Atlas of Genetics and Cytogenetics in Oncology and Haematology

Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

GLS (Glutaminase)

Written2019-02José A. Campos-Sandoval, Mercedes Martin-Rufián, Javier Márquez
Department of Molecular Biology and Biochemistry, Faculty of Sciences, Campus de Teatinos, University of Málaga, 29071 Málaga, Spain, and Instituto de Investigación Biomédica de Málaga (IBIMA), 29010 Málaga, Spain;,,

Abstract After metabolic reprogramming, many cancer cells become glutamine addicted, that is, they depend on a high consumption of this amino acid for their survival and proliferation. Glutaminase catalyzes the stoichiometric conversion of L-glutamine to L-glutamate and ammonium ions, the first step of glutaminolysis. GLS gene encodes two isoforms, known as kidney-type glutaminase (KGA) and glutaminase C (GAC). Upregulation of GLS is a common feature of many tumors and, in recent years, this enzyme and its interacting partners have attracted much attention as potential new targets for cancer therapy. Considerable effort is being devoted towards the development of small-molecule inhibitors of GLS.

Keywords Glutaminase, glutamine addiction, anticancer therapy, BPTES, CB-839, compound 968, breast cancer, colorectal cancer, glioblastoma, hepatocellular carcinoma, leukemia, lung cancer, melanoma, ovarian cancer, prostate cancer.

(Note : for Links provided by Atlas : click)


Alias (NCBI)GA
KGA (kidney-type glutaminase)
GAC (glutaminase C)
PAG (phosphate-activated glutaminase)
HGNC Alias symbKIAA0838
LocusID (NCBI) 2744
Atlas_Id 45600
Location 2q32.2  [Link to chromosome band 2q32]
Location_base_pair Starts at 190880821 and ends at 190965544 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping GLS.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)


  Genomic structure of human glutaminase GLS gene and alternative transcripts KGA and GAC. Introns are depicted as solid light blue lines and exons as numbered dark blue boxes. Dashed red or dotted black lines indicate the exons involved in the generation of KGA and GAC transcripts, respectively (Campos-Sandoval et al., 2015).
Description Human GLS gene is located on chromosome 2 (Aledo et al., 2000). It is composed of 19 exons and spans approximately 82 kb (Porter et al., 2002). The gene resides on the forward strand. It starts at 190880821 and ends at 190965552 from pter (NCBI, GeneID 2744).
Transcription Two different transcripts coding for functional proteins arise from this gene by a mechanism of alternative splicing: a long KGA transcript, first isolated from brain, which contains exons 1-14 and 16-19 of the GLS gene (Nagase et al., 1998; Holcomb et al., 2000; Porter et al., 2002), and a shorter GAC transcript, formed by the first 15 exons and originally described in human colon cancer cells (Elgadi et al., 1999). A third transcript has been found in heart and skeletal muscle that codes for a much shorter protein (GAM) with no measurable catalytic activity (Elgadi et al., 1999).
Several mechanisms regulate glutaminase expression. The first one to be described is based on the presence of AU-rich pH-responsive instability elements within the 3'-nontranslated region of GLS mRNA. These elements are implicated in the rapid turnover of mRNAs by exonucleolytic degradation. The onset of metabolic acidosis results in the increased binding activity of a RNA-binding protein CRYZ (identified as ζ-crystallin/NADPH quinone reductase) with high affinity for the pH-responsive elements, that selectively stabilizes GLS mRNA (Hansen et al., 1996; Tang and Curthoys, 2001). Upregulation of GAC by the long non-coding RNA (lncRNA) colon cancer-associated transcript 2 ( CCAT2) has recently been reported in colon cancer. This lncRNA interacts with the cleavage factor I (CFIm) complex in an allele-specific manner and select the poly(A) site within 14th intron of GLS pre-mRNA, resulting in the preferential splicing of GAC isoform (Redis et al., 2016). MicroRNAs (miRNAs) are also implicated in GLS expression. Through downregulation of MIR23A / MIR23B, which target GLS mRNA, the oncogenic transcription factor MYC (v?myc myelocytomatosis viral oncogene homolog) indirectly relieves repression of GLS in lymphoma and prostate cancer cells (Gao et al., 2009). The MTOR complex 1/ RPS6KB1 (mTORC1/S6K1 (mammalian target of rapamycin complex 1/ribosomal protein S6 kinase beta-1)) signaling pathway positively regulates GLS expression by enhancing the translation efficiency of Myc mRNA. After inhibition of mTORC1 with rapamycin, an increase in miR-23a/b levels was observed (Csibi et al., 2014). The activation of RELA (v-rel avian reticuloendotheliosis viral oncogene homolog A, also known as p65), a member of nuclear factor kappa B (NF-kB) family, also decreases miR-23a expression in leukemic cells, inducing GLS expression (Rathore et al., 2012). Another transcription factor, JUN (v-jun avian sarcoma virus 17 oncogene homolog), when activated downstream of oncogenic Rho GTPase signaling, increases GLS expression in breast cancer cells by direct binding to its gene promoter (Lukey et al., 2016). After being activated by transforming growth factor (TGF)-β and Wnt (Wingless-type MMTV integration site family)-3a, the homeodomain transcription factor DLX2 (distal-less homeobox-2), involved in embryonic and tumor development, also upregulates GLS expression (Lee SY et al., 2016a). Transcription of GLS gene is also activated in HIV-1 infected cells by interferon (IFN)-α through signal transducer and activator of transcription 1 ( STAT1) phosphorylation, leading to glutamate overproduction (Zhao et al., 2012). Retinoblastoma protein ( RB1), a tumor suppressor that modulates cell cycle checkpoints, also regulates glutamine metabolism. Deletion of RB family revealed an increase in GLS protein and activity (Reynolds et al., 2014).


