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Literature summary for 6.3.1.2 extracted from
- Inhibition of glutamine synthetase a potential drug target in Mycobacterium tuberculosis (2014), Molecules, 19, 13161-13176 .
Application
| Application | Comment | Organism |
|---|---|---|
| drug development | glutamine synthetase is a potential drug target in Mycobacterium tuberculosis | Mycobacterium tuberculosis |
Inhibitors
| Inhibitors | Comment | Organism | Structure |
|---|---|---|---|
| (1R,3R)-1-amino-3-(hydroxy(methyl)phosphoryl)cyclohexane-1-carboxylic acid | - |
Mycobacterium tuberculosis |  |
| (1R,3R)-1-amino-3-(hydroxy(methyl)phosphoryl)cyclopentane-1-carboxylic acid | - |
Mycobacterium tuberculosis | |
| (2R)-2-amino-4-(hydroxyamino)butanoic acid | - |
Mycobacterium tuberculosis | |
| (2R)-2-amino-4-(S-methane-N-phosphonosulfonimidoyl)butanoic acid | - |
Mycobacterium tuberculosis | |
| (2R)-2-amino-4-(S-methanesulfonimidoyl)butanoic acid | - |
Mycobacterium tuberculosis | |
| (5S)-5-hydroxy-D-lysine | - |
Mycobacterium tuberculosis | |
| 1-[(3,4-dichlorophenyl)methyl]-3,7-dimethyl-8-(morpholin-4-yl)-3,7-dihydro-1H-purine-2,6-dione | - |
Mycobacterium tuberculosis | |
| 1-[(3,4-dichlorophenyl)methyl]-8-[(2-methoxyethyl)amino]-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione | - |
Mycobacterium tuberculosis | |
| 2-amino-2-ethyl-4-[hydroxy(methyl)phosphoryl]butanoic acid | - |
Mycobacterium tuberculosis | |
| 2-amino-4-(methanesulfinyl)butanoic acid | 60% inhibition at 10 mM | Mycobacterium tuberculosis | |
| 2-amino-4-(methanesulfonyl)butanoic acid | 78% inhibition at 10 mM | Mycobacterium tuberculosis | |
| 2-amino-4-phosphonobutanoic acid | - |
Mycobacterium tuberculosis | |
| 2-amino-4-sulfamoylbutanoic acid | - |
Mycobacterium tuberculosis | |
| 2-amino-4-[(aminomethyl)(hydroxy)phosphoryl]butanoic acid | - |
Mycobacterium tuberculosis | |
| 2-[(1H-benzimidazol-1-yl)methoxy]ethyl diethyl phosphate | competitive versus ATP | Mycobacterium tuberculosis | |
| 2-[4-[6-bromo-3-(butylamino)imidazo[1,2-a]pyridin-2-yl]phenoxy]acetamide | - |
Mycobacterium tuberculosis | |
| 2-[4-[6-bromo-3-(butylamino)imidazo[1,2-a]pyridin-2-yl]phenoxy]ethan-1-ol | - |
Mycobacterium tuberculosis | |
| 2-[[4-[6-bromo-3-(butylamino)imidazo[1,2-a]pyridin-2-yl]phenyl](methyl)amino]ethan-1-ol | - |
Mycobacterium tuberculosis | |
| 3-[6-bromo-3-(butylamino)imidazo[1,2-a]pyridin-2-yl]benzoic acid | - |
Mycobacterium tuberculosis | |
| 3-[6-bromo-3-(butylamino)imidazo[1,2-a]pyridin-2-yl]phenol | - |
Mycobacterium tuberculosis | |
| 3-[6-bromo-3-(cyclopentylamino)imidazo[1,2-a]pyridin-2-yl]benzoic acid | - |
Mycobacterium tuberculosis | |
| 3-[6-bromo-3-(cyclopentylamino)imidazo[1,2-a]pyridin-2-yl]phenol | - |
Mycobacterium tuberculosis | |
| 4-[(oxan-2-yl)oxy]-1-(prop-2-en-1-yl)-1H-pyrazolo[3,4-d]pyrimidine | competitive versus ATP | Mycobacterium tuberculosis | |
| 4-[2-tert-butyl-4-(6-methoxynaphthalen-2-yl)-1H-imidazol-5-yl]pyridin-2-amine | - |
Mycobacterium tuberculosis | |
| 4-[2-tert-butyl-4-(6-methoxynaphthalen-2-yl)-1H-imidazol-5-yl]pyridine | - |
Mycobacterium tuberculosis | |
| 4-[hydroxy(methyl)phosphoryl]homoserine | - |
Mycobacterium tuberculosis | |
| 4-[hydroxy(methyl)phosphoryl]isovaline | - |
Mycobacterium tuberculosis | |
| 4-[hydroxy(methyl)phosphoryl]norvaline | - |
Mycobacterium tuberculosis | |
| 5-[6-bromo-3-(butylamino)imidazo[1,2-a]pyridin-2-yl]-2-methoxyphenol | - |
Mycobacterium tuberculosis | |
| 5-[6-bromo-3-(cyclopentylamino)imidazo[1,2-a]pyridin-2-yl]-2-methoxyphenol | - |
Mycobacterium tuberculosis | |
| 6-bromo-N-butyl-2-[4-[2-(dimethylamino)ethoxy]phenyl]imidazo[1,2-a]pyridin-3-amine | - |
Mycobacterium tuberculosis | |
| diethyl [2-(3-hydroxyanilino)-2-oxoethyl]phosphonate | competitive versus ATP | Mycobacterium tuberculosis | |
