User:Tom Gluick/glutamine synthetase: Difference between revisions
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Glutamine synthetase appears to come in three major phylogenetically related classes of structures[http://pfam.sanger.ac.uk/family?acc=PF00120]. The GS-I class is found in many prokaryotes consists of twelve identical subunits arranged as two stacked and interlocking hexameric rings. The crystal structure of the Salmonella typhimurium enzyme has been solved and published in 1989, and its regulation is a subject of textbook discussion[http://www.ebi.ac.uk/pdbsum/2gls]. Briefly, the enzyme is regulated precisely via feedback inhibition by metabolic products such as glycine, alanine, carbamoyl phosphate, CTP and five others, and covalent modification via the adenylylation of tyrosyl residue. Crystal structures for Salmonella typhimurium glutamine synthetase illustrate adenylylated, unadenylylated, and ligand bound states (1lgr[http://www.proteopedia.org/wiki/index.php/1lgr], 2gls[http://www.proteopedia.org/wiki/index.php/2gls], 2lgo[http://www.proteopedia.org/wiki/index.php/2lgo], 1f1h[http://www.proteopedia.org/wiki/index.php/1f1h], 1fs2[http://www.proteopedia.org/wiki/index.php/1fs2] and 1fpy[http://www.proteopedia.org/wiki/index.php/1fpy]). Explaining how this enzyme works is the focus of your projects. <br/> <br/> | Glutamine synthetase appears to come in three major phylogenetically related classes of structures[http://pfam.sanger.ac.uk/family?acc=PF00120]. The GS-I class is found in many prokaryotes consists of twelve identical subunits arranged as two stacked and interlocking hexameric rings. The crystal structure of the Salmonella typhimurium enzyme has been solved and published in 1989, and its regulation is a subject of textbook discussion[http://www.ebi.ac.uk/pdbsum/2gls]. Briefly, the enzyme is regulated precisely via feedback inhibition by metabolic products such as glycine, alanine, carbamoyl phosphate, CTP and five others, and covalent modification via the adenylylation of tyrosyl residue. Crystal structures for Salmonella typhimurium glutamine synthetase illustrate adenylylated, unadenylylated, and ligand bound states (1lgr[http://www.proteopedia.org/wiki/index.php/1lgr], 2gls[http://www.proteopedia.org/wiki/index.php/2gls], 2lgo[http://www.proteopedia.org/wiki/index.php/2lgo], 1f1h[http://www.proteopedia.org/wiki/index.php/1f1h], 1fs2[http://www.proteopedia.org/wiki/index.php/1fs2] and 1fpy[http://www.proteopedia.org/wiki/index.php/1fpy]). Explaining how this enzyme works is the focus of your projects. <br/> <br/> | ||
The human enzyme is classed as GS-II. The quaternary structure consists of ten identical subunits arranged as two pentameric rings stacked atop each other [http://www.ebi.ac.uk/pdbsum/2d3b. ] as shown in the Java Applet on the right hand side of the page. It is activated by Mn and several other divalent metal cations and α-keotglutarate; the enzyme is inhibited by methionine sulfoxime, glycine and carbamoyl phosphate.<ref>Haussinger, D., Schleiss, F., Glutamine metabolism and signaling in the liver, Forntiers in Bioscience 2007, 12, 371-391.</ref> <br/> <br/> | The human enzyme is classed as GS-II. The quaternary structure consists of ten identical subunits arranged as two pentameric rings stacked atop each other [http://www.ebi.ac.uk/pdbsum/2d3b. ] as shown in the Java Applet on the right hand side of the page. It is activated by Mn and several other divalent metal cations and α-keotglutarate; the enzyme is inhibited by methionine sulfoxime, glycine and carbamoyl phosphate.<ref>Haussinger, D., & Schleiss, F., Glutamine metabolism and signaling in the liver, Forntiers in Bioscience 2007, 12, 371-391.</ref> <br/> <br/> | ||
Glutamine synthetase is a key component in controlling ammonia concentrations, maintaining nitrogen balance among organs, acid-base homeostasis, gene regulation and signaling.<ref> Curi, R Glutamine, gene expression, and cell function. Frontiers in Bioscience 2007 12: 344-357. <ref | Glutamine synthetase is a key component in controlling ammonia concentrations, maintaining nitrogen balance among organs, acid-base homeostasis, gene regulation and signaling.<ref> Curi, R., Glutamine, gene expression, and cell function. Frontiers in Bioscience 2007 12: 344-357. </ref> Glutamine homeostasis is maintained in part via regulating transcription and GS protein degradation. <ref> Labow, B. I., ''et.al.'', Mechanisms Governing the Expression of the Enzymes of Glutamine | ||
Metabolism—Glutaminase and Glutamine Synthetase. J. Nutr. 2001 131: 2467S–2474S.</ref>. | Metabolism—Glutaminase and Glutamine Synthetase. J. Nutr. 2001 131: 2467S–2474S.</ref>. | ||
In ureoteles, glutamine serves as a nontoxic shuttle of excess ammonia as its transported from tissues not capable of processing ammonia further through the blood to the liver where amide nitrogen eventually ends up in urea. For neurons in the brain to function normally, the excititory glutamate generated by the neuron is absorbed by the astrocyte and recycled to glutamine by GS.<ref> Albrecht, J. Glutamine in the central nervous system: function and dysfunction. Frontiers in Bioscience 2007 12:332-343. </ref> | In ureoteles, glutamine serves as a nontoxic shuttle of excess ammonia as its transported from tissues not capable of processing ammonia further through the blood to the liver where amide nitrogen eventually ends up in urea. For neurons in the brain to function normally, the excititory glutamate generated by the neuron is absorbed by the astrocyte and recycled to glutamine by GS.<ref> Albrecht, J., Glutamine in the central nervous system: function and dysfunction. Frontiers in Bioscience 2007 12:332-343. </ref> | ||
Disruptions in glutamine homeostasis brought about through cancer, trauma or HiV infection can lead to organ failure and death. Although extremely rare and only seen in the children of consnaguionoius couples, that defects in GLUL ( the gene encoding for gluatmine synthetase) causes a congenital disorder leading to brain malformation and death in neonates[http://ca.expasy.org/cgi-bin/niceprot.pl?P15104].<ref>Haberle, J. et.al., Congenital Glutamine Deficiency with Glutamine Synthetase Mutations. New Engl J Med 2003 353:1926-33.</ref> | Disruptions in glutamine homeostasis brought about through cancer, trauma or HiV infection can lead to organ failure and death. Although extremely rare and only seen in the children of consnaguionoius couples, that defects in GLUL ( the gene encoding for gluatmine synthetase) causes a congenital disorder leading to brain malformation and death in neonates[http://ca.expasy.org/cgi-bin/niceprot.pl?P15104].<ref>Haberle, J., ''et.al.'', Congenital Glutamine Deficiency with Glutamine Synthetase Mutations. New Engl J Med 2003 353:1926-33.</ref> | ||
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