Note In recent years, considerable effort is being devoted towards the development of small-molecule inhibitors that target GLS and its interacting partners (Katt et al., 2017; Matés et al., 2018). Structural information of truncated or full recombinant human GLS complexed with substrate (glutamine), product (glutamate), the allosteric activator phosphate or inhibitors is now available (DelaBarre et al., 2011; Cassago et al., 2012; Thangavelu et al., 2012; Pasquali et al., 2017).
  Schematic diagram of GLS isoforms showing the localization of predicted domains and motifs by sequence analysis (Márquez et al., 2016).
Description Purification:
A 10000-fold purification of glutaminase (KGA) from pig kidney was achieved by Kvamme et al. (1970) using alternative solubilization and precipitacion steps, based on its property to aggregate in phosphate-borate buffers and to disaggregate in Tris-HCl buffers. KGA may appear as three different forms: a dimeric and inactive form in Tris-HCl buffer; a tetrameric and active form after combination of two dimers when dialyzed against phosphate buffer; and a polymeric form with mass higher that 2000 kDa in the presence of phosphate-borate buffer. These polymers consist of double-stranded helices (Kvamme at al., 1970; Olsen et al., 1970; Godfrey et al., 1977).
KGA transcript (ORF: 2010 nt) codes a 669-residues protein, with a predicted molecular mass of 73.5 kDa. GAC transcript (ORF: 1797 nt) codes a 598-residues protein, with a predicted molecular mass of 65.5 kDa. Both precursors are identical in almost all their primary structure (exons 1-14, residues 1-550), except in the C-terminal region (residues 551-669 for KGA; 551-598 for GAC). They are composed of a N-terminal domain folded into an EF-hand-like four-helix bundle (Pasquali et al., 2017) and a central glutaminase domain from residues 220 to 530, which belongs to the beta lactamase/transpeptidase-like superfamily and contains the catalytic active site (Thangavelu et al., 2012). In addition, the C-terminal region of KGA possesses three ankyrin repeats, also present in GLS2 proteins but not in the GAC isoform (Pasquali et al., 2017), and KEN (Lys-Glu-Asn) and D (destruction) boxes. The ankyrin repeats are protein-protein interaction modules of 33 residues that have been found in many important proteins such as transcriptional factors, cell cycle regulators, cytoskeletal organizers, etc. (Sedgwick and Smerdon, 1999; Mosavi et al., 2004). Both KEN and D boxes are recognized by the ubiquitin ligase APC/C-Cdh1 (anaphase-promoting complex/cyclosome-Cdh1) which targets KGA for degradation by the proteasome (Colombo et al., 2011). The GLS precursor also has a putative N-terminal mitochondrial targeting sequence of 16 residues (Shapiro et al., 1991). The Curthoys laboratory, in a series of studies on the biosynthesis and processing of the rat KGA, found that the 74 kDa precursor is processed in the mitochondria by a matrix processing peptidase to yield two subunits of 66 (cleavage site at residue 72) and 68 kDa with a 3:1 stoichiometry (Perera et al., 1990; Srinivasan et al., 1995). For the human GLS, only a 66 kDa protein has been detected when expressed as a recombinant protein using the baculovirus expression system (Holcomb et al., 2000). As previously described for GLS2 (Olalla et al., 2002), GLS proteins show a LXXLL motif or nuclear receptor box from Leu144 to Leu148 (Cassago et al., 2012). In recent years, several groups have revealed the structure of GLS based on X-ray crystallography. In the asymmetric unit, GLS is organized as a tetramer where the monomers interact through two sets of interfaces at the glutaminase domains. This domain is composed of two subdomains: an α/β subdomain that contains five-stranded anti-parallel β-sheet surrounded by several α-helices, and an α-helical subdomain with seven α-helices. Two GLS monomers are joined by a long interface of their respective α-helical subdomains to form an inactive dimer. Two opposing dimers then associate by a short interface involving two pairs of equivalent anti-parallel α-helices (α-13) at the α /β subdomains, which come into contact by hydrophobic interactions. (DeLaBarre et al., 2011; Cassago et al., 2012; Thangavelu et al, 2012). When a phenylalanine residue (Phe394 in the mouse GAC) in the short dimer interface was mutated to a serine one, GAC persisted as an inactive dimer even at high concentrations of phosphate (Cassago et al., 2012). The presence of salt bridges between Asp391 and Lys401 at both ends of the pairing helices further stabilizes the quaternary structure. The replacement of Asp391 by a lysine residue had a similar effect to that caused by the phenylalanine substitution (Li et al., 2016).
Kinetic properties:
Both GLS isoforms require a polyvalent anion to be active. A decade after Krebs (1935) proposed the existence of two different types of glutaminase, one of them (GLS) strongly inhibited by the product glutamic acid, Carter and Greenstein (1947) observed an accelerated deamidation of glutamine in aqueous rat-liver extracts in the presence of phosphate, arsenate or sulfate and suggested that this effect could be due to an augmentation of the activity of glutaminase enzyme. Errera and Greenstein (1949) characterized it as phosphate-activated glutaminase. It was later found that phosphate induced the association of catalytically inactive dimers into active tetramers, whereas glutamate caused inhibition of glutaminase by reversing this process (Godfrey et al., 1977; Morehouse and Curthoys, 1981). At a concentration of phosphate of 100 mM, tetramerization of glutaminase is produced and the enzyme reaches its maximum activity. The activation by phosphate is sigmoidal, with a K0.5 of 25 mM and a Hill index of 1.5. When phosphate concentration is increased, both the inhibition by glutamate -which is competitive with respect to glutamine- and the KM for glutamine decrease (Haser et al., 1985). Although the activity of the purified enzyme is completely dependent on added phosphate, it was not known if the high concentration of phosphate required for the in vitro reaction could also occur in the intracellular site of glutaminase action or whether phosphate was the substitute of an unknown natural activator (Sayre and Roberts, 1958). In addition to phosphate, a wide variety of physiological compounds (tricarboxylic acids, nucleotide triphosphates, acyl-CoA derivatives) was found that could act as activators (or inhibitors) of glutaminase (O'Donovan and Lotspeich, 1966; Weil-Malherbe, 1969; Kvamme and Torgner, 1975). However, recent X-ray analysis has provided support for the candidature of phosphate as a relevant in vivo effector: crystal structure of glutaminase shows that each GAC monomer encloses a single phosphate ion inside its active site. It has been proposed that, after binding of phosphate, a flexible activation loop located near the short dimer interface undergoes a major conformational change that stabilizes the active site and promotes catalytic turnover (Thangavelu et al., 2012; Li et al., 2016, Stalnecker et al., 2017).
Interacting partners:
The first binding partner for KGA to be described was the caytaxin ATCAY (or BNIP-H for BNIP-2 homology), a protein exclusively expressed in neural tissues and encoded by a gene linked to Cayman ataxia and dystonia. This protein interacts with KGA through a conserved protein-protein interaction domain known as the BNIP-2 and Cdc42GAP homology (BCH) domain. Caytaxin regulates the intracellular localization and activity of KGA: it relocalized KGA from cell body to neurite terminals and reduced glutamate levels by inhibiting its activity (Buschdorf et al., 2006). Subsequently, another member of the family of BCH-domain containing proteins, PRUNE2 (prune homolog 2 with BCH domain, also known as BMCC1s), has been shown to directly interact with KGA. This protein, associated to microtubules and intermediate filaments in astrocytes and neurons, may influence import of KGA to mitochondria: overexpression of PRUNE2 in mouse neurons led to an accumulation of KGA within the cytoplasm (Boulay et al., 2013). Very recently, GLS has been reported to interact with peroxisome proliferator-activated receptor gamma ( PPARG) in the nuclei of prostate cancer cells, and this interaction decreased the nuclear receptor activity (de Guzzi Cassago et al., 2018).
Post-translational modifications:
Aside from the regulation of GLS gene expression, several post-translational modifications affect glutaminase activity, with implications for cancer cells metabolism. Most of the identified modifications correspond to phosphorylation of serine, tyrosine and threonine residues (see Ascenção et al., 2018 for references), although the effect of specific modified residues on GLS activity has only recently been studied. Thangavelu et al. (2012) revealed that GLS activity in human breast adenocarcinoma cells was dependent on phosphorylation by epidermal growth factor ( EGF) via the RAF/MEK/ERK signaling module and was completely abolished after treatment with MEK inhibitors or co-expression with protein phosphatase PP2A. Han et al. (2018) have recently found that GLS activity is drastically reduced when one of the ten identified phosphorylation sites, Ser314 at the glutaminase domain, is mutated to alanine. A remarkable reduction in Ser314 phosphorilation and GLS activity occurs when cell lysates of several tumor types are treated with alkaline phosphatase. This phosphorylation is regulated by the NF-kB-PKCε ( PRKCE protein kinase C-epsilon) axis. After treatment with a NF-kB inhibitor, GLS activity could be restored with the overexpression of PKCε (Han et al., 2018). In contrast, phosphorylation of Ser95 at the N-terminal domain inhibits GLS activity, but its mechanism of deregulation in cancer cells is still unknown (Ascenção et al., 2018). Another post-translational modification that affects GLS activity is succinylation. The mitochondrial protein sirtuin 5 ( SIRT5), which removes short-chain acyl moieties from lysine residues, regulates GLS activity by reducing its level of succinylation (Polleta et al., 2015). Acetylation has also been speculated to regulate GLS activity. Several lysine residues that occur at the α-helix-13 has been identified as sites of this modification and their acetylation could prevent the formation of active tetramers (McDonald et al., 2015). As already mentioned above, KGA is also modified by ubiquitination at its C-terminal region (Colombo et al., 2011).
Drug inhibitors:
The first glutaminase inhibitors to be discovered several decades ago were L-glutamine analogs isolated from Streptomyces, such as azaserine, diazo-O-norleucine (DON) and acivicin. They act as irreversible competitive inhibitors for GLS and other glutamine-utilizing enzymes: DON binds covalently to residue Ser286 at the GLS active site (Thangavelu et al., 2014). Although they show a significant inhibitory effect on several types of tumors in preclinical tests, their pronounced toxicity has compromised the therapeutical potential of these compounds (Ahluwalia et al., 1990). The bisthiadiazole derivatives form the second important group of inhibitors that was described the past few years, the prototype being BPTES (Robinson et al., 2007). A more potent derivative of BPTES, CB-839 (Gross et al., 2014), is being tested in clinical trials (more information at database). These non-competitive allosteric inhibitors bind to the interface between two dimers, stabilizing an inactive tetrameric form of GLS (DeLaBarre et al., 2011; Thangavelu et al., 2012). The newest molecule in this group is the compound UPGL00004, with similar binding affinity as CB-839 but with better microsomal stability (Huang et al., 2018). The third group of inhibitors is represented by compound 968, a benzophenanthridinone that binds to a pocket at the interface between two GLS monomers. Unlike BPTES, compound 968 preferentially binds to the monomeric, inactive form of GLS, and is unable to inhibit GLS which has been pre-activated with phosphate (Wang et al., 2010; Stalnecker et al., 2017). Other new GLS inhibitors recently described are physapubescin K, (Cheng et al., 2017; Wu et al., 2017), zaprinast (Elhammali et al., 2014) and brachyantheraoside A8 (Li et al., 2017). One essential point of GLS inhibition is that these novel compounds lack the high degree of toxicity observed with glutamine mimetics (Matés et al., 2018). For an overview of glutaminase inhibitors, see: Katt et al., 2017; Song et al., 2018; Wu et al., 2018; Xu et al, 2018.
Expression The rat KGA isoform has been found in all nonhepatic tissues with glutaminase activity, including fetal liver (Smith and Watford, 1990; Curthoys and Watford, 1995). In human tissues, the KGA isoform is expressed in kidney, brain, heart, lung and pancreas, but not in skeletal muscle or liver (Aledo et al., 2000). The human GAC isoform, first described in a cancer cell line, is found principally in cardiac muscle and pancreas, at lower levels in lung, kidney and placenta, and is not detected in brain or liver. (Elgadi et al., 1999). GLS proteins are also overexpressed in a wide variety of tumors compared to normal tissues, with GAC being the predominant isoform in many of them, such as breast carcinoma (Elgadi et al., 1999), prostate cancer (Gao et al., 2009), non-small cell lung cancer (van den Heuvel et al., 2012), leukemia (Pérez-Gómez et al., 2005; Matre et al., 2016), glioma (Szeliga et al., 2008; Tanaka et al., 2015), among others.
Localisation Errera and Greenstein (1949) proposed for the first time a mitochondrial location for glutaminase in liver, and subsequently different authors demonstrated experimentally this location in both liver and other organs such as kidney, brain and intestine (Klingman and Handler, 1958; Guha, 1961; Katunuma et al., 1967; Pinkus and Windmueller, 1977). However, some authors have described a non-mitochondrial cytoplasmic pool of glutaminase (Aoki et al., 1991). In a recent study with several tumor cell lines, Cassago et al. (2012) have reported a cytosolic localization for KGA, with only GAC located in mitochondria. These findings suggest that the intracellular localization of GLS may depend on other factors other than the mitochondrial targeting sequence at its N-terminus. The sub-mitochondrial location of glutaminase has been studied extensively, but it is still a controversial issue. Although glutaminase seems to be associated with the inner mitochondrial membrane (IMM), different orientations of the enzyme have been proposed: to both sides of the IMM (Kvamme and Olsen, 1979), the intermembrane space (c-side) (Kvamme et al., 1991; Roberg et al., 1995), or the matrix space (m-side) (Shapiro et al., 1985; Aledo et al., 1997).
Function GLS (E.C. catalyzes the hydrolytic deamidation of L-glutamine to form L-glutamate and ammonium, the first step of glutaminolysis. This enzyme fulfills essential tasks related to tissue-specific function. In kidney, glutaminase reaction is the initial step in renal ammoniagenesis. As mentioned above, GLS is induced through its mRNA stabilization in response to metabolic acidosis. This results in an increased consumption of glutamine extracted from plasma in the proximal convolute tubules and the excretion of the generated ammonium ions in the urine. The further metabolization of α-ketoglutarate (α-KG) yields bicarbonate ions that are transported into blood to restore the acid-base balance (Curthoys, 2001). In brain, GLS participates in the synthesis and recycling of glutamate, the principal excitatory neurotransmitter, through the astrocytic-neuronal glutamate-glutamine cycle (Nicklas et al., 1987; Daikhin and Yudkoff, 2000). Knockout mice for the Gls gene die shortly after birth due to impaired glutamatergic synaptic function, stressing the importance of this enzyme in glutamatergic transmission (Masson et al., 2006). Moreover, it has been shown that small interfering RNA (siRNA) silencing of GLS in neural progenitor cells impaired their differentiation, proliferation and survival, suggesting a critical role of GLS in neurogenesis (Wang et al., 2014).
Besides its role in normal tissues, glutaminase is highly expressed in tumors, where its activity has been correlated with malignancy (Knox et al., 1967; Linder-Horowitz et al., 1969; Kovacevik and McGivan, 1983). Many cancer cells develop what has been called "glutamine addiction", a term now widely used to reflect the strong dependence for this essential nitrogen substrate after metabolic reprogramming (Wise et al., 2008). Silencing GLS expression by genetic knockdown or inhibiting its activity with drug inhibitors reveal the critical role of GLS in this addiction. Thus, the specific inhibition of GLS by antisense mRNA slowed tumor cell growth and induced phenotypic changes that made these cells vulnerable to the host's immune system (Lobo et al., 2000; Segura et al., 2001). In addition, GLS enables cancer cells to counteract ROS. Glutamate is the precursor of glutathione (GSH) and a source or reducing equivalents (Hensley et al., 2013). Based on the abundant published data on recent years on the role of glutaminase in cancer, this enzyme has become a potential drug target for therapeutic intervention (Matés et al., 2018).

