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Literature summary extracted from

  • Crispim, M.; Damasceno, F.S.; Hernandez, A.; Barison, M.J.; Pretto Sauter, I.; Souza Pavani, R.; Santos Moura, A.; Pral, E.M.F.; Cortez, M.; Elias , M.C.; Silber, A.M.
    The glutamine synthetase of Trypanosoma cruzi is required for its resistance to ammonium accumulation and evasion of the parasitophorous vacuole during host-cell infection (2018), PLOS Negl. Trop. Dis., 10, e0006170 .
    View publication on PubMedView publication on EuropePMC

Application

EC Number Application Comment Organism
6.3.1.2 pharmacology since glutamine synthetase is the first metabolic enzyme involved in Trypanosoma cruzi evasion from the parasitophorous vacuole it is a potential target for designing anti-Trypanosoma cruzi drugs Trypanosoma cruzi

Cloned(Commentary)

EC Number Cloned (Comment) Organism
6.3.1.2 expression in Escherichia coli Trypanosoma cruzi

Inhibitors

EC Number Inhibitors Comment Organism Structure
6.3.1.2 Ca2+ inhibitory effect on Mg2+-driven activity Trypanosoma cruzi
6.3.1.2 EDTA
-
 Trypanosoma cruzi
6.3.1.2 methionine sulfoximine competitive inhibitor with respect to L-glutamate Trypanosoma cruzi

KM Value [mM]

EC Number KM Value [mM] KM Value Maximum [mM] Substrate Comment Organism Structure
6.3.1.2 0.38
-
 ATP recombinant enzyme, coupled reactions assay, pH and temperature not specified in the publication Trypanosoma cruzi
6.3.1.2 0.39
-
 ATP recombinant enzyme, Malachite green assay, pH and temperature not specified in the publication Trypanosoma cruzi
6.3.1.2 0.44
-
 L-glutamate recombinant enzyme, coupled reactions assay, pH and temperature not specified in the publication Trypanosoma cruzi
6.3.1.2 0.47
-
 L-glutamate recombinant enzyme, Malachite green assay, pH and temperature not specified in the publication Trypanosoma cruzi
6.3.1.2 0.78
-
 NH4+ recombinant enzyme, Malachite green assay, pH and temperature not specified in the publication Trypanosoma cruzi
6.3.1.2 0.79
-
 NH4+ recombinant enzyme, coupled reactions assay, pH and temperature not specified in the publication Trypanosoma cruzi

Localization

EC Number Localization Comment Organism GeneOntology No. Textmining
6.3.1.2 cytosol the enzyme is spread throughout the cytoplasm and inside the mitochondrial lumen in all life cycle forms Trypanosoma cruzi 5829
-
6.3.1.2 mitochondrion the enzyme is spread throughout the cytoplasm and inside the mitochondrial lumen in all life cycle forms Trypanosoma cruzi 5739
-

Metals/Ions

EC Number Metals/Ions Comment Organism Structure
6.3.1.2 Co2+ enzyme activity is dependent on the presence of divalent cations. Co2+ is able to support activity levels above 50% compared with magnesium in standard conditions of substrates, temperature and pH Trypanosoma cruzi
6.3.1.2 Mg2+ enzyme activity is dependent on the presence of divalent cations. Mg2+ is the most effective cation Trypanosoma cruzi
6.3.1.2 Mn2+ enzyme activity is dependent on the presence of divalent cations. Mn2+ is able to support activity levels above 50% compared with magnesium in standard conditions of substrates, temperature and pH Trypanosoma cruzi

Organism

EC Number Organism UniProt Comment Textmining
6.3.1.2 Trypanosoma cruzi Q4CN04
-
-
6.3.1.2 Trypanosoma cruzi CL Brener Q4CN04
-
-

Purification (Commentary)

EC Number Purification (Comment) Organism
6.3.1.2
-
 Trypanosoma cruzi

Source Tissue

EC Number Source Tissue Comment Organism Textmining
6.3.1.2 amastigote expression levels are maximal in the amastigote stage of the life cycle, when amino acids are preferably consumed, and NH4+ production is predictable Trypanosoma cruzi
-
6.3.1.2 epimastigote
-
 Trypanosoma cruzi
-
6.3.1.2 trypomastigote
-
 Trypanosoma cruzi
-

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
6.3.1.2 ATP + adipate + NH4+ 75% of the activity observed with glutamate Trypanosoma cruzi ADP + phosphate + ?
-
 ?
6.3.1.2 ATP + adipate + NH4+ 75% of the activity observed with glutamate Trypanosoma cruzi CL Brener ADP + phosphate + ?
-
 ?
6.3.1.2 ATP + gamma-aminobutyrate + NH4+ 50% of the activity observed with glutamate Trypanosoma cruzi ADP + phosphate + ?
-
 ?
6.3.1.2 ATP + gamma-aminobutyrate + NH4+ 50% of the activity observed with glutamate Trypanosoma cruzi CL Brener ADP + phosphate + ?
-
 ?
6.3.1.2 ATP + L-glutamate + NH4+ the enzyme is specific for glutamate. Aspartate, asparagine or histidine support less than 10% of the activity observed with glutamate. All the other amino acids do not promote ATP hydrolysis Trypanosoma cruzi ADP + phosphate + L-glutamine
-
 ?
6.3.1.2 ATP + L-glutamate + NH4+ the enzyme is specific for glutamate. Aspartate, asparagine or histidine support less than 10% of the activity observed with glutamate. All the other amino acids do not promote ATP hydrolysis Trypanosoma cruzi CL Brener ADP + phosphate + L-glutamine
-
 ?
6.3.1.2 ATP + pentanedioate + NH4+ 50% of the activity observed with glutamate Trypanosoma cruzi ADP + phosphate + ?
-
 ?
6.3.1.2 ATP + pentanedioate + NH4+ 50% of the activity observed with glutamate Trypanosoma cruzi CL Brener ADP + phosphate + ?
-
 ?

