Variations in the Promoter Region of the Glutaminase Gene and the Development of Hepatic Encephalopathy in Patients With Cirrhosis

Romero–Gómez, Manuel; Jover, M.; Campo, J.A. Del; Royo, José Luis; Hoyas, E.; Galán, José Jorge; Montoliú, Carmina; Baccaro, E.; Guevara, Mónica; Córdoba, Juan; Soriano, Germán; Navarro, José María; Martínez‐Sierra, Carmen; Grande, Lourdes; Galindo, Antonio; Mira, Emilia; Mañes, Santos; Ruiz, Agustı́n

doi:10.7326/0003-4819-153-5-201009070-00002

Cited by 75 publications

(45 citation statements)

References 32 publications

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“…Understanding how KGA itself is activated by the Raf-Mek signaling will also provide an alternative approach to further examine whether deregulation of KGA and its hyperactivation can be linked to this pathway. This could be the basis for abnormal cell growth in cancers and possibly other metabolic and neuronal disorders involving glutamate or ammonia as a main metabolite, such as hyperinsulinism/ hyperammonemia/hepatic encephalopathy and neurotransmission (25,26). In this regard, we show that KGA forms a complex with Raf-1, Mek2, and Erk1/2, as well as the protein phosphatase PP2A, which can be anchored on a common scaffold protein or present as different subcomplexes.…”

Section: Discussionmentioning

confidence: 75%

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

Thangavelu¹,

Pan

Karlberg

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

185

227

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Besides thriving on altered glucose metabolism, cancer cells undergo glutaminolysis to meet their energy demands. As the first enzyme in catalyzing glutaminolysis, human kidney-type glutaminase isoform (KGA) is becoming an attractive target for small molecules such as BPTES [bis-2-(5 phenylacetamido-1, 2, 4-thiadiazol-2-yl) ethyl sulfide], although the regulatory mechanism of KGA remains unknown. On the basis of crystal structures, we reveal that BPTES binds to an allosteric pocket at the dimer interface of KGA, triggering a dramatic conformational change of the key loop (Glu312-Pro329) near the catalytic site and rendering it inactive. The binding mode of BPTES on the hydrophobic pocket explains its specificity to KGA. Interestingly, KGA activity in cells is stimulated by EGF, and KGA associates with all three kinase components of the Raf-1/Mek2/Erk signaling module. However, the enhanced activity is abrogated by kinase-dead, dominant negative mutants of Raf-1 (Raf-1-K375M) and Mek2 (Mek2-K101A), protein phosphatase PP2A, and Mek-inhibitor U0126, indicative of phosphorylation-dependent regulation. Furthermore, treating cells that coexpressed Mek2-K101A and KGA with suboptimal level of BPTES leads to synergistic inhibition on cell proliferation. Consequently, mutating the crucial hydrophobic residues at this key loop abrogates KGA activity and cell proliferation, despite the binding of constitutive active Mek2-S222/226D. These studies therefore offer insights into (i) allosteric inhibition of KGA by BPTES, revealing the dynamic nature of KGA's active and inhibitory sites, and (ii) cross-talk and regulation of KGA activities by EGF-mediated Raf-Mek-Erk signaling. These findings will help in the design of better inhibitors and strategies for the treatment of cancers addicted with glutamine metabolism.Warburg effect | RAS/MAPK | crystallography T he Warburg effect in cancer biology describes the tendency of cancer cells to take up more glucose than most normal cells, despite the availability of oxygen (1, 2). In addition to altered glucose metabolism, glutaminolysis (catabolism of glutamine to ATP and lactate) is another hallmark of cancer cells (2, 3). In glutaminolysis, mitochondrial glutaminase catalyzes the conversion of glutamine to glutamate (4), which is further catabolized in the Krebs cycle for the production of ATP, nucleotides, certain amino acids, lipids, and glutathione (2, 5).Humans express two glutaminase isoforms: KGA (kidney-type) and LGA (liver-type) from two closely related genes (6). Although KGA is important for promoting growth, nothing is known about the precise mechanism of its activation or inhibition and how its functions are regulated under physiological or pathophysiological conditions. Inhibition of rat KGA activity by antisense mRNA results in decreased growth and tumorigenicity of Ehrlich ascites tumor cells (7), reduced level of glutathione, and induced apoptosis (8), whereas Myc, an oncogenic transcription factor, stimulates KGA expression and glutamine metabolism (5). Interestingly...

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Section: Discussionmentioning

confidence: 75%

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

Thangavelu¹,

Pan

Karlberg

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

185

227

View full text Add to dashboard Cite

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“…Thus, polymorphisms in the gene coding for glutaminase predicts the development of HE in cirrhotic patients [4]. In the systemic circulation, NH4+ is increased due to reduced urea cycle enzyme activity that occurs in liver failure and/or portosystemic shunting.…”

mentioning

confidence: 99%

Understanding hepatic encephalopathy

2017

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“…Therefore, refined genome analyses are necessary to clarify the link between a typical array of genes with altered expression and the risk and severity of HE and further enable the design of polygenic disease predisposition tests. Romero-Gomez et al 2010). In the current study, patients with cirrhosis were divided in two groups based on the presence of TACC haplotype of the glutaminase gene.…”

Section: Javier Ampuero: Application Of Genomics In Hepatic Encephalomentioning

confidence: 99%

New technologies – new insights into the pathogenesis of hepatic encephalopathy

et al. 2016

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Variations in the Promoter Region of the Glutaminase Gene and the Development of Hepatic Encephalopathy in Patients With Cirrhosis

Abstract: Instituto de Salud Carlos III, Spanish Ministry of Health.

Cited by 75 publications

References 32 publications

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

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

Understanding hepatic encephalopathy

New technologies – new insights into the pathogenesis of hepatic encephalopathy

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