Implicated in

Entity Breast cancer
Note Breast cancer exhibits subtype-specific phenotype of glutamine dependence. Triple negative breast cancer (TNBC) showed higher GLS expression than ERBB2 (Erb-B2 receptor tyrosine kinase 2)-positive or luminal subtypes (Kung et al., 2011; Kim et al., 2013; Lampa et al., 2017). In a study with a panel of breast cancer cell lines, GLS inhibitor CB-839 had an anti-proliferative effect on TNBC cells but not on estrogen receptor (ER)-positive or ERBB2-positive cell lines. This effect was associated with a significant decrease in both glutamine consumption and levels of tricarboxylic acid (TCA) cycle intermediates. Sensitivity of TNBC cells to CB-839 was correlated with an elevated expression of GAC but not KGA (Gross et al., 2014). The new GLS inhibitor UPGL00004 had a similar effect: it potently inhibited growth in TNBC but not in receptor-positive cells (Huang et al., 2018). A higher activity of MYC in cells of this subtype could maintain expression of GLS (Kung et al., 2011). Another effect of GLS inhibition with CB-839 was a decrease in MTOR activity. Both GLS and mTOR inhibition synergized in TNBC cells (Lampa et al., 2017). GLS expression is also upregulated by ERBB2 activation. When non-tumorigenic breast epithelial cells were transformed with a constitutive active form of ERBB2, GLS mRNA and protein levels were increased through activation of NF-kB signaling (Qie et al., 2014). In a similar model, knockdown of ephrin-A1, a ligand of EPH receptor A2 ( EPHA2), enhanced GLS activity through increased levels of Rho GTPase and addition of α-KG restored proliferation inhibited by compound 968 (Youngblood et al., 2016). Activation of JUN downstream of Rho GTPase signaling led to enhanced glutaminase activity (Lukey et al., 2016). An inverse correlation between the expression of glutamine synthetase (GS, encoded by GLUL) and GLS has been observed in luminal and TNBC cells. Moreover, GLUL repression led to an increase of GLS mRNA levels, and ectopic GDH over-expression reduced those levels (Kung et al., 2011).
Entity Colorectal cancer
Note GLS expression is upregulated in colorectal cancer (CRC) tissues compared to adjacent normal tissues (Huang et al., 2014). In recent years, several mechanisms have been described to regulate GLS expression in colorectal cancer. Supranutritional doses of selenite induced GLS ubiquitination by APC/C-CDH1, leading to suppression of glutaminolysis and increasing apoptosis in CRC cells (Zhao et al., 2017). Heat shock factor 1 ( HSF1) participates in malignant transformation in many types of tumors. In CRC, high levels of HSF1 correlates with poor survival. Through inhibition of MIR137 which targets GLS, HSF1 stimulates GLS expression, resulting in enhanced glutaminolysis and MTOR activation (Li et al., 2018). MYCN downstream regulated gene 2 ( NDRG2), a tumor suppressor, has been shown to regulate GLS expression. When overexpressed in CRC cells, NDRG2 inhibited glucolysis and glutaminolysis via repression of MYC. (Xu et al., 2015). GLS expression seems to be also regulated by TP53. Costunolide, a natural sesquiterpene lactone with antitumoral activity, stimulated the nuclear translocation of TP53 and downregulated GLS mRNA and protein levels, resulting in lower intracellular levels of glutamate and α-KG. Treatment with a TP53 inhibitor rescued GLS expression, indicating that activation of TP53 was required for costunolide to downregulate GLS expression in CRC cells (Hu et al., 2018).
Entity Glioblastoma
Note The effect of glutaminase inhibition on glioblastoma (GBM) have been addressed in isocitrate dehydrogenase ( IDH1 or IDH2) wild type or mutant cell lines. GBM cells that harbour IDH mutations acumulate 2-hydroxyglutarate (2-HG), an oncometabolite primarily derived from glutamine (Dang et al., 2009). When compared to IDH wild type cells, IDH mutant cells treated with the GLS inhibitor BPTES showed a slower growth rate that could be restored by adding exogenous α-KG (Seltzer et al., 2010). 2-HG inhibits the synthesis of glutamate by α-KG-dependent branched-chain amino acid aminotransferases BCAT1 and BCAT2 and, as a consequence, dependence of these cells on glutaminase for glutamate and GSH biosynthesis increases. Inhibition of GLS with CB-839 made IDH mutant cells more susceptible to reactive oxygen species (ROS)-induced cell death and radiation. Based on these findings, a combination of CB-839, the alkylating agent temozolomide and radiation is now being tested in patients with IDH1 mutant gliomas (McBrayer et al., 2018). ROS generation by treatment with oxidizing agents synergized with GLS silencing or GLS2 overexpression to suppress malignant properties of GBM cells (Martèn-Rufián et al., 2014). In IDH wild type GBM cells, pharmacological NOTCH pathway blockade reduced the levels of GLS mRNA, which was reflected in reduced intracellular glutamate concentration (Kahlert et al., 2016). MiRNAs also play an important role in glutamine metabolism of glioblastoma. Thus, MIR153 has been found to be downregulated in glioblastoma and its overexpression inhibits cell growth and promotes apoptosis by directly targeting GLS expression (Liu et al., 2017). Compensatory anaplerotic mechanisms have also been described in GBM. In those that use glutamine as the preferred anaplerotic precursor, inhibition of GLS is accompanied by augmented activity of pyruvate carboxylase to stimulate glycolytic metabolism (Cheng et al., 2011). Conversely, glioblastoma cells respond to deficit in glycolysis after mTOR inhibition by increasing glutamine metabolism through elevated GLS expression. Combination of MTOR and GLS inhibition caused suppression of tumor growth in vivo (Tanaka et al., 2015).
Entity Hepatocellular carcinoma
Note Hepatocellular carcinoma (HCC) is one of the most aggressive cancers. A high correlation between growth rate and dedifferentiation of rat hepatomas and GLS activity was already described 50 years ago (Linder-Horowitz et al., 1969). In a recent study, a large set of clinical samples of HCC and normal liver was analysed and GLS was found to be highly expressed in tumor samples, whereas GLS2 was preferentially expressed in normal cells. During malignant progression, a switch from GLS2 to GLS was observed. High GLS and/or low GLS2 expression in HCC determined poor prognosis in patients with this tumor (Yu et al., 2015). Several mechanisms that regulate GLS expression in HCC have been described. Wnt/β-catenin pathway, associated to HCC stemness, promotes GLS expression. After treatment with an agonist of Wnt/β-catenin pathway, both GLS mRNA and protein increased. In addition, the increase in ROS caused by treatment with compound 968 decreased the amount of nuclear β-catenin ( CTNNB1) and subsequently inhibited expression of target genes implicated in HCC stemness (Li et al., 2019). RELA also controls GLS expression in HCC and its inactivation reduced GLS mRNA levels. Dysregulation of RELA and GLS correlated with poor prognosis in HCC patients (Dong et al., 2018). HCC cells with a mesenchymal phenotype showed higher levels of TGF-β than their epithelial counterparts, and this resulted in increased GLS expression and glutamine anaplerosis (Soukupova et al., 2017). A lncRNA that participates in HCC progression, HOXA distal transcript antisense RNA ( HOTTIP), is negatively regulated by MIR192 and MIR204 and this regulation modulates GLS expression. Inhibition of HOTTIP by siRNA or by ectopic expression of miR-192/-204 suppressed GLS expression and hence HCC proliferation (Ge et al., 2015). A therapeutic strategy combining GLS inhibition with ROS induction has been tested in HCC cells. Treatment with compound 968 and dihydroartemisinin (an anti-cancer drug that enhances ROS production) synergistically sensitized HCC cells to ROS-induced cytotoxicity resulting in apoptosis (Wang et al., 2016).
Entity Leukemia
Note In a study with leukemia cells from medullar blood of human patients, both GLS and GLS2 isoforms were expressed, although GLS accounted for the majority of glutaminase activity in these cells. Furthermore, GLS expression was positively correlated with the rate of proliferation (Pérez-Gómez et al., 2005). Acute myeloid leukemia (AML) cells that harbour IDH mutations are glutamine addicted and their growth could be suppressed by treatment with BPTES (Emadi et al., 2014). Analysis of AML cell lines showed high levels of GAC, while KGA was expressed at low level. Inhibition of GLS with BPTES or CB-839 caused reduction of key metabolites downstream of glutamate, including TCA cycle intermediates and GSH. CB-839 exposure also reduced levels of oncometabolite 2-HG and this reduction associated with signs of differentiation (Matre et al., 2016). Combined therapy with GLS inhibitors dramatically reduced proliferation in AML models. Thus, GAC inhibition by CB-839 sinergized with BCL2 (B-Cell Leukemia/Lymphoma 2) (Jacque et al., 2015) or FLT3 (FMS-like tyrosine kinase 3) inhibition (Gregory et al., 2018) to induce loss of viability through apoptotic cell death. Synergistic antileukemic effects were also observed after treatment with BPTES in combination with NOTCH1 inhibition (Herranz et al., 2015). MiRNAs have also been implicated in glutamine metabolism in leukemic cells. Thus, an increase in expression and translocation of RELA to the nucleus was observed in leukemic Jurkat T cells growing in medium with glutamine, which caused a higher NF-kB activity. Activation of RELA reduced MIR23A expression, leading to a higher expression of GLS. Overexpression of MIR23A in these cells impaired glutamine metabolism and caused mitochondrial dysfunction and cell death (Rathore et al., 2012).
Entity Lung cancer
Note GAC is the predominant GLS isoform in glutamine-dependent non-small cell lung cancer (NSCLC). The increased GAC:KGA ratio observed in these cells, compared with normal lung tissue, was due to a significant decrease of KGA expression in tumoral cells. GAC knockdown in glutamine-dependent cells strongly reduced cell growth, whereas the effect of KGA knockdown was much less pronounced, suggesting that GAC is the more essential GLS isoform in these cells (van den Heuvel et al., 2012). GAC protein levels were similar between tumor and normal tissues: the high glutaminase activity in NSCLC cells resulted from GAC phosphorylation (Han et al., 2018). However, other authors have found that GLS expression is significantly higher in NSCLC than in cells from normal lung tissues (Lee JS et al., 2016b). A 2-fold increase in GAC levels and a reduction in KGA and pyruvate carboxylase levels were observed in NSCLC cells that underwent ephitelial to mesenchymal transition induced by TGF-β, making these cells more susceptible to GLS inhibition, as shown by impaired TCA cycle anaplerosis and increased sensitivity to oxidative stress after treatment with BPTES (Ulanet et al., 2014). Synergic treatments that combine inhibition of GLS and other drug targets have been described in recent studies. Thus, treatment with GLS inhibitor compound 968 sensitized lung cancer cells to apigenin-mediated apoptosis (Lee YM et al., 2016c). Dual treatment with GLS inhibitor BPTES and thymidylate synthase inhibitor 5-fluorouracil resulted in the reversal of NSCLC in a preclinical xenograft model (Lee JS et al., 2016b). In epidermal growth factor receptor ( EGFR) mutant lung cancer cells, targeted inhibition of EGFR signaling and GLS with erlotinib and CB-839, respectively, induced a reduction in glucose and glutamine transporters levels and led to tumor regression in xenograft models (Momcilovic et al., 2017). Unfortunately, acquired resistance is developed by patients with NSCLC after several months of treatment with erlotinib. Compound 968, when combined with erlotinib, inhibited the proliferation of erlotinib-resistant NSCLC cells by decreasing the expression of EGFR (Xie et al., 2016). The adquired resistance of lung squamous cell carcinomas to MTOR inhibition via enhanced glutaminolysis was overcome by treatment with CB-839 (Momcilovic et al., 2018).
Entity Melanoma
Note Two miRNAs targeting GLS have been found to be downregulated in melanoma cells and their low levels associated with poor prognosis. When overexpressed, both miRNAs (MIR137 and MIR203) suppressed glutamine catabolism and proliferation of melanoma cells (Chang et al., 2016; Luan et al., 2018). MiRNA203 also sensitized resistant melanoma cells to temozolomide (Chang et al., 2016).
Entity Ovarian cancer
Note Patients with ovarian cancer who initially respond to platinum and taxane-based chemotherapy will develop drug resistance. Compared to sensitive cells, cisplatin-resistant cells showed glutamine dependence, associated with the upregulated expression of glutamine transporter SLC1A5 (ASCT2) and GLS mediated by higher levels of MYC. GLS overexpression in cisplatin-sensitive cells resulted in increased resistance to this agent. Conversely, knockdown of GLS re-sensitized resistant cells to cisplatin. Combination of BPTES and cisplatin synergistically increased apoptosis (Hudson et al., 2016). A similar effect on cell proliferation was obtained after treatment of ovarian cancer cells with paclitaxel and compound 968. This GLS inhibitor induced cell cycle arrest and apoptosis, and sensitized cells to paclitaxel (Yuan et al, 2016). Moreover, knockdown of both GLS isoforms by siRNA sensitized cells to chemotherapy more effectively than depletion of GAC or KGA alone (Masamha and LaFontaine, 2018). Another proposed therapeutic strategy combined inhibition of PI3K/Akt/mTOR axis (frequently activated in ovarian cancer cells) and GLS with PP242 (an inhibitor of mTORC1 and mTORC2) and CB-839, respectively. GLS inhibition resulted in a dramatic induction of PP242-mediated cell death not only by a reduced glutamine anaplerosis, but also by a decreased level of phosphorylated STAT3 (signal transducer and activator of transcription 3) (Guo et al., 2016).
Entity Prostate cancer
Note GLS is highly expressed in prostate cancers and positively correlates with tumor state and progression. In glutamine addicted prostate cancer cells, GLS regulates glucose uptake through inhibition of thioredoxin-interacting protein ( TXNIP) expression, a potent negative regulator of aerobic glycolisis and glucose uptake. When GLS activity was suppressed by siRNA or BPTES, TXNIP was remarkably induced and the invasive capacity of these cells significantly reduced (Pan et al., 2015). It was in these tumors that MYC, which contributes to their initiation and progression (Koh et al., 2010), was described to upregulate GLS expression through suppression of MIR-23a/b (Gao et al., 2009). Recent results show that GLS is highly expressed in large extracellular vesicles (LEVs) extruded from prostate cancer cells (Minciacchi et al., 2015). Release of these vesicles is dependent on glutamine metabolism. Thus, a significant reduction in the production of LEVs is observed when these cells are treated with BPTES (Dorai et al., 2018).