| methionine sulfoximine | MSO, originally isolated from the maize protein zein after treatment with nitrogen trichloride, targets the amino acid-binding site of the enzyme. Treatment of Mycobacterium tuberculosis with MSO inhibits both cell wall formation and bacterial growth. MSO initially binds as a competitive inhibitor and undergoes rapid phosphorylation by the glutamate synthetase, producing the active form, methionine sulfoximine phosphate (MSO-P). MSO-P binds essentially irreversibly to the active site, preventing entry of the glutamate substrate. The configuration of the two stereocenters is important for inhibitory activity. The (S,S)-diastereomer is 10times more potent than the (S,R)-isomer | Mycobacterium tuberculosis | |
| additional information | in contrast to methionine sulfoximine, MSO, the sulfone and sulfoxide analogues are weak, reversible enzyme inhibitors. Poor or no inhibition by 2-amino-4-(ethanesulfonyl)butanoic acid and amino[3-(methanesulfonyl)phenyl]acetic acid | Mycobacterium tuberculosis | |
| N-(1,1-dioxo-1lambda6-thiolan-3-yl)glycine | - |
Mycobacterium tuberculosis | |
| N-[(2S)-2-amino-4-[hydroxy(methyl)phosphoryl]butanoyl]-L-alanyl-L-alanine | - |
Mycobacterium tuberculosis | |
| Phosphinothricin | targets the amino acid-binding site of the enzyme | Mycobacterium tuberculosis | |
| [(3,5-dichloroanilino)methylene]bis(phosphonic acid) | - |
Mycobacterium tuberculosis | |
| [4-[6-bromo-3-(butylamino)imidazo[1,2-a]pyridin-2-yl]phenoxy]acetic acid | - |
Mycobacterium tuberculosis | |
Localization
| Localization | Comment | Organism | GeneOntology No. | Textmining |
|---|---|---|---|---|
| cell wall | - |
Mycobacterium tuberculosis | 5618 | - |
| extracellular | - |
Mycobacterium tuberculosis | - |
- |
Metals/Ions
| Metals/Ions | Comment | Organism | Structure |
|---|---|---|---|
| Mg2+ | to be in its active state, the enzyme requires magnesium or manganese ions, located in three metal sites designated as n1-n3 | Mycobacterium tuberculosis | |
| Mn2+ | to be in its active state, the enzyme requires magnesium or manganese ions, located in three metal sites designated as n1-n3 | Mycobacterium tuberculosis | |
Natural Substrates/ Products (Substrates)
| Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| ATP + L-glutamate + NH3 | Mycobacterium tuberculosis | - |
ADP + phosphate + L-glutamine | - |
? | |
| ATP + L-glutamate + NH3 | Mycobacterium tuberculosis ATCC 25618 / H37Rv | - |
ADP + phosphate + L-glutamine | - |
? | |
Organism
| Organism | UniProt | Comment | Textmining |
|---|---|---|---|
| Mycobacterium tuberculosis | P9WN39 | - |
- |
| Mycobacterium tuberculosis ATCC 25618 / H37Rv | P9WN39 | - |
- |
Reaction
| Reaction | Comment | Organism | Reaction ID |
|---|---|---|---|
| ATP + L-glutamate + NH3 = ADP + phosphate + L-glutamine | in the first step of catalysis, a tightly bound, activated intermediate, gamma-glutamyl phosphate, is formed when the terminal phosphate of ATP is transferred to the carboxylate side chain of the substrate glutamate. In the second step, an enzyme-bound ammonium ion is deprotonated, forming ammonia that attacks the carbonyl carbon of gamma-glutamyl phosphate to form a tetrahedral intermediate. The enzyme subsequently releases free phosphate and glutamine | Mycobacterium tuberculosis |
Substrates and Products (Substrate)
| Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| ATP + L-glutamate + NH3 | - |
Mycobacterium tuberculosis | ADP + phosphate + L-glutamine | - |
? | |
| ATP + L-glutamate + NH3 | - |
Mycobacterium tuberculosis ATCC 25618 / H37Rv | ADP + phosphate + L-glutamine | - |
? | |
Subunits
| Subunits | Comment | Organism |
|---|---|---|
| dodecamer | MtGS is a dodecamer formed of two hexameric rings stacked on top of each other. Each active site includes contributions from two adjacent subunits within a ring | Mycobacterium tuberculosis |
Synonyms
| Synonyms | Comment | Organism |
|---|---|---|
| GlnA1 | - |
Mycobacterium tuberculosis |
| MtGS | - |
Mycobacterium tuberculosis |
Cofactor
| Cofactor | Comment | Organism | Structure |
|---|---|---|---|
| ATP | - |
Mycobacterium tuberculosis | |
IC50 Value
| IC50 Value | IC50 Value Maximum | Comment | Organism | Inhibitor | Structure |
