Magnification, ×3,160,000. The results are thus consistent with results of ultracentrifugal and X-ray analyses showing that the enzyme is composed of 12 identical subunits and show that the subunits are arranged in two, superimposed hexagonal arrays.

R. C. Valentine et al. ( 11 ).

Citation: Stadtman E. 2004. Regulation of Glutamine Synthetase Activity, EcoSal Plus 2004; doi:10.1128/ecosalplus.3.6.1.6
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Image of Figure 2
Figure 2

B. M. Shapiro and A. Ginsburg ( 1 ).

Citation: Stadtman E. 2004. Regulation of Glutamine Synthetase Activity, EcoSal Plus 2004; doi:10.1128/ecosalplus.3.6.1.6
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Figure 3

R. C. Valentine et al. ( 11 ).

Citation: Stadtman E. 2004. Regulation of Glutamine Synthetase Activity, EcoSal Plus 2004; doi:10.1128/ecosalplus.3.6.1.6
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Image of Figure 4
Figure 4

Interrelationship between the cyclic interconversion of the regulatory protein between uridylylated [P(UMP)] and unuridylylated (P) forms (upper cycle), and the cyclic interconversion of glutamine synthetase (GS) between adenylylated [GS(AMP)] and unadenylylated forms (lower cycle), and the reciprocal control of these interconversions by glutamine (Gln) and α-ketoglutarate (α-KG). AT and AT denote the adenylylation and deadenylylation sites of the adenylyltransferase (AT), respectively; UT and UT denote the uridylylation and deuridylylation sites of uridylyltransferase, respectively. The values of refer to the average number (0 to 3) of P subunits of UT molecules that are uridylylated (upper cycle) or the number (0 to 12) of the GS subunits that are adenylated (lower cycle).

S. G. Rhee et al. ( 24 ).

Citation: Stadtman E. 2004. Regulation of Glutamine Synthetase Activity, EcoSal Plus 2004; doi:10.1128/ecosalplus.3.6.1.6
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Image of Figure 5
Figure 5

The heavy line (filled squares) shows how the number () of GS adenylylated subunits that were formed when a reaction mixture containing 95 μg of GS, 20 mMMgCl, 20mM orthophosphate (Pi), 1.0 mM ATP, 1.0 mM UTP, 15 mM α-ketoglutarate, 0.3 mM glutamine, and partially purified preparations of P, AT, and UT were incubated at pH 7.2, 37°C, for the times indicated. The other curves illustrate the effects of changing the concentration of only one of the various metabolites, as indicated.

E. R. Stadtman et al. ( 30 ), with minor modifications.

Citation: Stadtman E. 2004. Regulation of Glutamine Synthetase Activity, EcoSal Plus 2004; doi:10.1128/ecosalplus.3.6.1.6
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Image of Figure 6
Figure 6

Interrelationship between the uridylylation cycle, the adenylylation cycle, and the phosphorylation cycle that regulates glutamine synthetase transcription. The reciprocal controls of these interconversions by -glutamine (Gln) and α-ketoglutarate (α-KG) are shown: + indicates stimulation; – indicates inhibition. Abbreviations: GS, glutamine synthetase; P, regulatory protein; AT, and AT, adenylylation and deadenylylation sites, respectively, on the bifunctional adenylyltransferase; UT and UT, deuridylylation (uridylyl-removing) and uridylation sites, respectively, on the bifunctional uridylyltransferase. NR, product (also known as NTRC); NR and NR, product (also known as NTRB) catalyzing phosphorylation and dephosphorylation of NR, respectively.

S. G. Rhee et al. ( 30 ).

Citation: Stadtman E. 2004. Regulation of Glutamine Synthetase Activity, EcoSal Plus 2004; doi:10.1128/ecosalplus.3.6.1.6
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Figure 7

In step 1, HO and Fe generated in the mixed-function oxidation (MFO) system react at divalent metal-binding sites on GS leading to an oxidized form of the enzyme (GS) in which an arginine residue is converted to a carbonyl derivative. In step 2, the GS is degraded by intracellular neutral proteases.

Citation: Stadtman E. 2004. Regulation of Glutamine Synthetase Activity, EcoSal Plus 2004; doi:10.1128/ecosalplus.3.6.1.6
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Tables

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Table 1

Direct and indirect effectors of glutamine synthetase activity

Citation: Stadtman E. 2004. Regulation of Glutamine Synthetase Activity, EcoSal Plus 2004; doi:10.1128/ecosalplus.3.6.1.6

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