Metabolism and action of amino acid analog anti-cancer agents.
Ahluwalia GS, Grem JL, Hao Z, Cooney DA.
Pharmacol Ther 1990; 46 (2): 243-71.
PMID 2108451
Identification of two human glutaminase loci and tissue-specific expression of the two related genes.
Aledo JC, Gómez-Fabre PM, Olalla L, Márquez J.
Mamm Genome 2000; 11 (12): 1107-10.
PMID 11130979
Submitochondrial localization and membrane topography of Ehrlich ascitic tumour cell glutaminase.
Aledo JC, de Pedro E, Gómez-Fabre PM, Nez de Castro I, Márquez J.
Biochim Biophys Acta 1997; 1323 (2): 173-84.
PMID 9042341
Identification of mitochondrial and non-mitochondrial glutaminase within select neurons and glia of rat forebrain by electron microscopic immunocytochemistry.
Aoki C, Kaneko T, Starr A, Pickel VM.
J Neurosci Res 1991; 28 (4): 531-48.
PMID 1714509
N-terminal phosphorylation of glutaminase C decreases its enzymatic activity and cancer cell migration.
Asceno CFR, Nagampalli RSK, Islam Z, Pinheiro MP, Menezes Dos Reis L, Pauletti BA, de Guzzi Cassago CA, Granato DC, Paes Leme AF, Dias SMG.
Biochimie 2018; 154: 69-76.
PMID 30092248
Bmcc1s interacts with the phosphate-activated glutaminase in the brain.
Boulay AC, Burbassi S, Lorenzo HK, Loew D, Ezan P, Giaume C, Cohen-Salmon M.
Biochimie 2013; 95 (4): 799-807.
PMID 23246912
Brain-specific BNIP-2-homology protein Caytaxin relocalises glutaminase to neurite terminals and reduces glutamate levels.
Buschdorf JP, Li Chew L, Zhang B, Cao Q, Liang FY, Liou YC, Zhou YT, Low BC.
J Cell Sci 2006; 119 (Pt 16): 3337-50.
PMID 16899818
Glutaminases in brain: multiple isoforms for many purposes.
Campos-Sandoval JA, Martèn-Rufián M, Cardona C, Lobo C, Peñalver A, Márquez J.
Neurochem Int 2015; 88: 1-5.
PMID 25837287
Acceleration of enzymatic desamidation of glutamine by several inorganic anions.
Carter CE, Greenstein JP.
J Natl Cancer Inst 1947; 7 (6): 433-6.
PMID 20257045
Mitochondrial localization and structure-based phosphate activation mechanism of Glutaminase C with implications for cancer metabolism.
Cassago A, Ferreira AP, Ferreira IM, Fornezari C, Gomes ER, Greene KS, Pereira HM, Garratt RC, Dias SM, Ambrosio AL.
Proc Natl Acad Sci USA 2012; 109 (4): 1092-7.
PMID 22228304
Sensitization of melanoma cells to temozolomide by overexpression of microRNA 203 through direct targeting of glutaminase-mediated glutamine metabolism.
Chang X, Zhu W, Zhang H, Lian S.
Clin Exp Dermatol 2017; 42 (6): 614-21.
PMID 28597996
Physapubescin, a natural withanolide as a kidney-type glutaminase (KGA) inhibitor.
Cheng L, Wu CR, Zhu LH, Li H, Chen LX.
Bioorg Med Chem Lett 2017; 27 (5): 1243-6.
PMID 28174105
Pyruvate carboxylase is required for glutamine-independent growth of tumor cells.
Cheng T, Sudderth J, Yang C, Mullen AR, Jin ES, Matés JM, DeBerardinis RJ.
Proc Natl Acad Sci USA 2011; 108 (21): 8674-9.
PMID 21555572
Molecular basis for the differential use of glucose and glutamine in cell proliferation as revealed by synchronized HeLa cells.
Colombo SL, Palacios-Callender M, Frakich N, Carcamo S, Kovacs I, Tudzarova S, Moncada S.
Proc Natl Acad Sci USA 2011; 108 (52): 21069-74.
PMID 22106309
The mTORC1/S6K1 pathway regulates glutamine metabolism through the eIF4B-dependent control of c-Myc translation.
Csibi A, Lee G, Yoon SO, Tong H, Ilter D, Elia I, Fendt SM, Roberts TM, Blenis J.
Curr Biol 2014; 24 (19): 2274-80.
PMID 25220053
Regulation of glutaminase activity and glutamine metabolism.
Curthoys NP, Watford M.
Annu Rev Nutr 1995; 15: 133-59.
PMID 8527215
Role of mitochondrial glutaminase in rat renal glutamine metabolism.
Curthoys NP.
J Nutr 2001; 131 (9 Suppl): 2491S-5S.
PMID 11533299
Compartmentation of brain glutamate metabolism in neurons and glia.
Daikhin Y, Yudkoff M.
J Nutr 2000; 130 (4S Suppl): 1026S-31S.
PMID 10736375
Cancer-associated IDH1 mutations produce 2-hydroxyglutarate.
Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, Fantin VR, Jang HG, Jin S, Keenan MC, Marks KM, Prins RM, Ward PS, Yen KE, Liau LM, Rabinowitz JD, Cantley LC, Thompson CB, Vander Heiden MG, Su SM.
Nature 2009; 462 (7274): 739-44.
PMID 19935646
Full-length human glutaminase in complex with an allosteric inhibitor.
DeLaBarre B, Gross S, Fang C, Gao Y, Jha A, Jiang F, Song J J, Wei W, Hurov JB.
Biochemistry 2011; 50 (50): 10764-70.
PMID 22049910
Nuclear factor-?B p65 regulates glutaminase 1 expression in human hepatocellular carcinoma.
Dong M, Miao L, Zhang F, Li S, Han J, Yu R, Qie S.
Onco Targets Ther 2018; 11: 3721-9.
PMID 29988727
NRH:quinone oxidoreductase 2 (NQO2) and glutaminase (GLS) both play a role in large extracellular vesicles (LEV) formation in preclinical LNCaP-C4-2B prostate cancer model of progressive metastasis.
Dorai T, Shah A, Summers F, Mathew R, Huang J, Hsieh TC, Wu JM.
Prostate 2018; 78 (15): 1181-95.
PMID 30009389
Cloning and analysis of unique human glutaminase isoforms generated by tissue-specific alternative splicing.
Elgadi KM, Meguid RA, Qian M, Souba WW, Abcouwer SF.
Physiol Genomics 1999; 1 (2): 51-62.
PMID 11015561
A high-throughput fluorimetric assay for 2-hydroxyglutarate identifies Zaprinast as a glutaminase inhibitor.
Elhammali A, Ippolito JE, Collins L, Crowley J, Marasa J, Piwnica-Worms D.
Cancer Discov 2014; 4 (7): 828-39.
PMID 24740997
Inhibition of glutaminase selectively suppresses the growth of primary acute myeloid leukemia cells with IDH mutations.
Emadi A, Jun SA, Tsukamoto T, Fathi AT, Minden MD, Dang CV.
Exp Hematol 2014; 42 (4): 247-51.
PMID 24333121
Phosphate-activated glutaminase in kidney and other tissues.
Errera M, Greenstein JP.
J Biol Chem 1949; 178 (1): 495-502.
PMID 18112132
c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism.
Gao P, Tchernyshyov I, Chang TC, Lee YS, Kita K, Ochi T, Zeller KI, De Marzo AM, Van Eyk JE, Mendell JT, Dang CV.
Nature 2009; 458 (7239): 762-5.
PMID 19219026
MiRNA-192 and miRNA-204 directly suppress lncRNA HOTTIP and interrupt GLS1-mediated glutaminolysis in hepatocellular carcinoma.
Ge Y, Yan X, Jin Y, Yang X, Yu X, Zhou L, Han S, Yuan Q, Yang M.
PLoS Genet 2015; 11 (12): e1005726.
PMID 26710269
Correlation between activation and dimer formation of rat renal phosphate-dependent glutaminase.
Godfrey S, Kuhlenschmidt T, Curthoys P.
J Biol Chem 1977; 252 (6): 1927-31.
PMID 845154
Glutaminase inhibition improves FLT3 inhibitor therapy for acute myeloid leukemia.
Gregory MA, Nemkov T, Reisz JA, Zaberezhnyy V, Hansen KC, D'Alessandro A, DeGregori J.
Exp Hematol 2018; 58: 52-8.
PMID 28947392
Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer.
Gross MI, Demo SD, Dennison JB, Chen L, Chernov-Rogan T, Goyal B, Janes JR, Laidig GJ, Lewis ER, Li J, Mackinnon AL, Parlati F, Rodriguez ML, Shwonek PJ, Sjogren EB, Stanton TF, Wang T, Yang J, Zhao F, Bennett MK.
Mol Cancer Ther 2014; 13 (4): 890-901.
PMID 24523301
Intracellular localization of glutaminase I in rat liver.
Guha SR.
Enzymologia 1961; 23: 94-100.
PMID 13709552
Blockage of glutaminolysis enhances the sensitivity of ovarian cancer cells to PI3K/mTOR inhibition involvement of STAT3 signaling.
Guo L, Zhou B, Liu Z, Xu Y, Lu H, Xia M, Guo E, Shan W, Chen G, Wang C.
Tumour Biol 2016; 37 (8): 11007-15.
PMID 26894601
Phosphorylation of glutaminase by PKC ? is essential for its enzymatic activity and critically contributes to tumorigenesis.
Han T, Zhan W, Gan M, Liu F, Yu B, Chin YE, Wang JB.
Cell Res 2018; 28 (6): 655-69.
PMID 29515166