|---|---|---|---|---|---|
| 0.000049 | - |
pH and temperature not specified in the publication | Mycobacterium tuberculosis | 4-[2-tert-butyl-4-(6-methoxynaphthalen-2-yl)-1H-imidazol-5-yl]pyridin-2-amine | |
| 0.00038 | - |
pH and temperature not specified in the publication | Mycobacterium tuberculosis | 3-[6-bromo-3-(cyclopentylamino)imidazo[1,2-a]pyridin-2-yl]benzoic acid | |
| 0.0006 | - |
pH and temperature not specified in the publication | Mycobacterium tuberculosis | 3-[6-bromo-3-(butylamino)imidazo[1,2-a]pyridin-2-yl]benzoic acid | |
| 0.0014 | - |
pH and temperature not specified in the publication | Mycobacterium tuberculosis | 3-[6-bromo-3-(butylamino)imidazo[1,2-a]pyridin-2-yl]phenol | |
| 0.0016 | - |
pH and temperature not specified in the publication | Mycobacterium tuberculosis | [4-[6-bromo-3-(butylamino)imidazo[1,2-a]pyridin-2-yl]phenoxy]acetic acid | |
| 0.0019 | - |
pH and temperature not specified in the publication | Mycobacterium tuberculosis | 5-[6-bromo-3-(butylamino)imidazo[1,2-a]pyridin-2-yl]-2-methoxyphenol | |
| 0.0025 | - |
pH and temperature not specified in the publication | Mycobacterium tuberculosis | 5-[6-bromo-3-(cyclopentylamino)imidazo[1,2-a]pyridin-2-yl]-2-methoxyphenol | |
| 0.0025 | - |
pH and temperature not specified in the publication | Mycobacterium tuberculosis | 1-[(3,4-dichlorophenyl)methyl]-3,7-dimethyl-8-(morpholin-4-yl)-3,7-dihydro-1H-purine-2,6-dione | |
| 0.003 | - |
pH and temperature not specified in the publication | Mycobacterium tuberculosis | 2-[4-[6-bromo-3-(butylamino)imidazo[1,2-a]pyridin-2-yl]phenoxy]ethan-1-ol | |
| 0.0031 | - |
pH and temperature not specified in the publication | Mycobacterium tuberculosis | 4-[2-tert-butyl-4-(6-methoxynaphthalen-2-yl)-1H-imidazol-5-yl]pyridine | |
| 0.0033 | - |
pH and temperature not specified in the publication | Mycobacterium tuberculosis | 3-[6-bromo-3-(cyclopentylamino)imidazo[1,2-a]pyridin-2-yl]phenol | |
| 0.0058 | - |
pH and temperature not specified in the publication | Mycobacterium tuberculosis | 6-bromo-N-butyl-2-[4-[2-(dimethylamino)ethoxy]phenyl]imidazo[1,2-a]pyridin-3-amine | |
| 0.0063 | - |
pH and temperature not specified in the publication | Mycobacterium tuberculosis | 2-[4-[6-bromo-3-(butylamino)imidazo[1,2-a]pyridin-2-yl]phenoxy]acetamide | |
| 0.0083 | - |
pH and temperature not specified in the publication | Mycobacterium tuberculosis | 2-[[4-[6-bromo-3-(butylamino)imidazo[1,2-a]pyridin-2-yl]phenyl](methyl)amino]ethan-1-ol | |
| 0.017 | - |
pH and temperature not specified in the publication | Mycobacterium tuberculosis | 1-[(3,4-dichlorophenyl)methyl]-8-[(2-methoxyethyl)amino]-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione | |
| 0.051 | - |
pH and temperature not specified in the publication | Mycobacterium tuberculosis | methionine sulfoximine | |
Expression
| Organism | Comment | Expression |
|---|---|---|
| Mycobacterium tuberculosis | the activity of the enzyme is down-regulated under conditions of excess nitrogen through covalent addition of an AMP moiety to Tyr406 (MtGS numbering) by the regulatory enzyme, GlnE | down |
General Information
| General Information | Comment | Organism |
|---|---|---|
| additional information | enzyme structure-activity relationship, overview | Mycobacterium tuberculosis |
| physiological function | the enzyme catalyses the ATP-dependent condensation of ammonium and L-glutamate, thus forming L-glutamine, ADP, phosphate and a proton. The enzyme is highly expressed and essential for the growth of the bacteria both in vitro and in vivo. The Mycobacterium tuberculosis enzyme plays an important role in cell wall biosynthesis, specifically via the production of a poly-L-glutamate-glutamine component found exclusively in pathogenic mycobacteria. Extracellular Mycobacterium tuberculosis enzyme may also affect pH modulation in phagosomes and consequently prevent phagosome-lysosome fusion | Mycobacterium tuberculosis |
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