Glutaminase Explained

glutaminase
Ec Number:3.5.1.2
Cas Number:9001-47-2
Go Code:0004359
Symbol:Glutaminase
Glutaminase
Pfam:PF04960
Pfam Clan:CL0013
Interpro:IPR015868
Scop:1mki

Glutaminase (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 + → glutamate +

Tissue distribution

Glutaminase is expressed and active in periportal hepatocytes, where it generates ammonium for urea synthesis, as does glutamate dehydrogenase.[1] 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.[2]

Regulation

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.[3]

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.”[4]

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.[1]

glutaminase (kidney, mitochondrial)[5]
Hgncid:4331
Symbol:GLS
Entrezgene:2744
Omim:138280
Refseq:NM_014905
Uniprot:O94925
Ecnumber:3.5.1.2
Chromosome:2
Arm:q
Band:32
Locussupplementarydata:-q34
glutaminase 2
(liver)
Hgncid:29570
Symbol:GLS2
Entrezgene:27165
Omim:606365
Refseq:NM_013267
Uniprot:Q9UI32
Ecnumber:3.5.1.2
Chromosome:12
Arm:q
Band:13

Related proteins

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

Many cancers rely on glutaminase thus glutaminase inhibitors have been proposed as a cancer treatment.[6] [7] Some glutaminase inhibitors such as JHU-083[8] 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.[9]

External links

Notes and References

  1. Botman D, Tigchelaar W, Van Noorden CJ . 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 . November 2014 . 25163927 . 10.1369/0022155414551177 . 4230542.
  2. Olalla L, Gutiérrez A, Campos JA, Khan ZU, Alonso FJ, Segura JA, Márquez J, Aledo JC . 6 . Nuclear localization of L-type glutaminase in mammalian brain . The Journal of Biological Chemistry . 277 . 41 . 38939–44 . October 2002 . 12163477 . 10.1074/jbc.C200373200 . free.
  3. Masola B, Ngubane NP . 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 . December 2010 . 20831857 . 10.1016/j.abb.2010.09.002.
  4. Suzuki S, Tanaka T, Poyurovsky MV, Nagano H, Mayama T, Ohkubo S, Lokshin M, Hosokawa H, Nakayama T, Suzuki Y, Sugano S, Sato E, Nagao T, Yokote K, Tatsuno I, Prives C . 6 . 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 . April 2010 . 2010PNAS..107.7461S . 20351271 . 10.1073/pnas.1002459107 . free . 2867754.
  5. DeBerardinis RJ, Cheng T . Q's next: the diverse functions of glutamine in metabolism, cell biology and cancer . Oncogene . 29 . 3 . 313–24 . January 2010 . 19881548 . 2809806 . 10.1038/onc.2009.358 .
  6. Chen L, Cui H . Targeting Glutamine Induces Apoptosis: A Cancer Therapy Approach . International Journal of Molecular Sciences . 16 . 9 . 22830–55 . September 2015 . 26402672 . 10.3390/ijms160922830 . free . 4613338.
  7. Sheikh TN, Patwardhan PP, Cremers S, Schwartz GK . Targeted inhibition of glutaminase as a potential new approach for the treatment of NF1 associated soft tissue malignancies . Oncotarget . 8 . 55 . 94054–68 . November 2017 . 29212209 . 10.18632/oncotarget.21573 . 5706855.
  8. 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 . 3 . 1 . vdaa149 . 2021 . 33681764 . 7920530 . 10.1093/noajnl/vdaa149 .
  9. Johmura Y, Yamanaka T, Omori S, Wang TW, Sugiura Y, Matsumoto M, Suzuki N, Kumamoto S, Yamaguchi K, Hatakeyama S, Takami T, Yamaguchi R, Shimizu E, Ikeda K, Okahashi N, Mikawa R, Suematsu M, Arita M, Sugimoto M, Nakayama KI, Furukawa Y, Imoto S, Nakanishi M . 6 . Senolysis by glutaminolysis inhibition ameliorates various age-associated disorders . Science . 371 . 6526 . 265–270 . January 2021 . 2021Sci...371..265J . 33446552 . 10.1126/science.abb5916 . 231606800.