The 3'-nontranslated region of rat renal glutaminase mRNA contains a pH-responsive stability element.
Hansen WR, Barsic-Tress N, Taylor L, Curthoys NP.
Am J Physiol 1996; 271(1 Pt 2): F126-31.
PMID 8760253
Glutamine and cancer: cell biology, physiology, and clinical opportunities.
Hensley CT, Wasti AT, DeBerardinis RJ.
J Clin Invest 2013; 123 (9): 3678-84.
PMID 23999442
Metabolic reprogramming induces resistance to anti-NOTCH1 therapies in T cell acute lymphoblastic leukemia.
Herranz D, Ambesi-Impiombato A, Sudderth J, Sánchez-Martèn M, Belver L, Tosello V, Xu L, Wendorff AA, Castillo M, Haydu JE, Márquez J, Matés JM, Kung AL, Rayport S, Cordon-Cardo C, DeBerardinis RJ, Ferrando AA.
Nat Med 2015; 21 (10): 1182-9.
PMID 26390244
Activation of p53 by costunolide blocks glutaminolysis and inhibits proliferation in human colorectal cancer cells.
Hu M, Liu L, Yao W.
Gene 2018; 678: 261-9.
PMID 30103008
Expression of glutaminase is upregulated in colorectal cancer and of clinical significance.
Huang F, Zhang Q, Ma H, Lv Q, Zhang T.
Int J Clin Exp Pathol;7 (3): 1093-100.
PMID 24696726
Altered glutamine metabolism in platinum resistant ovarian cancer.
Hudson CD, Savadelis A, Nagaraj AB, Joseph P, Avril S, DiFeo A, Avril N.
Oncotarget 2016; 7 (27): 41637-49.
PMID 27191653
Targeting glutaminolysis has antileukemic activity in acute myeloid leukemia and synergizes with BCL-2 inhibition.
Jacque N, Ronchetti AM, Larrue C, Meunier G, Birsen R, Willems L, Saland E, Decroocq J, Maciel TT, Lambert M, Poulain L, Hospital MA, Sujobert P, Joseph L, Chapuis N, Lacombe C, Moura IC, Demo S, Sarry JE, Recher C, Mayeux P, Tamburini J, Bouscary D.
Blood 2015; 126 (11): 1346-56.
PMID 26186940
Alterations in cellular metabolome after pharmacological inhibition of Notch in glioblastoma cells.
Kahlert UD, Cheng M, Koch K, Marchionni L, Fan X, Raabe EH, Maciaczyk J, Glunde K, Eberhart CG.
Int J Cancer 2016; 138 (5): 1246-55.
PMID 26422827
A tale of two glutaminases: homologous enzymes with distinct roles in tumorigenesis.
Katt WP, Lukey MJ, Cerione RA.
Future Med Chem 2017; 9 (2): 223-43.
PMID 28111979
Organ specific control of glutamine metabolism.
Katunuma N, Huzino A, Tomino I.
Adv Enzyme Regul 1967; 5: 55-69.
PMID 5603270
Expression of glutamine metabolism-related proteins according to molecular subtype of breast cancer.
Kim S, Kim DH, Jung WH, Koo JS.
Endocr Relat Cancer 2013;20 (3): 339-48.
PMID 23507704
Partial purification and properties of renal glutaminase.
Klingman JD, Handler P.
J Biol Chem 1958; 232 (1): 369-80.
PMID 13549426
Glutaminase activities in normal and neoplastic tissues of the rat.
Knox WE, Tremblay GC, Spanier BB, Friedell GH.
Cancer Res 1967; 27 (8): 1456-8.
PMID 6047874
MYC and prostate cancer.
Koh CM, Bieberich CJ, Dang CV, Nelson WG, Yegnasubramanian S, De Marzo AM.
Genes Cancer 2010; 1 (6): 617-28.
PMID 21779461
Mitochondrial metabolism of glutamine and glutamate and its physiological significance.
Kovacevic Z, McGivan JD.
Physiol Rev 1983; 63 (2): 547-605.
PMID 6132422
Metabolism of amino-acids: The synthesis of glutamine from glutamic acid and ammonia, and the enzymic hydrolysis of glutamine in animal tissues. The ankyrin repeat: a diversity of interactions on a common structural framework.
Krebs HA. Sedgwick SG, Smerdon SJ.
Biochem J 1935; 29 (8): 1951-69. Trends Biochem Sci 1999; 24 (8): 311-6.
PMID 10431175
Glutamine synthetase is a genetic determinant of cell type-specific glutamine independence in breast epithelia.
Kung HN, Marks JR, Chi JT.
PLoS Genet 2011;7 (8): e1002229.
PMID 21852960
Evidence for two species of mammalian phosphate-activated glutaminase having different regulatory properties.
Kvamme E, Olsen BE.
FEBS Lett 1979; 107 (1): 33-6.
PMID 499555
Evidence indicating that pig renal phosphate-activated glutaminase has a functionally predominant external localization in the inner mitochondrial membrane.
Kvamme E, Torgner IA, Roberg B.
J Biol Chem 1991; 266 (20): 13185-92.
PMID 2071598
Glutaminase from pig renal cortex: I. purification and general properties.
Kvamme E, Tveit B, Svenneby G.
J Biol Chem 1970; 245 (8): 1871-7.
PMID 4985904
Glutaminase is essential for the growth of triple-negative breast cancer cells with a deregulated glutamine metabolism pathway and its suppression synergizes with mTOR inhibition.
Lampa M, Arlt H, He T, Ospina B, Reeves J, Zhang B, Murtie J, Deng G, Barberis C, Hoffmann D, Cheng H, Pollard J, Winter C, Richon V, Garcia-Escheverria C, Adrian F, Wiederschain D, Srinivasan L.
PLoS One 2017; 12 (9): e0185092.
PMID 28950000
Dual targeting of glutaminase 1 and thymidylate synthase elicits death synergistically in NSCLC.
Lee JS, Kang JH, Lee SH, Hong D, Son J, Hong KM, Song J, Kim SY.
Cell Death Dis 2016b; 7 (12): e2511.
PMID 27929535
Dlx-2 and glutaminase upregulate epithelial-mesenchymal transition and glycolytic switch.
Lee SY, Jeon HM, Ju MK, Jeong EK, Kim CH, Park HG, Han SI, Kang HS.
Oncotarget 2016a; 7(7): 7925-39.
PMID 26771232
Inhibition of glutamine utilization sensitizes lung cancer cells to apigenin-induced apoptosis resulting from metabolic and oxidative stress.
Lee YM, Lee G, Oh TI, Kim BM, Shim DW, Lee KH, Kim YJ, Lim BO, Lim JH.
Int J Oncol 2016c; 48 (1): 399-408.
PMID 26573871
Targeting glutaminase 1 attenuates stemness properties in hepatocellular carcinoma by increasing reactive oxygen species and suppressing Wnt/beta-catenin pathway.
Li B, Cao Y, Meng G, Qian L, Xu T, Yan C, Luo O, Wang S, Wei J, Ding Y, Yu D.
EBioMedicine 2019; 39: 239-54.
PMID 30555042
Heat shock factor 1 epigenetically stimulates glutaminase-1-dependent mTOR activation to promote colorectal carcinogenesis.
Li J, Song P, Jiang T, Dai D, Wang H, Sun J, Zhu L, Xu W, Feng L, Shin VY, Morrison H, Wang X, Jin H.
Mol Ther 2018; 26 (7): 1828-39.
PMID 29730197
Brachyantheraoside A8, a new natural nor-oleanane triterpenoid as a kidney-type glutaminase inhibitor from Stauntonia brachyanthera.
Li R, Wei P, Wang Y, Liu Y, Liu X, Meng D.
RSC Adv 2017; 7: 52533-42. DOI 10.1039/C7RA11270J
Glutaminase activities and growth rates of rat hepatomas.
Linder-Horowitz M, Knox WE, Morris HP.
Cancer Res 1969; 29 (6): 1195-9.
PMID 4307782
MicroRNA-153 regulates glutamine metabolism in glioblastoma through targeting glutaminase.
Liu Z, Wang J, Li Y, Fan J, Chen L, Xu R.
Tumour Biol 2017; 39 (2): 1010428317691429.
PMID 28218035
Inhibition of glutaminase expression by antisense mRNA decreases growth and tumourigenicity of tumour cells.
Lobo C, Ruiz-Bellido MA, Aledo JC, Márquez J, Nez De Castro I, Alonso FJ.
Biochem J 2000; 348 (Pt 2): 257-61.
PMID 10816417
miR-137 inhibits glutamine catabolism and growth of malignant melanoma by targeting glutaminase
Luan W, Zhou Z, Zhu Y, Xia Y, Wang J, Xu B.
Biochem Biophys Res Commun 2018; 495 (1): 46-52.
PMID 29097210
The oncogenic transcription factor c-Jun regulates glutaminase expression and sensitizes cells to glutaminase-targeted therapy.
Lukey MJ, Greene KS, Erickson JW, Wilson KF, Cerione RA.
Nat Commun 2016; 7: 11321.
PMID 27089238
Márquez J, Matés JM, Campos-Sandoval JA.
Adv Neurobiol 2016; 13: 133-71.
PMID 27885629
Both GLS silencing and GLS2 overexpression synergize with oxidative stress against proliferation of glioma cells.
Martèn-Rufián M, Nascimento-Gomes R, Higuero A, Crisma AR, Campos-Sandoval JA, Gómez-Garcèa MC, Cardona C, Cheng T, Lobo C, Segura JA, Alonso FJ, Szeliga M, Albrecht J, Curi R, Márquez J, Colquhoun A, Deberardinis RJ, Matés JM.
