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Literature summary for 6.3.1.2 extracted from
- 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 .
Application
| Application | Comment | Organism |
|---|---|---|
| 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)
| Cloned (Comment) | Organism |
|---|---|
| expression in Escherichia coli | Trypanosoma cruzi |
Inhibitors
| Inhibitors | Comment | Organism | Structure |
|---|---|---|---|
| Ca2+ | inhibitory effect on Mg2+-driven activity | Trypanosoma cruzi |  |
| EDTA | - |
Trypanosoma cruzi | |
| methionine sulfoximine | competitive inhibitor with respect to L-glutamate | Trypanosoma cruzi | |
KM Value [mM]
| KM Value [mM] | KM Value Maximum [mM] | Substrate | Comment | Organism | Structure |
|---|---|---|---|---|---|
| 0.38 | - |
ATP | recombinant enzyme, coupled reactions assay, pH and temperature not specified in the publication | Trypanosoma cruzi | |
| 0.39 | - |
ATP | recombinant enzyme, Malachite green assay, pH and temperature not specified in the publication | Trypanosoma cruzi | |
| 0.44 | - |
L-glutamate | recombinant enzyme, coupled reactions assay, pH and temperature not specified in the publication | Trypanosoma cruzi | |
| 0.47 | - |
L-glutamate | recombinant enzyme, Malachite green assay, pH and temperature not specified in the publication | Trypanosoma cruzi | |
| 0.78 | - |
NH4+ | recombinant enzyme, Malachite green assay, pH and temperature not specified in the publication | Trypanosoma cruzi | |
| 0.79 | - |
NH4+ | recombinant enzyme, coupled reactions assay, pH and temperature not specified in the publication | Trypanosoma cruzi | |
Localization
| Localization | Comment | Organism | GeneOntology No. | Textmining |
|---|---|---|---|---|
| cytosol | the enzyme is spread throughout the cytoplasm and inside the mitochondrial lumen in all life cycle forms | Trypanosoma cruzi | 5829 | - |
| mitochondrion | the enzyme is spread throughout the cytoplasm and inside the mitochondrial lumen in all life cycle forms | Trypanosoma cruzi | 5739 | - |
Metals/Ions
| Metals/Ions | Comment | Organism | Structure |
|---|---|---|---|
| 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 | |
| Mg2+ | enzyme activity is dependent on the presence of divalent cations. Mg2+ is the most effective cation | Trypanosoma cruzi | |
| 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
| Organism | UniProt | Comment | Textmining |
|---|---|---|---|
| Trypanosoma cruzi | Q4CN04 | - |
- |
| Trypanosoma cruzi CL Brener | Q4CN04 | - |
- |
Purification (Commentary)
| Purification (Comment) | Organism |
|---|---|
- |
Trypanosoma cruzi |
Source Tissue
| Source Tissue | Comment | Organism | Textmining |
|---|---|---|---|
| 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 | - |
| epimastigote | - |
Trypanosoma cruzi | - |
| trypomastigote | - |
Trypanosoma cruzi | - |
Substrates and Products (Substrate)
| Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| ATP + adipate + NH4+ | 75% of the activity observed with glutamate | Trypanosoma cruzi | ADP + phosphate + ? | - |
? | |
| ATP + adipate + NH4+ | 75% of the activity observed with glutamate | Trypanosoma cruzi CL Brener | ADP + phosphate + ? | - |
? | |
| ATP + gamma-aminobutyrate + NH4+ | 50% of the activity observed with glutamate | Trypanosoma cruzi | ADP + phosphate + ? | - |
? | |
| ATP + gamma-aminobutyrate + NH4+ | 50% of the activity observed with glutamate | Trypanosoma cruzi CL Brener | ADP + phosphate + ? | - |
? | |
| 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 | - |
? | |
| 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 | - |
? | |
| ATP + pentanedioate + NH4+ | 50% of the activity observed with glutamate | Trypanosoma cruzi | ADP + phosphate + ? | - |
? | |
| ATP + pentanedioate + NH4+ | 50% of the activity observed with glutamate | Trypanosoma cruzi CL Brener | ADP + phosphate + ? | - |
? | |
Turnover Number [1/s]
| Turnover Number Minimum [1/s] | Turnover Number Maximum [1/s] | Substrate | Comment | Organism | Structure |
|---|---|---|---|---|---|
| 357 | - |
L-glutamate | recombinant enzyme, Malachite green assay, pH and temperature not specified in the publication | Trypanosoma cruzi | |
| 359 | - |
ATP | recombinant enzyme, Malachite green assay, pH and temperature not specified in the publication | Trypanosoma cruzi | |
| 392 | - |
L-glutamate | recombinant enzyme, coupled reactions assay, pH and temperature not specified in the publication | Trypanosoma cruzi | |
| 396 | - |
ATP | recombinant enzyme, coupled reactions assay, pH and temperature not specified in the publication | Trypanosoma cruzi | |
| 480 | - |
NH4+ | recombinant enzyme, Malachite green assay, pH and temperature not specified in the publication | Trypanosoma cruzi | |
| 535 | - |
NH4+ | recombinant enzyme, coupled reactions assay, pH and temperature not specified in the publication | Trypanosoma cruzi | |
pH Optimum
| pH Optimum Minimum | pH Optimum Maximum | Comment | Organism |
|---|---|---|---|
| 8 | - |
- |
Trypanosoma cruzi |
pH Range
| pH Minimum | pH Maximum | Comment | Organism |
|---|---|---|---|
| 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]
| Ki Value [mM] | Ki Value maximum [mM] | Inhibitor | Comment | Organism | Structure |
|---|---|---|---|---|---|
| 0.00389 | - |
methionine sulfoximine | recombinant enzyme, pH and temperature not specified in the publication | Trypanosoma cruzi | |
IC50 Value
| IC50 Value | IC50 Value Maximum | Comment | Organism | Inhibitor | Structure |
|---|---|---|---|---|---|
| 0.0207 | - |
recombinant enzyme, pH and temperature not specified in the publication | Trypanosoma cruzi | methionine sulfoximine | |
Expression
| Organism | Comment | Expression |
|---|---|---|
| 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
| General Information | Comment | Organism |
|---|---|---|
| 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 |
| 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]
| kcat/KM Value [1/mMs-1] | kcat/KM Value Maximum [1/mMs-1] | Substrate | Comment | Organism | Structure |
|---|---|---|---|---|---|
| 620 | - |
NH4+ | recombinant enzyme, Malachite green assay, pH and temperature not specified in the publication | Trypanosoma cruzi | |
| 680 | - |
NH4+ | recombinant enzyme, coupled reactions assay, pH and temperature not specified in the publication | Trypanosoma cruzi | |
| 860 | - |
L-glutamate | recombinant enzyme, Malachite green assay, pH and temperature not specified in the publication | Trypanosoma cruzi | |
| 890 | - |
L-glutamate | recombinant enzyme, coupled reactions assay, pH and temperature not specified in the publication | Trypanosoma cruzi | |
| 930 | - |
ATP | recombinant enzyme, Malachite green assay, pH and temperature not specified in the publication | Trypanosoma cruzi | |
| 1050 | - |
ATP | recombinant enzyme, coupled reactions assay, pH and temperature not specified in the publication | Trypanosoma cruzi | |
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