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EC no.
CAS no.9001-47-2
IntEnzIntEnz view
ExPASyNiceZyme view
MetaCycmetabolic pathway
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
probable glutaminase from bacillus subtilis complexed with 6-diazo-5-oxo-ʟ-norleucine
Pfam clanCL0013
Available protein structures:
Pfam  structures / ECOD  
PDBsumstructure summary

Glutaminase (EC, glutaminase I, L-glutaminase, glutamine aminohydrolase) is an amidohydrolase enzyme that generates glutamate from glutamine. Glutaminase has tissue-specific isoenzymes. Glutaminase has an important role in glial cells.

Glutaminase catalyzes the following reaction:

Glutamine + H2Oglutamate + NH+4

Tissue distribution[edit]

Glutaminase is expressed and active in periportal hepatocytes, where it generates ammonium for urea synthesis, as does glutamate dehydrogenase.[2] 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, 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. 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, 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. 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.[3]


ADP is the strongest adenine nucleotide activator of glutaminase. Studies have also suggested ADP lowered the Km for glutamine and increased the Vmax. They found that these effects were increased even more when ATP was present.[4]

The end product of the glutaminase reaction, glutamate, is a strong inhibitor of the reaction. Changes in glutamate dehydrogenase, which converts glutamate to 2-oxoglutarate and thereby decreases intramitochondrial glutamate levels, are thereby an important regulatory mechanism of glutaminase activity.

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.”[5]


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.[1]


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.[2]

glutaminase (kidney, mitochondrial)[6]
NCBI gene2744
Other data
EC number3.5.1.2
LocusChr. 2 q32-q34
Search for
glutaminase 2
NCBI gene27165
Other data
EC number3.5.1.2
LocusChr. 12 q13
Search for

Related proteins[edit]

Glutaminases belong to a larger family that includes serine-dependent beta-lactamases and penicillin-binding proteins. 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 isozymes that may both be designated A (GlsA1 and GlsA2).

Clinical significance[edit]

Many cancers rely on glutaminase thus glutaminase inhibitors have been proposed as a cancer treatment.[7][8] Some glutaminase inhibitors such as JHU-083[9] are in 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.[10]


  1. ^ a b PDB: 3A56​; Hashizume R, Mizutani K, Takahashi N, Matsubara H, Matsunaga A, Yamaguchi S, Mikami B (2010). "Crystal structure of protein-glutaminase". doi:10.2210/pdb3a56/pdb. {{cite journal}}: Cite journal requires |journal= (help)
  2. ^ a b Botman D, Tigchelaar W, Van Noorden CJ (November 2014). "Determination of phosphate-activated glutaminase activity and its kinetics in mouse tissues using metabolic mapping (quantitative enzyme histochemistry)". The Journal of Histochemistry and Cytochemistry. 62 (11): 813–26. doi:10.1369/0022155414551177. PMC 4230542. PMID 25163927.
  3. ^ Olalla L, Gutiérrez A, Campos JA, Khan ZU, Alonso FJ, Segura JA, et al. (October 2002). "Nuclear localization of L-type glutaminase in mammalian brain". The Journal of Biological Chemistry. 277 (41): 38939–44. doi:10.1074/jbc.C200373200. PMID 12163477.
  4. ^ Masola B, Ngubane NP (December 2010). "The activity of phosphate-dependent glutaminase from the rat small intestine is modulated by ADP and is dependent on integrity of mitochondria". Archives of Biochemistry and Biophysics. 504 (2): 197–203. doi:10.1016/ PMID 20831857.
  5. ^ Suzuki S, Tanaka T, Poyurovsky MV, Nagano H, Mayama T, Ohkubo S, et al. (April 2010). "Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen species". Proceedings of the National Academy of Sciences of the United States of America. 107 (16): 7461–6. Bibcode:2010PNAS..107.7461S. doi:10.1073/pnas.1002459107. PMC 2867754. PMID 20351271.
  6. ^ DeBerardinis RJ, Cheng T. Q's next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene. 2010 Jan 21;29(3):313-24. doi: 10.1038/onc.2009.358. Epub 2009 Nov 2. PMID 19881548; PMCID: PMC2809806.
  7. ^ Chen L, Cui H (September 2015). "Targeting Glutamine Induces Apoptosis: A Cancer Therapy Approach". International Journal of Molecular Sciences. 16 (9): 22830–55. doi:10.3390/ijms160922830. PMC 4613338. PMID 26402672.
  8. ^ Sheikh TN, Patwardhan PP, Cremers S, Schwartz GK (November 2017). "Targeted inhibition of glutaminase as a potential new approach for the treatment of NF1 associated soft tissue malignancies". Oncotarget. 8 (55): 94054–94068. doi:10.18632/oncotarget.21573. PMC 5706855. PMID 29212209.
  9. ^ Yamashita AS, da Costa Rosa M, Stumpo V, Rais R, Slusher BS, Riggins GJ. The glutamine antagonist prodrug JHU-083 slows malignant glioma growth and disrupts mTOR signaling. Neurooncol Adv. 2020 Oct 29;3(1):vdaa149. doi:10.1093/noajnl/vdaa149 PMID 33681764
  10. ^ Johmura Y, Yamanaka T, Omori S, Wang TW, Sugiura Y, Matsumoto M, et al. (January 2021). "Senolysis by glutaminolysis inhibition ameliorates various age-associated disorders". Science. 371 (6526): 265–270. Bibcode:2021Sci...371..265J. doi:10.1126/science.abb5916. PMID 33446552. S2CID 231606800.

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