J Mol Med 2014; 92 (3): 277-90.
PMID 24276018
Molecular targeting of glutaminase sensitizes ovarian cancer cells to chemotherapy.
Masamha CP, LaFontaine P.
J Cell Biochem 2018; 119 (7): 6136-45.
PMID 29633308
Mice lacking brain/kidney phosphate-activated glutaminase have impaired glutamatergic synaptic transmission, altered breathing, disorganized goal-directed behavior and die shortly after birth.
Masson J, Darmon M, Conjard A, Chuhma N, Ropert N, Thoby-Brisson M, Foutz AS, Parrot S, Miller GM, Jorisch R, Polan J, Hamon M, Hen R, Rayport S.
J Neurosci 2006; 26 (17): 4660-71.
PMID 16641247
Glutaminase isoenzymes in the metabolic therapy of cancer.
Matés JM, Campos-Sandoval JA, Márquez J.
Biochim Biophys Acta Rev Cancer 2018; 1870 (2): 158-64.
PMID 30053497
Inhibiting glutaminase in acute myeloid leukemia: metabolic dependency of selected AML subtypes.
Matre P, Velez J, Jacamo R, Qi Y, Su X, Cai T, Chan SM, Lodi A, Sweeney SR, Ma H, Davis RE, Baran N, Haferlach T, Su X, Flores ER, Gonzalez D, Konoplev S, Samudio I, DiNardo C, Majeti R, Schimmer AD, Li W, Wang T, Tiziani S, Konopleva M.
Oncotarget 2016; 7 (48): 79722-35.
PMID 27806325
Transaminase Inhibition by 2-Hydroxyglutarate Impairs Glutamate Biosynthesis and Redox Homeostasis in Glioma.
McBrayer SK, Mayers JR, DiNatale GJ, Shi DD, Khanal J, Chakraborty AA, Sarosiek KA, Briggs KJ, Robbins AK, Sewastianik T, Shareef SJ, Olenchock BA, Parker SJ, Tateishi K, Spinelli JB, Islam M, Haigis MC, Looper RE, Ligon KL, Bernstein BE, Carrasco RD, Cahill DP, Asara JM, Metallo CM, Yennawar NH, Vander Heiden MG, Kaelin WG Jr.
Cell 2018; 175 (1): 101-116. e25.
PMID 30220459
Effect of lysine to alanine mutations on the phosphate activation and BPTES inhibition of glutaminase.
McDonald CJ, Acheff E, Kennedy R, Taylor L, Curthoys NP.
Neurochem Int 2015; 88: 10-4.
PMID 25510640
Large oncosomes contain distinct protein cargo and represent a separate functional class of tumor-derived extracellular vesicles.
Minciacchi VR, You S, Spinelli C, Morley S, Zandian M, Aspuria PJ, Cavallini L, Ciardiello C, Reis Sobreiro M, Morello M, Kharmate G, Jang SC, Kim DK, Hosseini-Beheshti E, Tomlinson Guns E, Gleave M, Gho YS, Mathivanan S, Yang W, Freeman MR, Di Vizio D.
Oncotarget 2015; 6 (13): 11327-41.
PMID 25857301
The GSK3 signaling axis regulates adaptive glutamine metabolism in lung squamous cell carcinoma.
Momcilovic M, Bailey ST, Lee JT, Fishbein MC, Braas D, Go J, Graeber TG, Parlati F, Demo S, Li R, Walser TC, Gricowski M, Shuman R, Ibarra J, Fridman D, Phelps ME, Badran K, St John M, Bernthal NM, Federman N, Yanagawa J, Dubinett SM, Sadeghi S, Christofk HR, Shackelford DB.
Cancer Cell 2018; 33 (5): 905-21. e5.
PMID 29763624
Properties of rat renal phosphate-dependent glutaminase coupled to Sepharose. Evidence that dimerization is essential for activation.
Morehouse RF, Curthoys NP.
Biochem J 1981; 193 (3): 709-16.
PMID 7305957
The ankyrin repeat as molecular architecture for protein recognition.
Mosavi LK, Cammett TJ, Desrosiers DC, Peng ZY.
Protein Sci 2004; 13 (6): 1435-48.
PMID 15152081
Prediction of the coding sequences of unidentified human genes. XII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro.
Nagase T, Ishikawa K, Suyama M, Kikuno R, Hirosawa M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O.
DNA Res 1998; 5 (6): 355-64.
PMID 10048485
Interactions between neurons and glia in glutamate/glutamine compartmentation.
Nicklas WJ, Zeevalk G, Hyndman A.
Biochem Soc Trans 1987; 15 (2): 208-10.
PMID 2884147
Activation of kidney mitochondrial glutaminase by inorganic phosphate and organic acids.
O'Donovan DJ, Lotspeich WD.
Nature 1966; 212 (5065): 930-2.
PMID 6005667
Nuclear localization of L-type glutaminase in mammalian brain.
Olalla L, Gutiérrez A, Campos JA, Khan ZU, Alonso FJ, Segura JA, Márquez J, Aledo JC.
J Biol Chem 2002; 277 (41): 38939-44.
PMID 12163477
Formation and ultrastructure of enzymically active polymers of pig renal glutaminase.
Olsen BR, Svenneby G, Kvamme E, Tveit B, Eskeland T.
J Mol Biol 1970; 52 (2): 239-45.
PMID 5530398
Co-expression of glutaminase K and L i soenzymes in human tumour cells.
Pérez-Gómez C, Campos-Sandoval JA, Alonso FJ, Segura JA, Manzanares E, Ruiz-Sánchez P, González ME, Márquez J, Matés JM.
Biochem J 2005; 386 (Pt 3): 535-42.
PMID 15496140
Elevated expression of glutaminase confers glucose utilization via glutaminolysis in prostate cancer.
Pan T, Gao L, Wu G, Shen G, Xie S, Wen H, Yang J, Zhou Y, Tu Z, Qian W.
Biochem Biophys Res Commun 2015; 456 (1): 452-8.
PMID 25482439
The origin and evolution of human glutaminases and their atypical C-terminal ankyrin repeats.
Pasquali CC, Islam Z, Adamoski D, Ferreira IM, Righeto RD, Bettini J, Portugal RV, Yue WW, Gonzalez A, Dias SMG, Ambrosio ALB.
J Biol Chem 2017; 292 (27): 11572-85.
PMID 28526749
Biosynthesis and processing of renal mitochondrial glutaminase in cultured proximal tubular epithelial cells and in isolated mitochondria.
Perera SY, Chen TC, Curthoys NP.
J Biol Chem 1990; 265 (29): 17764-70.
PMID 2211660
Phosphate-dependent glutaminase of small intestine: localization and role in intestinal glutamine metabolism.
Pinkus LM, Windmueller HG.
Arch Biochem Biophys 1977; 182 (2): 506-17.
PMID 900947
SIRT5 regulation of ammonia-induced autophagy and mitophagy.
Polletta L, Vernucci E, Carnevale I, Arcangeli T, Rotili D, Palmerio S, Steegborn C, Nowak T, Schutkowski M, Pellegrini L, Sansone L, Villanova L, Runci A, Pucci B, Morgante E, Fini M, Mai A, Russo MA, Tafani M.
Autophagy 2015; 11 (2): 253-70.
PMID 25700560
Complexity and species variation of the kidney-type glutaminase gene.
Porter DL, Ibrahim H, Taylor L, Curthoys NP.
Physiol Genomics 2002; 9 (3): 157-66.
PMID 12045296
ErbB2 activation upregulates glutaminase 1 expression which promotes breast cancer cell proliferation.
Qie S, Chu C, Li W, Wang C, Sang N.
J Cell Biochem 2014; 115 (3): 498-509.
PMID 24122876
The NF-kB member p65 controls glutamine metabolism through miR-23a.
Rathore MG, Saumet A, Rossi JF, de Bettignies C, Tempé D, Lecellier CH, Villalba M.
Int J Biochem Cell Biol 2012; 44 (9): 1448-56.
PMID 22634383
Allele-Specific Reprogramming of Cancer Metabolism by the Long Non-coding RNA CCAT2.
Redis RS, Vela LE, Lu W, Ferreira de Oliveira J, Ivan C, Rodriguez-Aguayo C, Adamoski D, Pasculli B, Taguchi A, Chen Y, Fernandez AF, Valledor L, Van Roosbroeck K, Chang S, Shah M, Kinnebrew G, Han L, Atlasi Y, Cheung LH, Huang GY, Monroig P, Ramirez MS, Catela Ivkovic T, Van L, Ling H, Gafà R, Kapitanovic S, Lanza G, Bankson JA, Huang P, Lai SY, Bast RC, Rosenblum MG, Radovich M, Ivan M, Bartholomeusz G, Liang H, Fraga MF, Widger WR, Hanash S, Berindan-Neagoe I, Lopez-Berestein G, Ambrosio ALB, Gomes Dias SM, Calin GA.
Mol Cell 2016; 61 (4): 520-34.
PMID 26853146
Control of glutamine metabolism by the tumor suppressor Rb.
Reynolds MR, Lane AN, Robertson B, Kemp S, Liu Y, Hill BG, Dean DC, Clem BF.
Oncogene 2014; 33 (5): 556-66.
PMID 23353822
The orientation of phosphate activated glutaminase in the inner mitochondrial membrane of synaptic and non-synaptic rat brain mitochondria.
Roberg B, Torgner IA, Kvamme E.
Neurochem Int 1995; 27 (4-5): 367-76.
PMID 8845737
Novel mechanism of inhibition of rat kidney-type glutaminase by bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES).
Robinson MM, McBryant SJ, Tsukamoto T, Rojas C, Ferraris DV, Hamilton SK, Hansen JC, Curthoys NP.
