One (Gluta) Mean Protein

I'd like to give you a couple reasons why glutamine synthetase is pretty much the best protein ever...

1.Glutamine synthetase is definitely a looker.





This protein has 12 identical subunits that are joined in a beautifully symmetric array (all structures are of PDB ID FP.

The subunits are arranged in two identical faces which are stacked on top of each other.

The two faces of the protein interact primarily by the subunit pairs that are stacked on top of each other; each subunit has an α helix which extends as a sort of "thong" into a hydrophobic pocket of the subunit below it.¹

2. Glutamine synthetase performs a reaction that is critical for life.

The enzyme catalyzes the condensation of an ammonia and a glutamate to form glutamine.  This happens through the intermediate of glutamate γ-phosphate, which is formed when the enzyme transfers a phosphoryl group from an ATP to the glutamate ² (reaction mechanism image thanks to geraldinemorgan.cl).

 

During the glutamine synthetase reaction, an ATP, a glutamate, and an ammonium diffuse into the active site of glutamate synthase. Active sites are cylindrical and located at each interface of adjacent subunits; each subunit is catalytically active.

The substrates are coordinated to two magnesium ions.  In the image below, magnesiums are depicted as spheres, ADP is in red (used in the crystal structure instead of ATP), and the glutamate analogue and inhibitor phosphinothricin is shown in blue.

This reaction has several crucial functions.  First, it is a key step in nitrogen fixation, allowing plants to incorporate ammonia they receive from symbiotic bacteria into nontoxic glutamine, for transport through the plant.  The reaction also allows glutamine synthetase to scavange free ammonia and glutamate.  This is critical in neurons, where both substances are toxic in high concentration and must be carefully regulated.  Some research suggests that damaged glutamine synthetase contributes to Alzheimer's Disease. The oxidative stress created by amyloid plaques damages glutamine synthase, which is concentrated in neural support cells called astrocytes, and the protein's toxic substrates build up and harm neurons.³  Finally, glutamine synthetase is a key transporter of nitrogen, and supplies nitrogen for synthesis  compounds such as nucleotides and certain amino acids.

3. Glutamine synthetase is exquisitely regulated on several levels.  

This intricate regulation suggests the importance of the glutamine synthetase reaction for cells to function.  First, at least nine molecules, all of which are eventual endproducts of the glutamine synthetase reaction, allosterically regulate the enzyme in a "dimmer switch" fashion.  The many subunits of the enzyme change their interaction with each other when the allosteric effectors bind, and the enzyme shifts from a taut, active conformation to a relaxed, inactive confirmation.  Further, the shift in enzyme activity is not all-or-none.  Instead, the allosteric modulators have a gradual additive effect, so that the activity of the enzyme is fine-tuned to the cell's overall need for nitrogen, and does not reflect the quantities of only one nitrogen-containing molecule.  Glutamine synthetase can also be covalently modified.  An adenylyltransferase can covalently attach an AMP to a tyrosine residue on each subunit.  Each adenylated tyrosine decreases the activity of the enzyme and increases its susceptibility to allosteric inhibition.  The enzymes responsible for adenylation are further subject to regulation, increasing the sensitivity of glutamine synthetase to the concentrations of its products and substrates.⁴  

References:

1. Yamashita, M. M.; Almassy, R. J.; Janson, C. A.; Duilio, C.; Eisenberg, D. J. Biol. Chem. 1989, 264,   17681-17690.

2.   Cox, M. M., and Nelson, D. L. In Lehninger: Principles of Biochemistry,  5th Edition.  Katherine, A.; Rossignol, R.; Britch, J.; Shriner, P.; McCaffrey, P.; Geller, E.; Moscateli, B.; Eds. W.H. Freeman and Company: New York, 2008.

3.  Tumani, H.; GuoQiu, Shen; Peter, J.; Bruck W.  Arch Neurol. 1999, 56, 1241-1246.

4.  Stadtman, E. J. Biol. Chem. 2001, 276, 44357-44364.