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Literature summary for 6.1.1.4 extracted from

  • Gudzera, O.I.; Golub, A.G.; Bdzhola, V.G.; Volynets, G.P.; Kovalenko, O.P.; Boyarshin, K.S.; Yaremchuk, A.D.; Protopopov, M.V.; Yarmoluk, S.M.; Tukalo, M.A.
    Identification of Mycobacterium tuberculosis leucyl-tRNA synthetase (LeuRS) inhibitors among the derivatives of 5-phenylamino-2H-[1,2,4]triazin-3-one (2016), J. Enzyme Inhib. Med. Chem., 31, 201-207 .
    View publication on PubMed

Application

Application Comment Organism
drug development leucyl-tRNA synthetase (LeuRS) is an attractive therapeutic target and a target for development of drugs Mycobacterium tuberculosis

Cloned(Commentary)

Cloned (Comment) Organism
gene LARS, recombinant expression of C-terminally His-tagged enzyme in Escherichia coli strain Rosetta (DE3) Homo sapiens
gene leuS, recombinant expression of His-tagged enzyme in Escherichia coli strain Rosetta (DE3) Mycobacterium tuberculosis

Inhibitors

Inhibitors Comment Organism Structure
2-(2,5-dimethylanilino)-5,6,7,8-tetrahydroquinazolin-4(3H)-one residual activity compared to wild-type enzyme is 71% Mycobacterium tuberculosis
2-(2-hydroxy-5-methylanilino)-3,5,6,7-tetrahydro-4H-cyclopenta[d]pyrimidin-4-one residual activity compared to wild-type enzyme is 40% Mycobacterium tuberculosis
2-(2-hydroxy-5-methylanilino)-6-propylpyrimidin-4(3H)-one residual activity compared to wild-type enzyme is 93% Mycobacterium tuberculosis
2-(2-hydroxy-5-methylanilino)quinazolin-4(3H)-one residual activity compared to wild-type enzyme is 26% Mycobacterium tuberculosis
2-(2-hydroxyanilino)-6-methylpyrimidin-4(3H)-one residual activity compared to wild-type enzyme is 42% Mycobacterium tuberculosis
2-(2-hydroxyanilino)pyrimidin-4(3H)-one residual activity compared to wild-type enzyme is 37% Mycobacterium tuberculosis
2-(2-hydroxyanilino)quinazolin-4(3H)-one residual activity compared to wild-type enzyme is 36% Mycobacterium tuberculosis
2-(3-hydroxy-4-methylanilino)-6-propylpyrimidin-4(3H)-one residual activity compared to wild-type enzyme is 36% Mycobacterium tuberculosis
2-(3-hydroxyanilino)-6-methylpyrimidin-4(3H)-one residual activity compared to wild-type enzyme is 39% Mycobacterium tuberculosis
2-(3-hydroxyanilino)quinazolin-4(3H)-one residual activity compared to wild-type enzyme is 26% Mycobacterium tuberculosis
2-(4-hydroxy-2-methylanilino)-5,6,7,8-tetrahydroquinazolin-4(3H)-one residual activity compared to wild-type enzyme is 70% Mycobacterium tuberculosis
2-(4-hydroxy-2-methylanilino)-6-(propan-2-yl)pyrimidin-4(3H)-one residual activity compared to wild-type enzyme is 29% Mycobacterium tuberculosis
2-(4-hydroxy-2-methylanilino)-6-methylpyrimidin-4(3H)-one residual activity compared to wild-type enzyme is 61% Mycobacterium tuberculosis
2-(4-hydroxy-2-methylanilino)-6-phenylpyrimidin-4(3H)-one residual activity compared to wild-type enzyme is 94% Mycobacterium tuberculosis
2-(4-hydroxyanilino)-6-methylpyrimidin-4(3H)-one residual activity compared to wild-type enzyme is 28% Mycobacterium tuberculosis
2-(5-chloro-2-hydroxyanilino)-6-propylpyrimidin-4(3H)-one residual activity compared to wild-type enzyme is 86% Mycobacterium tuberculosis
3-(2-hydroxy-5-methylanilino)-1,2,4-triazin-5(4H)-one residual activity compared to wild-type enzyme is 70% Mycobacterium tuberculosis
3-(2-hydroxy-5-methylanilino)-6-methyl-1,2,4-triazin-5(4H)-one residual activity compared to wild-type enzyme is 44% Mycobacterium tuberculosis
3-(2-hydroxy-5-methylanilino)-6-phenyl-1,2,4-triazin-5(4H)-one residual activity compared to wild-type enzyme is 36% Mycobacterium tuberculosis
3-(2-hydroxyanilino)-6-methyl-1,2,4-triazin-5(4H)-one residual activity compared to wild-type enzyme is 38% Mycobacterium tuberculosis
3-(3-hydroxy-4-methylanilino)-6-methyl-1,2,4-triazin-5(4H)-one residual activity compared to wild-type enzyme is 83% Mycobacterium tuberculosis
3-(3-hydroxyanilino)-6-methyl-1,2,4-triazin-5(4H)-one residual activity compared to wild-type enzyme is 40% Mycobacterium tuberculosis
3-(3-hydroxyanilino)-6-phenyl-1,2,4-triazin-5(4H)-one residual activity compared to wild-type enzyme is 57% Mycobacterium tuberculosis
3-(4-hydroxy-2-methylanilino)-1,2,4-triazin-5(4H)-one residual activity compared to wild-type enzyme is 51% Mycobacterium tuberculosis
3-(4-hydroxy-2-methylanilino)-6-methyl-1,2,4-triazin-5(4H)-one residual activity compared to wild-type enzyme is 70% Mycobacterium tuberculosis