Biochem J 2007; 406 (3): 407-14.
PMID 17581113
Ehrlich ascites tumor cells expressing anti-sense glutaminase mRNA lose their capacity to evade the mouse immune system.
Segura JA, Ruiz-Bellido MA, Arenas M, Lobo C, Márquez J, Alonso FJ.
Int J Cancer 2001; 91 (3): 379-84.
PMID 11169963
The ankyrin repeat: a diversity of interactions on a common structural framework.
Sedgwick SG, Smerdon SJ.
Trends Biochem Sci 1999; 24 (8): 311-6.
PMID 10431175
Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1.
Seltzer MJ, Bennett BD, Joshi AD, Gao P, Thomas AG, Ferraris DV, Tsukamoto T, Rojas CJ, Slusher BS, Rabinowitz JD, Dang CV, Riggins GJ.
Cancer Res 2010; 70 (22): 8981-7.
PMID 21045145
The orientation of phosphate-dependent glutaminase on the inner membrane of rat renal mitochondria.
Shapiro RA, Haser WG, Curthoys NP.
Arch Biochem Biophys 1985; 243 (1): 1-7.
PMID 2998280
Molecular cloning of a cDNA for rat hepatic glutaminase. Sequence similarity to kidney-type glutaminase.
Smith EM, Watford M.
J Biol Chem 1990; 265 (18): 10631-6.
PMID 2191954
Recent Development of Small Molecule Glutaminase Inhibitors.
Song M, Kim SH, Im CY, Hwang HJ.
Curr Top Med Chem 2018; 18 (6): 432-43.
PMID 29793408
Role of the Transforming Growth Factor-? in regulating hepatocellular carcinoma oxidative metabolism.
Soukupova J, Malfettone A, Hyroová P, Hernández-Alvarez MI, Peñuelas-Haro I, Bertran E, Junza A, Capellades J, Giannelli G, Yanes O, Zorzano A, Perales JC, Fabregat I.
Sci Rep 2017; 7 (1): 12486.
PMID 28970582
In vitro characterization of the mitochondrial processing and the potential function of the 68-kDa subunit of renal glutaminase.
Srinivasan M, Kalousek F, Curthoys NP.
J Biol Chem 1995; 270 (3): 1185-90.
PMID 7836378
Mechanism by which a recently discovered allosteric inhibitor blocks glutamine metabolism in transformed cells.
Stalnecker CA, Ulrich SM, Li Y, Ramachandran S, McBrayer MK, DeBerardinis RJ, Cerione RA, Erickson JW.
Proc Natl Acad Sci USA 2015; 112 (2): 394-9.
PMID 25548170
Relative expression of mRNAS coding for glutaminase isoforms in CNS tissues and CNS tumors.
Szeliga M, Matyja E, Obara M, Grajkowska W, Czernicki T, Albrecht J.
Neurochem Res 2008; 33 (5): 808-13.
PMID 17940881
Compensatory glutamine metabolism promotes glioblastoma resistance to mTOR inhibitor treatment.
Tanaka K, Sasayama T, Irino Y, Takata K, Nagashima H, Satoh N, Kyotani K, Mizowaki T, Imahori T, Ejima Y, Masui K, Gini B, Yang H, Hosoda K, Sasaki R, Mischel PS, Kohmura E.
J Clin Invest 2015;125 (4): 1591-602.
PMID 25798620
Identification of zeta-crystallin/NADPH:quinone reductase as a renal glutaminase mRNA pH response element-binding protein.
Tang A, Curthoys NP.
J Biol Chem 2001; 276 (24): 21375-80.
PMID 11294877
Structural basis for the allosteric inhibitory mechanism of human kidney-type glutaminase (KGA) and its regulation by Raf-Mek-Erk signaling in cancer cell metabolism.
Thangavelu K, Pan CQ, Karlberg T, Balaji G, Uttamchandani M, Suresh V, Schüler H, Low BC, Sivaraman J.
Proc Natl Acad Sci USA 2012; 109 (20): 7705-10.
PMID 22538822
Mesenchymal phenotype predisposes lung cancer cells to impaired proliferation and redox stress in response to glutaminase inhibition.
Ulanet DB, Couto K, Jha A, Choe S, Wang A, Woo HK, Steadman M, DeLaBarre B, Gross S, Driggers E, Dorsch M, Hurov JB.
PLoS One 2014; 9 (12): e115144.
PMID 25502225
The glutaminase-1 inhibitor 968 enhances dihydroartemisinin-mediated antitumor efficacy in hepatocellular carcinoma cells.
Wang D, Meng G, Zheng M, Zhang Y, Chen A, Wu J, Wei J.
PLoS One 2016; 11 (11): e0166423.
PMID 27835669
Targeting mitochondrial glutaminase activity inhibits oncogenic transformation.
Wang JB, Erickson JW, Fuji R, Ramachandran S, Gao P, Dinavahi R, Wilson KF, Ambrosio AL, Dias SM, Dang CV, Cerione RA.
Cancer Cell 2010; 18 (3): 207-19.
PMID 20832749
Glutaminase 1 is essential for the differentiation, proliferation, and survival of human neural progenitor cells.
Wang Y, Huang Y, Zhao L, Li Y, Zheng J.
Stem Cells Dev 2014; 23 (22): 2782-90.
PMID 24923593
Activators and inhibitors of brain glutaminase.
Weil-Malherbe H.
J Neurochem 1969; 16 (3): 855-64.
PMID 5822627
Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction.
Wise DR, DeBerardinis RJ, Mancuso A, Sayed N, Zhang XY, Pfeiffer HK, Nissim I, Daikhin E, Yudkoff M, McMahon SB, Thompson CB.
Proc Natl Acad Sci USA 2008; 105 (48): 18782-7.
PMID 19033189
Glutaminase inhibitors: a patent review.
Wu C, Chen L, Jin S, Li H.
Expert Opin Ther Pat 2018; 28 (11): 823-35.
PMID 30273516
A natural inhibitor of kidney-type glutaminase: a withanolide from Physalis pubescens with potent anti-tumor activity.
Wu C, Zheng M, Gao S, Luan S, Cheng L, Wang L, Li J, Chen L, Li H.
Oncotarget 2017; 8 (69): 113516-30.
PMID 29371926
Inhibition of mitochondrial glutaminase activity reverses acquired erlotinib resistance in non-small cell lung cancer.
Xie C, Jin J, Bao X, Zhan WH, Han TY, Gan M, Zhang C, Wang J.
Oncotarget 2016; 7 (1): 610-21.
PMID 26575584
Tumor suppressor NDRG2 inhibits glycolysis and glutaminolysis in colorectal cancer cells by repressing c-Myc expression.
Xu X, Li J, Sun X, Guo Y, Chu D, Wei L, Li X, Yang G, Liu X, Yao L, Zhang J, Shen L.
Oncotarget 2015; 6 (28): 26161-76.
PMID 26317652
Overview of the development of glutaminase inhibitors: achievements and future directions.
Xu X, Meng Y, Li L, Xu P, Wang J, Li Z Bian J.
J Med Chem 2018; [Epub ahead of print].
PMID 30148361
The ephrin-A1/EPHA2 signaling axis regulates glutamine metabolism in HER2-positive breast cancer.
Youngblood VM, Kim LC, Edwards DN, Hwang Y, Santapuram PR, Stirdivant SM, Lu P, Ye F, Brantley-Sieders DM, Chen J.
Cancer Res 2016; 76 (7): 1825-36.
PMID 26833123
Kidney-type glutaminase (GLS1) is a biomarker for pathologic diagnosis and prognosis of hepatocellular carcinoma.
Yu D, Shi X, Meng G, Chen J, Yan C, Jiang Y, Wei J, Ding Y.
Oncotarget 2015; 6 (10): 7619-31.
PMID 25844758
Glutaminase inhibitor compound 968 inhibits cell proliferation and sensitizes paclitaxel in ovarian cancer.
Yuan L, Sheng X, Clark LH, Zhang L, Guo H, Jones HM, Willson AK, Gehrig PA, Zhou C, Bae-Jump VL.
Am J Transl Res 2016; 8 (10): 4265-77.
PMID 27830010
Selenite inhibits glutamine metabolism and induces apoptosis by regulating GLS1 protein degradation via APC/C-CDH1 pathway in colorectal cancer cells.
Zhao J, Zhou R, Hui K, Yang Y, Zhang Q, Ci Y, Shi L, Xu C, Huang F, Hu Y.
Oncotarget 2017; 8 (12): 18832-47.
PMID 27902968
Interferon-? regulates glutaminase 1 promoter through STAT1 phosphorylation: relevance to HIV-1 associated neurocognitive disorders.
Zhao L, Huang Y, Tian C, Taylor L, Curthoys N, Wang Y, Vernon H, Zheng J.
PLoS One 2012; 7 (3): e32995.
PMID 22479354
Glutaminase affects the transcriptional activity of peroxisome proliferator-activated receptor ? (PPAR?) via direct interaction.
de Guzzi Cassago CA, Dias MM, Pinheiro MP, Pasquali CC, Bastos ACS, Islam Z, Consonni SR, de Oliveira JF, Gomes EM, Asceno CFR, Honorato R, Pauletti BA, Indolfo NC, Filho HVR, de Oliveira PSL, Figueira ACM, Paes Leme AF, Ambrosio ALB, Dias SMG.
Biochemistry 2018; 57 (44): 6293-307.
PMID 30295466
Analysis of glutamine dependency in non-small cell lung cancer: GLS1 splice variant GAC is essential for cancer cell growth.
van den Heuvel AP, Jing J, Wooster RF, Bachman KE.
Cancer Biol Ther 2012; 13 (12): 1185-94.
PMID 22892846


