Refined Atomic Model of Glutamine Synthetasea at 3.5 A Resolution
Glutamine Synthetase is a homododecamer (it is composed of 12 identical subunits). It catalyzes the reaction of ammonia with glutamate to form glutamine, with ATP providing the source of free energy for the reaction. The reaction occurs via an intermediate in which the R-group COO- becomes phosphorylated. The enzyme has two identical faces, and each face has six identical subunits arranged so that the face has six-fold rotational symmetry. Within each six-subunit face, the subunits are arranged such that there is an active site at the interface of neighboring subunits. Six beta sheets from one subunit and two beta sheets from its neighbor form a cylinder around the active site. Within the active site, there are two magnesium ions. One of these complexes with an ATP, one complexes with a glutamate. The most important interaction between the two faces are hydrophobic interactions. The c-terminus of a subunit from one face forms a "thong" that extends into a pocket in the adjacent subunit on the opposite face.
Glutamine Synthetase in Cerebrospinal Fluid, Serum Brain: A Diagnostic Marker for Alzheimer Disease
Glutamine synthetase is important in protecting neuronal cells; both of its substrates, ammonia and glutamate, are toxic to neurons. The enzyme is concentrated in astrocytes, neuronal support cells. In Alzheimer's Disease, researchers have reported low activity of glutamine synthetase, suggesting that buildup of the enzyme's substrates may contribute to Alzheimer's Disease. The authors of this paper suggest that oxidative damage from amyloid plaques inactivates glutamine synthetase. Inactive glutamine synthetase then is deposited in the cerebral spinal fluid, leading to higher glutamine synthetase levels in the cerebral spinal fluid of Alzheimer's patients.
The Story of Glutamine Synthetase Regulation
Glutamine synthetase is carefully regulated by large number of allosteric effectors and by covalent modification. There are at least nine known allosteric inhibitors of glutamine synthetase. Many of these are products formed from glutamine, and thus form feedback inhibition, keeping the glutamine synthetase from disrupting the nitrogen supply in cells by overproducing glutamine. Glutamine synthetase can also be covalently modified; one or two tyrosine residues on the exterior of the protein can be adenylated. This adenylation increases the susceptibility of the protein to its allosteric effectors. Further, the protein that adenylates glutamine synthetase is itself carefully regulated by other metabolites relevant to glutamine formation and degradation, greatly increasing the sensitivity of glutamine synthetase activity.
Glutamine Synthetase is a homododecamer (it is composed of 12 identical subunits). It catalyzes the reaction of ammonia with glutamate to form glutamine, with ATP providing the source of free energy for the reaction. The reaction occurs via an intermediate in which the R-group COO- becomes phosphorylated. The enzyme has two identical faces, and each face has six identical subunits arranged so that the face has six-fold rotational symmetry. Within each six-subunit face, the subunits are arranged such that there is an active site at the interface of neighboring subunits. Six beta sheets from one subunit and two beta sheets from its neighbor form a cylinder around the active site. Within the active site, there are two magnesium ions. One of these complexes with an ATP, one complexes with a glutamate. The most important interaction between the two faces are hydrophobic interactions. The c-terminus of a subunit from one face forms a "thong" that extends into a pocket in the adjacent subunit on the opposite face.
Glutamine Synthetase in Cerebrospinal Fluid, Serum Brain: A Diagnostic Marker for Alzheimer Disease
Glutamine synthetase is important in protecting neuronal cells; both of its substrates, ammonia and glutamate, are toxic to neurons. The enzyme is concentrated in astrocytes, neuronal support cells. In Alzheimer's Disease, researchers have reported low activity of glutamine synthetase, suggesting that buildup of the enzyme's substrates may contribute to Alzheimer's Disease. The authors of this paper suggest that oxidative damage from amyloid plaques inactivates glutamine synthetase. Inactive glutamine synthetase then is deposited in the cerebral spinal fluid, leading to higher glutamine synthetase levels in the cerebral spinal fluid of Alzheimer's patients.
The Story of Glutamine Synthetase Regulation
Glutamine synthetase is carefully regulated by large number of allosteric effectors and by covalent modification. There are at least nine known allosteric inhibitors of glutamine synthetase. Many of these are products formed from glutamine, and thus form feedback inhibition, keeping the glutamine synthetase from disrupting the nitrogen supply in cells by overproducing glutamine. Glutamine synthetase can also be covalently modified; one or two tyrosine residues on the exterior of the protein can be adenylated. This adenylation increases the susceptibility of the protein to its allosteric effectors. Further, the protein that adenylates glutamine synthetase is itself carefully regulated by other metabolites relevant to glutamine formation and degradation, greatly increasing the sensitivity of glutamine synthetase activity.