Turnover Number [1/s]

EC Number Turnover Number Minimum [1/s] Turnover Number Maximum [1/s] Substrate Comment Organism Structure
6.3.1.2 357
-
 L-glutamate recombinant enzyme, Malachite green assay, pH and temperature not specified in the publication Trypanosoma cruzi
6.3.1.2 359
-
 ATP recombinant enzyme, Malachite green assay, pH and temperature not specified in the publication Trypanosoma cruzi
6.3.1.2 392
-
 L-glutamate recombinant enzyme, coupled reactions assay, pH and temperature not specified in the publication Trypanosoma cruzi
6.3.1.2 396
-
 ATP recombinant enzyme, coupled reactions assay, pH and temperature not specified in the publication Trypanosoma cruzi
6.3.1.2 480
-
 NH4+ recombinant enzyme, Malachite green assay, pH and temperature not specified in the publication Trypanosoma cruzi
6.3.1.2 535
-
 NH4+ recombinant enzyme, coupled reactions assay, pH and temperature not specified in the publication Trypanosoma cruzi

pH Optimum

EC Number pH Optimum Minimum pH Optimum Maximum Comment Organism
6.3.1.2 8
-
-
 Trypanosoma cruzi

pH Range

EC Number pH Minimum pH Maximum Comment Organism
6.3.1.2 6.5 8.5 pH 6.5: about 50% of maximal activity, pH 8.5: about 60% of maximal activity Trypanosoma cruzi

Ki Value [mM]

EC Number Ki Value [mM] Ki Value maximum [mM] Inhibitor Comment Organism Structure
6.3.1.2 0.00389
-
 methionine sulfoximine recombinant enzyme, pH and temperature not specified in the publication Trypanosoma cruzi

IC50 Value

EC Number IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
6.3.1.2 0.0207
-
 recombinant enzyme, pH and temperature not specified in the publication Trypanosoma cruzi methionine sulfoximine

Expression

EC Number Organism Comment Expression
6.3.1.2 Trypanosoma cruzi expression levels are maximal in the amastigote stage of the life cycle, when amino acids are preferably consumed, and NH4+ production is predictable up

General Information

EC Number General Information Comment Organism
6.3.1.2 drug target since glutamine synthetase is the first metabolic enzyme involved in Trypanosoma cruzi evasion from the parasitophorous vacuole it is a potential target for designing anti-Trypanosoma cruzi drugs Trypanosoma cruzi
6.3.1.2 physiological function the enzyme is indispensable under excess ammonium conditions. It is required for the resistance of the organism to ammonium accumulation and evasion of the parasitophorous vacuole during host-cell infection. The enzyme contributes to the management of excess ammonium and uses it to form the amino acid glutamine. During its life cycle, the parasite invades mammalian host cells and transiently becomes enclosed in a tight vacuole, where it differentiates into the amastigote, an amino acid consumer stage. Amastigotes must escape from the vacuole into the host-cell cytoplasm to initiate intracellular replication. The inhibition of Trypanosoma cruzi glutamine synthetase aborts parasite evasion from the vacuole. The enzyme contributes to the control of ammonium produced by parasite metabolism, as ammonium increases the internal pH of the parasitophorous vacuole, making the enzymes for the Trypanosoma cruzi evasion process non-functional Trypanosoma cruzi

kcat/KM [mM/s]

EC Number kcat/KM Value [1/mMs-1] kcat/KM Value Maximum [1/mMs-1] Substrate Comment Organism Structure
6.3.1.2 620
-
 NH4+ recombinant enzyme, Malachite green assay, pH and temperature not specified in the publication Trypanosoma cruzi
6.3.1.2 680
-
 NH4+ recombinant enzyme, coupled reactions assay, pH and temperature not specified in the publication Trypanosoma cruzi
6.3.1.2 860
-
 L-glutamate recombinant enzyme, Malachite green assay, pH and temperature not specified in the publication Trypanosoma cruzi
6.3.1.2 890
-
 L-glutamate recombinant enzyme, coupled reactions assay, pH and temperature not specified in the publication Trypanosoma cruzi
6.3.1.2 930
-
 ATP recombinant enzyme, Malachite green assay, pH and temperature not specified in the publication Trypanosoma cruzi
6.3.1.2 1050
-
 ATP recombinant enzyme, coupled reactions assay, pH and temperature not specified in the publication Trypanosoma cruzi