This paper should be referenced as such :
José A Campos-Sandoval, Mercedes Martin-Rufián, Javier Márquez
GLS (Glutaminase)
Atlas Genet Cytogenet Oncol Haematol. 2019;23(9):256-268.
Free journal version : [ pdf ]   [ DOI ]

External links


HGNC (Hugo)GLS   4331
Entrez_Gene (NCBI)GLS    glutaminase
AliasesAAD20; CASGID; DEE71; EIEE71; 
GeneCards (Weizmann)GLS
Ensembl hg19 (Hinxton)ENSG00000115419 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000115419 [Gene_View]  ENSG00000115419 [Sequence]  chr2:190880821-190965544 [Contig_View]  GLS [Vega]
ICGC DataPortalENSG00000115419
TCGA cBioPortalGLS
Genatlas (Paris)GLS
SOURCE (Princeton)GLS
Genetics Home Reference (NIH)GLS
Genomic and cartography
GoldenPath hg38 (UCSC)GLS  -     chr2:190880821-190965544 +  2q32.2   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)GLS  -     2q32.2   [Description]    (hg19-Feb_2009)
GoldenPathGLS - 2q32.2 [CytoView hg19]  GLS - 2q32.2 [CytoView hg38]
Genome Data Viewer NCBIGLS [Mapview hg19]  
OMIM138280   618328   618339   618412   
Gene and transcription
Genbank (Entrez)AB020645 AF097492 AF097493 AF097494 AF097495
RefSeq transcript (Entrez)NM_001256310 NM_014905
Consensus coding sequences : CCDS (NCBI)GLS
Gene ExpressionGLS [ NCBI-GEO ]   GLS [ EBI - ARRAY_EXPRESS ]   GLS [ SEEK ]   GLS [ MEM ]
Gene Expression Viewer (FireBrowse)GLS [ Firebrowse - Broad ]
GenevisibleExpression of GLS in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)2744
GTEX Portal (Tissue expression)GLS
Human Protein AtlasENSG00000115419-GLS [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtO94925   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtO94925  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProO94925
Domaine pattern : Prosite (Expaxy)ANK_REP_REGION (PS50297)    ANK_REPEAT (PS50088)   
Domains : Interpro (EBI)Ankyrin_rpt    Ankyrin_rpt-contain_dom    Ankyrin_rpt-contain_sf    Beta-lactam/transpept-like    Glutaminase    Glutaminase_EF-hand   
Domain families : Pfam (Sanger)Ank_2 (PF12796)    EF-hand_14 (PF17959)    Glutaminase (PF04960)   
Domain families : Pfam (NCBI)pfam12796    pfam17959    pfam04960   
Domain families : Smart (EMBL)ANK (SM00248)  
Conserved Domain (NCBI)GLS
PDB (RSDB)3CZD    3UNW    3UO9    3VOY    3VOZ    3VP0    3VP1    3VP2    3VP3    3VP4    4O7D    5D3O    5FI2    5FI6    5FI7    5HL1    5I94    5JYO    5JYP    5U0I    5U0J    5UQE    5WJ6    6UJG    6UJM    6UK6    6UKB    6UL9    6ULA    6ULJ    6UMC    6UMD    6UME    6UMF   
PDB Europe3CZD    3UNW    3UO9    3VOY    3VOZ    3VP0    3VP1    3VP2    3VP3    3VP4    4O7D    5D3O    5FI2    5FI6    5FI7    5HL1    5I94    5JYO    5JYP    5U0I    5U0J    5UQE    5WJ6    6UJG    6UJM    6UK6    6UKB    6UL9    6ULA    6ULJ    6UMC    6UMD    6UME    6UMF   
PDB (PDBSum)3CZD    3UNW    3UO9    3VOY    3VOZ    3VP0    3VP1    3VP2    3VP3    3VP4    4O7D    5D3O    5FI2    5FI6    5FI7    5HL1    5I94    5JYO    5JYP    5U0I    5U0J    5UQE    5WJ6    6UJG    6UJM    6UK6    6UKB    6UL9    6ULA    6ULJ    6UMC    6UMD    6UME    6UMF   
PDB (IMB)3CZD    3UNW    3UO9    3VOY    3VOZ    3VP0    3VP1    3VP2    3VP3    3VP4    4O7D    5D3O    5FI2    5FI6    5FI7    5HL1    5I94    5JYO    5JYP    5U0I    5U0J    5UQE    5WJ6    6UJG    6UJM    6UK6    6UKB    6UL9    6ULA    6ULJ    6UMC    6UMD    6UME    6UMF   
Structural Biology KnowledgeBase3CZD    3UNW    3UO9    3VOY    3VOZ    3VP0    3VP1    3VP2    3VP3    3VP4    4O7D    5D3O    5FI2    5FI6    5FI7    5HL1    5I94    5JYO    5JYP    5U0I    5U0J    5UQE    5WJ6    6UJG    6UJM    6UK6    6UKB    6UL9    6ULA    6ULJ    6UMC    6UMD    6UME    6UMF   
SCOP (Structural Classification of Proteins)3CZD    3UNW    3UO9    3VOY    3VOZ    3VP0    3VP1    3VP2    3VP3    3VP4    4O7D    5D3O    5FI2    5FI6    5FI7    5HL1    5I94    5JYO    5JYP    5U0I    5U0J    5UQE    5WJ6    6UJG    6UJM    6UK6    6UKB    6UL9    6ULA    6ULJ    6UMC    6UMD    6UME    6UMF   
CATH (Classification of proteins structures)3CZD    3UNW    3UO9    3VOY    3VOZ    3VP0    3VP1    3VP2    3VP3    3VP4    4O7D    5D3O    5FI2    5FI6    5FI7    5HL1    5I94    5JYO    5JYP    5U0I    5U0J    5UQE    5WJ6    6UJG    6UJM    6UK6    6UKB    6UL9    6ULA    6ULJ    6UMC    6UMD    6UME    6UMF   
AlphaFold pdb e-kbO94925   
Human Protein Atlas [tissue]ENSG00000115419-GLS [tissue]
Protein Interaction databases
IntAct (EBI)O94925
Ontologies - Pathways
Ontology : AmiGOsuckling behavior  regulation of respiratory gaseous exchange by nervous system process  glutaminase activity  glutaminase activity  glutaminase activity  protein binding  mitochondrion  mitochondrion  mitochondrial matrix  cytosol  glutamate biosynthetic process  glutamate biosynthetic process  glutamate biosynthetic process  glutamine catabolic process  glutamine catabolic process  glutamine catabolic process  neurotransmitter transport  chemical synaptic transmission  glutamine family amino acid metabolic process  synapse  protein homotetramerization  glutamate homeostasis  
Ontology : EGO-EBIsuckling behavior  regulation of respiratory gaseous exchange by nervous system process  glutaminase activity  glutaminase activity  glutaminase activity  protein binding  mitochondrion  mitochondrion  mitochondrial matrix  cytosol  glutamate biosynthetic process  glutamate biosynthetic process  glutamate biosynthetic process  glutamine catabolic process  glutamine catabolic process  glutamine catabolic process  neurotransmitter transport  chemical synaptic transmission  glutamine family amino acid metabolic process  synapse  protein homotetramerization  glutamate homeostasis  
Pathways : KEGGAlanine, aspartate and glutamate metabolism    Arginine and proline metabolism    D-Glutamine and D-glutamate metabolism    Glutamatergic synapse    GABAergic synapse    Proximal tubule bicarbonate reclamation    MicroRNAs in cancer   
REACTOMEO94925 [protein]
REACTOME PathwaysR-HSA-70614 [pathway]   
NDEx NetworkGLS
Atlas of Cancer Signalling NetworkGLS
Wikipedia pathwaysGLS
Orthology - Evolution
GeneTree (enSembl)ENSG00000115419
Phylogenetic Trees/Animal Genes : TreeFamGLS
Homologs : HomoloGeneGLS
Homology/Alignments : Family Browser (UCSC)GLS
Gene fusions - Rearrangements
Fusion : MitelmanMYO1B::GLS [2q32.3/2q32.2]  
Fusion : FusionGDB3.5.1.2   
Fusion : QuiverGLS
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerGLS [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)GLS
Exome Variant ServerGLS
GNOMAD BrowserENSG00000115419
Varsome BrowserGLS
ACMGGLS variants
Genomic Variants (DGV)GLS [DGVbeta]
DECIPHERGLS [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisGLS 
ICGC Data PortalGLS 
TCGA Data PortalGLS 
Broad Tumor PortalGLS
OASIS PortalGLS [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICGLS  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DGLS
Mutations and Diseases : HGMDGLS
LOVD (Leiden Open Variation Database)[gene] [transcripts] [variants]
DgiDB (Drug Gene Interaction Database)GLS
DoCM (Curated mutations)GLS
CIViC (Clinical Interpretations of Variants in Cancer)GLS
NCG (London)GLS
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
OMIM138280    618328    618339    618412   
Genetic Testing Registry GLS
NextProtO94925 [Medical]
Target ValidationGLS
Huge Navigator GLS [HugePedia]
Clinical trials, drugs, therapy
Protein Interactions : CTDGLS
Pharm GKB GenePA28734
Clinical trialGLS
DataMed IndexGLS
PubMed142 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

Search in all EBI   NCBI

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Fri Oct 8 21:18:55 CEST 2021

Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

For comments and suggestions or contributions, please contact us