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Literature summary extracted from

  • Mowbray, S.; Kathiravan, M.; Pandey, A.; Odell, L.
    Inhibition of glutamine synthetase a potential drug target in Mycobacterium tuberculosis (2014), Molecules, 19, 13161-13176 .
    View publication on PubMedView publication on EuropePMC

Application

EC Number Application Comment Organism
6.3.1.2 drug development glutamine synthetase is a potential drug target in Mycobacterium tuberculosis Mycobacterium tuberculosis

Inhibitors

EC Number Inhibitors Comment Organism Structure
6.3.1.2 (1R,3R)-1-amino-3-(hydroxy(methyl)phosphoryl)cyclohexane-1-carboxylic acid
-
 Mycobacterium tuberculosis
6.3.1.2 (1R,3R)-1-amino-3-(hydroxy(methyl)phosphoryl)cyclopentane-1-carboxylic acid
-
 Mycobacterium tuberculosis
6.3.1.2 (2R)-2-amino-4-(hydroxyamino)butanoic acid
-
 Mycobacterium tuberculosis
6.3.1.2 (2R)-2-amino-4-(S-methane-N-phosphonosulfonimidoyl)butanoic acid
-
 Mycobacterium tuberculosis
6.3.1.2 (2R)-2-amino-4-(S-methanesulfonimidoyl)butanoic acid
-
 Mycobacterium tuberculosis
6.3.1.2 (5S)-5-hydroxy-D-lysine
-
 Mycobacterium tuberculosis
6.3.1.2 1-[(3,4-dichlorophenyl)methyl]-3,7-dimethyl-8-(morpholin-4-yl)-3,7-dihydro-1H-purine-2,6-dione
-
 Mycobacterium tuberculosis
6.3.1.2 1-[(3,4-dichlorophenyl)methyl]-8-[(2-methoxyethyl)amino]-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione
-
 Mycobacterium tuberculosis
6.3.1.2 2-amino-2-ethyl-4-[hydroxy(methyl)phosphoryl]butanoic acid
-
 Mycobacterium tuberculosis
6.3.1.2 2-amino-4-(methanesulfinyl)butanoic acid 60% inhibition at 10 mM Mycobacterium tuberculosis
6.3.1.2 2-amino-4-(methanesulfonyl)butanoic acid 78% inhibition at 10 mM Mycobacterium tuberculosis
6.3.1.2 2-amino-4-phosphonobutanoic acid
-
 Mycobacterium tuberculosis
6.3.1.2 2-amino-4-sulfamoylbutanoic acid
-
 Mycobacterium tuberculosis
6.3.1.2 2-amino-4-[(aminomethyl)(hydroxy)phosphoryl]butanoic acid
-
 Mycobacterium tuberculosis
6.3.1.2 2-[(1H-benzimidazol-1-yl)methoxy]ethyl diethyl phosphate competitive versus ATP Mycobacterium tuberculosis
6.3.1.2 2-[4-[6-bromo-3-(butylamino)imidazo[1,2-a]pyridin-2-yl]phenoxy]acetamide
-
 Mycobacterium tuberculosis
6.3.1.2 2-[4-[6-bromo-3-(butylamino)imidazo[1,2-a]pyridin-2-yl]phenoxy]ethan-1-ol
-
 Mycobacterium tuberculosis
6.3.1.2 2-[[4-[6-bromo-3-(butylamino)imidazo[1,2-a]pyridin-2-yl]phenyl](methyl)amino]ethan-1-ol
-
 Mycobacterium tuberculosis
6.3.1.2 3-[6-bromo-3-(butylamino)imidazo[1,2-a]pyridin-2-yl]benzoic acid
-
 Mycobacterium tuberculosis
6.3.1.2 3-[6-bromo-3-(butylamino)imidazo[1,2-a]pyridin-2-yl]phenol
-
 Mycobacterium tuberculosis
6.3.1.2 3-[6-bromo-3-(cyclopentylamino)imidazo[1,2-a]pyridin-2-yl]benzoic acid
-
 Mycobacterium tuberculosis
6.3.1.2 3-[6-bromo-3-(cyclopentylamino)imidazo[1,2-a]pyridin-2-yl]phenol
-
 Mycobacterium tuberculosis
6.3.1.2 4-[(oxan-2-yl)oxy]-1-(prop-2-en-1-yl)-1H-pyrazolo[3,4-d]pyrimidine competitive versus ATP Mycobacterium tuberculosis
6.3.1.2 4-[2-tert-butyl-4-(6-methoxynaphthalen-2-yl)-1H-imidazol-5-yl]pyridin-2-amine
-
 Mycobacterium tuberculosis
6.3.1.2 4-[2-tert-butyl-4-(6-methoxynaphthalen-2-yl)-1H-imidazol-5-yl]pyridine
-
 Mycobacterium tuberculosis
6.3.1.2 4-[hydroxy(methyl)phosphoryl]homoserine
-
 Mycobacterium tuberculosis
6.3.1.2 4-[hydroxy(methyl)phosphoryl]isovaline
-
 Mycobacterium tuberculosis
6.3.1.2 4-[hydroxy(methyl)phosphoryl]norvaline
-
 Mycobacterium tuberculosis
6.3.1.2 5-[6-bromo-3-(butylamino)imidazo[1,2-a]pyridin-2-yl]-2-methoxyphenol
-
 Mycobacterium tuberculosis
6.3.1.2 5-[6-bromo-3-(cyclopentylamino)imidazo[1,2-a]pyridin-2-yl]-2-methoxyphenol
-
 Mycobacterium tuberculosis
6.3.1.2 6-bromo-N-butyl-2-[4-[2-(dimethylamino)ethoxy]phenyl]imidazo[1,2-a]pyridin-3-amine
-
 Mycobacterium tuberculosis
6.3.1.2 diethyl [2-(3-hydroxyanilino)-2-oxoethyl]phosphonate competitive versus ATP Mycobacterium tuberculosis
6.3.1.2 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
6.3.1.2 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
6.3.1.2 N-(1,1-dioxo-1lambda6-thiolan-3-yl)glycine
-
 Mycobacterium tuberculosis
6.3.1.2 N-[(2S)-2-amino-4-[hydroxy(methyl)phosphoryl]butanoyl]-L-alanyl-L-alanine
-
 Mycobacterium tuberculosis
6.3.1.2 Phosphinothricin targets the amino acid-binding site of the enzyme Mycobacterium tuberculosis
6.3.1.2 [(3,5-dichloroanilino)methylene]bis(phosphonic acid)
-
 Mycobacterium tuberculosis
6.3.1.2 [4-[6-bromo-3-(butylamino)imidazo[1,2-a]pyridin-2-yl]phenoxy]acetic acid
-
 Mycobacterium tuberculosis

