Glutaminase
Encyclopedia
Glutaminase is an amidohydrolase
enzyme
which generates glutamate from glutamine
. Glutaminase has tissue-specific isoenzymes. Importantly, glutaminase is found in glial cell
s.
Glutaminase catalyzes the following reaction:
Glutamine
+ H2O → Glutamate + NH3
synthesis, as does glutamate dehydrogenase
. Glutaminase is also expressed in the epithelial cells of the renal tubules, where the produced ammonia is excreted as ammonium ions. This excretion of ammonium ions is an important mechanism of renal acid-base regulation. During an acidosis
, glutaminase is induced in the kidney, which leads to an increase in the amount of ammonium ions excreted. Glutaminase can also be found in the intestines, whereby hepatic portal ammonia can reach as high as 0.26 mM (compared to an arterial blood ammonia of 0.02 mM).
Phosphate-activated mitochondrial glutaminase (GLS2) is suggested to be linked with elevated metabolism, decreased intracellular reactive oxygen species (ROS) levels and overall decreased DNA oxidation in both normal and stressed cells. It is suggested that GLS2’s control of ROS levels facilitate “the ability of p53 to protect cells from accumulation of genomic damage and allows cells to survive after mild and repairable genotoxic stress.”
s and penicillin-binding protein
s. Many bacteria
have two isozymes. This model is based on selected known glutaminases and their homologs
within prokaryotes, with the exclusion of highly-derived (long branch) and architecturally varied homologs, so as to achieve conservative assignments. A sharp drop in scores occurs below 250, and cutoffs are set accordingly. The enzyme converts glutamine to glutamate, with the release of ammonia
. Members tend to be described as glutaminase A (glsA), where B (glsB) is unknown and may not be homologous (as in Rhizobium etli. Some species have two isozyme
s that may both be designated A (GlsA1 and GlsA2).
Amidohydrolase
Amidohydrolases are a type of hydrolase that acts upon amide bonds.They are categorized under EC number EC 3.5.1 and 3.5.2.Examples include:* Beta-lactamase* Histone deacetylase* Urease...
enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
which generates glutamate from glutamine
Glutamine
Glutamine is one of the 20 amino acids encoded by the standard genetic code. It is not recognized as an essential amino acid but may become conditionally essential in certain situations, including intensive athletic training or certain gastrointestinal disorders...
. Glutaminase has tissue-specific isoenzymes. Importantly, glutaminase is found in glial cell
Glial cell
Glial cells, sometimes called neuroglia or simply glia , are non-neuronal cells that maintain homeostasis, form myelin, and provide support and protection for neurons in the brain, and for neurons in other parts of the nervous system such as in the autonomous nervous system...
s.
Glutaminase catalyzes the following reaction:
Glutamine
Glutamine
Glutamine is one of the 20 amino acids encoded by the standard genetic code. It is not recognized as an essential amino acid but may become conditionally essential in certain situations, including intensive athletic training or certain gastrointestinal disorders...
+ H2O → Glutamate + NH3
Tissue distribution
Glutaminase is expressed in periportal hepatocytes, where it generates NH3 (ammonia) for ureaUrea
Urea or carbamide is an organic compound with the chemical formula CO2. The molecule has two —NH2 groups joined by a carbonyl functional group....
synthesis, as does glutamate dehydrogenase
Glutamate dehydrogenase
Glutamate dehydrogenase is an enzyme, present in most microbes and the mitochondria of eukaryotes, as are some of the other enzymes required for urea synthesis, that converts glutamate to α-Ketoglutarate, and vice versa. In animals, the produced ammonia is, however, usually bled off to the urea...
. Glutaminase is also expressed in the epithelial cells of the renal tubules, where the produced ammonia is excreted as ammonium ions. This excretion of ammonium ions is an important mechanism of renal acid-base regulation. During an acidosis
Acidosis
Acidosis is an increased acidity in the blood and other body tissue . If not further qualified, it usually refers to acidity of the blood plasma....
, glutaminase is induced in the kidney, which leads to an increase in the amount of ammonium ions excreted. Glutaminase can also be found in the intestines, whereby hepatic portal ammonia can reach as high as 0.26 mM (compared to an arterial blood ammonia of 0.02 mM).
Regulation
ADP is the strongest adenine nucleotide activator of glutaminase. Studies have also suggested ADP lowered the K(m) for glutamine and increased the V(max), they found these effects were increased even more when ATP was present.Phosphate-activated mitochondrial glutaminase (GLS2) is suggested to be linked with elevated metabolism, decreased intracellular reactive oxygen species (ROS) levels and overall decreased DNA oxidation in both normal and stressed cells. It is suggested that GLS2’s control of ROS levels facilitate “the ability of p53 to protect cells from accumulation of genomic damage and allows cells to survive after mild and repairable genotoxic stress.”
Structure
The structure of Glutaminase was determined using X-ray diffraction. The resolution of this protein is 1.73Å. Resolution measures the quality of the data that has been collected on the crystal containing the protein. There are 2 chains containing 305 residues that make up the length of this dimeric protein. On each strand 23% of Glutaminase, or 71 residues, are found in the 8 helices. 21%, or 95 residues, construct the 23 beta sheet strands.Isozymes
Humans express the following two glutaminase isozymes:Related proteins
Glutaminases belong to a larger family that includes serine-dependent beta-lactamaseBeta-lactamase
Beta-lactamases are enzymes produced by some bacteria and are responsible for their resistance to beta-lactam antibiotics like penicillins, cephamycins, and carbapenems . These antibiotics have a common element in their molecular structure: a four-atom ring known as a beta-lactam...
s and penicillin-binding protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s. Many bacteria
Zinc dependent phospholipase C
Zinc-dependent prokaryotic phospholipases C is a family of bacterial phospholipases C, some of which are also known as alpha toxins.Bacillus cereus contains a monomeric phospholipase C of 245 amino-acid residues. Although PLC prefers to acton phosphatidylcholine, it also shows weak catalytic...
have two isozymes. This model is based on selected known glutaminases and their homologs
Homology (biology)
Homology forms the basis of organization for comparative biology. In 1843, Richard Owen defined homology as "the same organ in different animals under every variety of form and function". Organs as different as a bat's wing, a seal's flipper, a cat's paw and a human hand have a common underlying...
within prokaryotes, with the exclusion of highly-derived (long branch) and architecturally varied homologs, so as to achieve conservative assignments. A sharp drop in scores occurs below 250, and cutoffs are set accordingly. The enzyme converts glutamine to glutamate, with the release of ammonia
Ammonia
Ammonia is a compound of nitrogen and hydrogen with the formula . It is a colourless gas with a characteristic pungent odour. Ammonia contributes significantly to the nutritional needs of terrestrial organisms by serving as a precursor to food and fertilizers. Ammonia, either directly or...
. Members tend to be described as glutaminase A (glsA), where B (glsB) is unknown and may not be homologous (as in Rhizobium etli. Some species have two isozyme
Isozyme
Isozymes are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. These enzymes usually display different kinetic parameters Isozymes (also known as isoenzymes) are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. These enzymes...
s that may both be designated A (GlsA1 and GlsA2).