leky-latky/glutaminaza/zvysena-aktivita

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 [1]

Onset of metabolic acidosis (metabolická acidóza)

• Results in the increased binding activity of a RNA-binding protein CRYZ (identified as ?-crystallin/NADPH quinone reductase)
• With high affinity for the pH-responsive elements
• Selectively stabilizes GLS mRNA (Hansen et al., 1996; Tang and Curthoys, 2001) [1]

Fosfor, arsen, sulfáty

• Accelerated deamidation of glutamine in aqueous rat-liver extracts in the presence of
• Phosphate,
• Arsenate
• Sulfate
• Could be due to an augmentation of the activity of glutaminase enzyme
• Errera and Greenstein (1949) characterized it as phosphate-activated glutaminase
• Phosphate induced the association of catalytically inactive dimers into active tetramers

Potraviny bohaté na fosfor

• Kypřící prášky do pečiva
• Mléko
• Syrovátka
• Tavící soli některých tavených sýrů

Potraviny kontaminované arsenem

• Rýže
• ?

MicroRNAs (miRNAs) downregulation

• Downregulation of MIR23A / MIR23B target GLS mRNA
• Oncogenic transcription factor MYC (myelocytomatosis viral oncogene homolog) indirectly relieves repression of GLS
• In lymphoma and prostate cancer cells (Gao et al., 2009) [1]

PRUNE2 (prune homolog 2 with BCH domain, also known as BMCC1s)

• Directly interact with KGA
• 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)
• GLS has been reported to interact with peroxisome proliferator-activated receptor gamma ( PPARG) in the nuclei of prostate cancer cells
• Interaction decreased the nuclear receptor activity (de Guzzi Cassago et al., 2018) [1]

Retinoblastoma protein ( RB1)

• Tumor suppressor
• Modulates cell cycle checkpoints
• Regulates glutamine metabolism
• Deletion of RB family
• Revealed an increase in GLS protein and activity (Reynolds et al., 2014) [1]

Phosphate

• 100 mM
• Tetramerization of glutaminase is produced
• Enzyme reaches its maximum activity
• Activation by phosphate is sigmoidal
• K0.5 of 25 mM
• Hill index of 1.5
• Phosphate concentration is increased
• Inhibition by glutamate is competitive with respect to glutamine- and the KM for glutamine decrease (Haser et al., 1985)
• Activity of the purified enzyme
• Completely dependent on added phosphate
• Phosphate as a relevant in vivo effector
• Each GAC monomer encloses a single phosphate ion inside its active site
• After binding of phosphate
• 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).

HIV-1 infected cells

• Upragulation of GLS by interferon (IFN)-alpha
• Through signal transducer and activator of transcription 1 ( STAT1) phosphorylation
• Leading to glutamate overproduction (Zhao et al., 2012) [1]

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)
• Being activated by
• Transforming growth factor (TGF)-beta
• Wnt (Wingless-type MMTV integration site family)-3a
• Homeodomain transcription factor DLX2 (distal-less homeobox-2) involved in embryonic and tumor development
• Also upregulates GLS expression (Lee SY et al., 2016a) [1]

Long non-coding RNA (lncRNA) colon cancer-associated transcript 2 ( CCAT2)

• Reported in colon cancer
• LncRNA interacts with the cleavage factor I (CFIm) complex
• In an allele-specific manner
• Select the poly(A) site within 14th intron of GLS pre-mRNA [1]
• Resulting in the preferential splicing of GAC isoform (Redis et al., 2016)

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
• Inhibition of mTORC1 with rapamycin
• Increase in miR-23a/b levels was observed (Csibi et al., 2014) [1]

Could act as activators (or inhibitors) of glutaminase

Tricarboxylic acids

Nucleotide triphosphates

Acyl-CoA derivatives

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
• Decreases miR-23a expression in leukemic cells
• Inducing GLS expression (Rathore et al., 2012) [1]