Localization

EC Number Localization Comment Organism GeneOntology No. Textmining
6.3.1.2 cell wall
-
 Mycobacterium tuberculosis 5618
-
6.3.1.2 extracellular
-
 Mycobacterium tuberculosis
-
-

Metals/Ions

EC Number Metals/Ions Comment Organism Structure
6.3.1.2 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
6.3.1.2 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)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
6.3.1.2 ATP + L-glutamate + NH3 Mycobacterium tuberculosis
-
 ADP + phosphate + L-glutamine
-
 ?
6.3.1.2 ATP + L-glutamate + NH3 Mycobacterium tuberculosis ATCC 25618 / H37Rv
-
 ADP + phosphate + L-glutamine
-
 ?

Organism

EC Number Organism UniProt Comment Textmining
6.3.1.2 Mycobacterium tuberculosis P9WN39
-
-
6.3.1.2 Mycobacterium tuberculosis ATCC 25618 / H37Rv P9WN39
-
-

Reaction

EC Number Reaction Comment Organism Reaction ID
6.3.1.2 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
a

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
6.3.1.2 ATP + L-glutamate + NH3
-
 Mycobacterium tuberculosis ADP + phosphate + L-glutamine
-
 ?
6.3.1.2 ATP + L-glutamate + NH3
-
 Mycobacterium tuberculosis ATCC 25618 / H37Rv ADP + phosphate + L-glutamine
-
 ?

Subunits

EC Number Subunits Comment Organism
6.3.1.2 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

EC Number Synonyms Comment Organism
6.3.1.2 GlnA1
-
 Mycobacterium tuberculosis
6.3.1.2 MtGS
-
 Mycobacterium tuberculosis

Cofactor

EC Number Cofactor Comment Organism Structure
6.3.1.2 ATP
-
 Mycobacterium tuberculosis

IC50 Value

EC Number IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
6.3.1.2 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
6.3.1.2 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
6.3.1.2 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
6.3.1.2 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
6.3.1.2 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
6.3.1.2 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
6.3.1.2 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
6.3.1.2 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
6.3.1.2 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
6.3.1.2 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
6.3.1.2 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
6.3.1.2 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
6.3.1.2 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
6.3.1.2 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
6.3.1.2 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
6.3.1.2 0.051
-
 pH and temperature not specified in the publication Mycobacterium tuberculosis methionine sulfoximine

Expression

EC Number Organism Comment Expression
6.3.1.2 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

EC Number General Information Comment Organism
6.3.1.2 additional information enzyme structure-activity relationship, overview Mycobacterium tuberculosis
6.3.1.2 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