Glutaminase (, ''glutaminase I'', ''L-glutaminase'', ''glutamine aminohydrolase'') is an

amidohydrolase Amidohydrolases (or amidases) 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 Ureases (), functionally, belong to t ...

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...

that generates glutamate from

glutamine Glutamine (symbol Gln or Q) is an α-amino acid that is used in the biosynthesis of proteins. Its side chain is similar to that of glutamic acid, except the carboxylic acid group is replaced by an amide. It is classified as a charge-neutral ...

. Glutaminase has tissue-specific isoenzymes. Glutaminase has an important role in

glial cell Glia, also called glial cells (gliocytes) or neuroglia, are non-neuronal cells in the central nervous system (brain and spinal cord) and the peripheral nervous system that do not produce electrical impulses. They maintain homeostasis, form myel ...

s. Glutaminase catalyzes the following reaction:

Glutamine Glutamine (symbol Gln or Q) is an α-amino acid that is used in the biosynthesis of proteins. Its side chain is similar to that of glutamic acid, except the carboxylic acid group is replaced by an amide. It is classified as a charge-neutral ...

+ H₂O → glutamate + NH₃

Tissue distribution

Glutaminase is expressed and active in periportal

hepatocytes A hepatocyte is a cell of the main parenchymal tissue of the liver. Hepatocytes make up 80% of the liver's mass. These cells are involved in: * Protein synthesis * Protein storage * Transformation of carbohydrates * Synthesis of cholesterol, ...

, where it generates NH₃ (ammonia) for

urea Urea, also known as carbamide, is an organic compound with chemical formula . This amide has two amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest amide of carbamic acid. Urea serves an important ...

synthesis, as does

glutamate dehydrogenase Glutamate dehydrogenase (GLDH, GDH) is an enzyme observed in both prokaryotes and eukaryotic mitochondria. The aforementioned reaction also yields ammonia, which in eukaryotes is canonically processed as a substrate in the urea cycle. Typical ...

. 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 chronic

acidosis Acidosis is a process causing increased acidity in the blood and other body tissues (i.e., an increase in hydrogen ion concentration). If not further qualified, it usually refers to acidity of the blood plasma. The term ''acidemia'' describes ...

, 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). One of the most important roles of glutaminase is found in the axonal terminals of neurons in the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...

. Glutamate is the most abundantly used excitatory neurotransmitter in the CNS. After being released into the synapse for neurotransmission, glutamate is rapidly taken up by nearby

astrocytes Astrocytes (from Ancient Greek , , "star" + , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of endo ...

, which convert it to glutamine. This glutamine is then supplied to the presynaptic terminals of the neurons, where glutaminases convert it back to glutamate for loading into

synaptic vesicles In a neuron, synaptic vesicles (or neurotransmitter vesicles) store various neurotransmitters that are released at the synapse. The release is regulated by a voltage-dependent calcium channel. Vesicles are essential for propagating nerve impulse ...

. Although both "kidney-type" (GLS1) and "liver-type" (GLS2) glutaminases are expressed in brain, GLS2 has been reported to exist only in cellular nuclei in CNS neurons.

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 that these effects were increased even more when ATP was present. Phosphate-activated mitochondrial glutaminase (GLS1) 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 facilitates “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 has been determined using X-ray diffraction to a resolution of up to 1.73 Å. There are 2 chains containing 305 residues that make up the length of this dimeric protein. On each strand, 23% of the amino acid content, or 71 residues, are found in the 8 helices. Twenty-one percent, or 95 residues, make up the 23 beta sheet strands.

Isozymes

Humans express 4 isoforms of glutaminase. ''GLS'' encodes 2 types of kidney-type glutaminase with a high activity and low Km. ''GLS2'' encodes 2 forms of liver-type glutaminase with a low activity and allosteric regulation.

Related proteins

Glutaminases belong to a larger family that includes serine-dependent

beta-lactamase Beta-lactamases, (β-lactamases) are enzymes () produced by bacteria that provide multi-resistance to beta-lactam antibiotics such as penicillins, cephalosporins, cephamycins, monobactams and carbapenems ( ertapenem), although carbap ...

s and penicillin-binding

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

s. Many

bacteria Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of prokaryotic microorganisms. Typically a few micrometr ...

have two

isozymes In biochemistry, isozymes (also known as isoenzymes or more generally as multiple forms of enzymes) are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. Isozymes usually have different kinetic parameters (e.g. dif ...

. This model is based on selected known glutaminases and their

homologs A couple of homologous chromosomes, or homologs, are a set of one maternal and one paternal chromosome that pair up with each other inside a cell during fertilization. Homologs have the same genes in the same loci where they provide points alon ...

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 is an inorganic compound of nitrogen and hydrogen with the formula . A stable binary hydride, and the simplest pnictogen hydride, ammonia is a colourless gas with a distinct pungent smell. Biologically, it is a common nitrogenous wa ...

. 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 In biochemistry, isozymes (also known as isoenzymes or more generally as multiple forms of enzymes) are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. Isozymes usually have different kinetic parameters (e.g. dif ...

s that may both be designated A (GlsA1 and GlsA2).

Clinical significance

Many cancers rely on glutaminase thus glutaminase inhibitors have been proposed as a cancer treatment. some glutaminase inhibitors are in mid-stage clinical trials. In 2021, it was reported that a GLS1 inhibitor eliminated senescent cells from various organs and tissues in aged mice, ameliorating age-associated tissue dysfunction. Results suggest that senescent cells rely on glutaminolysis, and inhibition of glutaminase 1 may offer a promising strategy for inducing senolysis in vivo.

References

External links

*
Research information on glutaminase (WikiGenes)
{{Portal bar, Biology, border=no EC 3.5.1 Glutamate (neurotransmitter)