3-(4-hydroxyanilino)-6-methyl-1,2,4-triazin-5(4H)-one residual activity compared to wild-type enzyme is 55% Mycobacterium tuberculosis
3-(4-hydroxyanilino)-6-phenyl-1,2,4-triazin-5(4H)-one residual activity compared to wild-type enzyme is 36% Mycobacterium tuberculosis
3-(5-chloro-2-hydroxyanilino)-1,2,4-triazin-5(4H)-one residual activity compared to wild-type enzyme is 45% Mycobacterium tuberculosis
3-(5-chloro-2-hydroxyanilino)-6-methyl-1,2,4-triazin-5(4H)-one residual activity compared to wild-type enzyme is 42% Mycobacterium tuberculosis
3-[(3-oxo-2,3-dihydro-1,2,4-triazin-5-yl)amino]benzoic acid residual activity compared to wild-type enzyme is 69% Mycobacterium tuberculosis
3-[(4-oxo-3,4-dihydroquinazolin-2-yl)amino]benzoic acid residual activity compared to wild-type enzyme is 36% Mycobacterium tuberculosis
3-[(6-methyl-3-oxo-2,3-dihydro-1,2,4-triazin-5-yl)amino]benzoic acid residual activity compared to wild-type enzyme is 57% Mycobacterium tuberculosis
3-[4-(2-oxopropyl)anilino]-6-phenyl-1,2,4-triazin-5(4H)-one residual activity compared to wild-type enzyme is 52% Mycobacterium tuberculosis
4-methyl-3-[(3-oxo-2,3-dihydro-1,2,4-triazin-5-yl)amino]benzoic acid residual activity compared to wild-type enzyme is 65% Mycobacterium tuberculosis
4-methyl-3-[(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)amino]benzoic acid residual activity compared to wild-type enzyme is 56% Mycobacterium tuberculosis
4-[(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)amino]benzoic acid residual activity compared to wild-type enzyme is 70% Mycobacterium tuberculosis
4-[(5-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)amino]benzoic acid residual activity compared to wild-type enzyme is 71% Mycobacterium tuberculosis
4-[(5-oxo-4,5-dihydro-1,2,4-triazin-3-yl)amino]benzoic acid residual activity compared to wild-type enzyme is 70% Mycobacterium tuberculosis
4-[(6-methyl-3-oxo-2,3-dihydro-1,2,4-triazin-5-yl)amino]benzoic acid residual activity compared to wild-type enzyme is 64% Mycobacterium tuberculosis
5-(2-hydroxy-4-methylanilino)-1,2,4-triazin-3(2H)-one residual activity compared to wild-type enzyme is 73% Mycobacterium tuberculosis
5-(2-hydroxy-5-methylanilino)-1,2,4-triazin-3(2H)-one residual activity compared to wild-type enzyme is 70% Mycobacterium tuberculosis
5-(2-hydroxyanilino)-1,2,4-triazin-3(2H)-one residual activity compared to wild-type enzyme is 72% Mycobacterium tuberculosis
5-(2-hydroxyanilino)-6-methyl-1,2,4-triazin-3(2H)-one residual activity compared to wild-type enzyme is 67% Mycobacterium tuberculosis
5-(4-hydroxy-2-methylanilino)-6-methyl-1,2,4-triazin-3(2H)-one residual activity compared to wild-type enzyme is 72% Mycobacterium tuberculosis
5-(4-hydroxyanilino)-1,2,4-triazin-3(2H)-one residual activity compared to wild-type enzyme is 70% Mycobacterium tuberculosis
5-(4-hydroxyanilino)-6-methyl-1,2,4-triazin-3(2H)-one residual activity compared to wild-type enzyme is 55% Mycobacterium tuberculosis
5-(5-chloro-2-hydroxy-phenylamino)-2H-[1,2,4]triazin-3-one binding mode, overview Homo sapiens
5-(5-chloro-2-hydroxy-phenylamino)-2H-[1,2,4]triazin-3-one residual activity compared to wild-type enzyme is 18%, binding mode, overview Mycobacterium tuberculosis
5-(5-chloro-2-hydroxy-phenylamino)-6-methyl-2H-[1,2,4]triazin-3-one binding mode, overview Homo sapiens
5-(5-chloro-2-hydroxy-phenylamino)-6-methyl-2H-[1,2,4]triazin-3-one residual activity compared to wild-type enzyme is 2.3%, binding mode, overview Mycobacterium tuberculosis
5-phenylamino-2H-[1,2,4]triazin-3-one
-
Mycobacterium tuberculosis
5-[(6-methyl-3-oxo-2,3-dihydro-1,2,4-triazin-5-yl)amino]benzene-1,3-dicarboxylic acid residual activity compared to wild-type enzyme is 72% Mycobacterium tuberculosis
additional information derivatives of 5-phenylamino-2H-[1,2,4]triazin-3-one as leucyl-tRNA synthetase (LeuRS) inhibitors, docking study, overview. The inhibitory activity of some compounds against pathogenic LeuRS is 10fold higher compared to the human enzyme. Hydrogen bond-foming amino acids in active site of LeuRS are Phe97, Tyr99, Glu103, His109, Tyr113, Asp137, Ser631, Gly678, Glu680, His681, Gln714, Ile717, Lys759, and Ile760 Homo sapiens
additional information derivatives of 5-phenylamino-2H-[1,2,4]triazin-3-one as leucyl-tRNA synthetase (LeuRS) inhibitors, docking study, overview. The inhibitory activity of some compounds against pathogenic LeuRS is 10fold higher compared to the human enzyme. Hydrogen bond-foming amino acids in active site of LeuRS are Phe97, Tyr99, Glu103, His109, Tyr113, Asp137, Ser631, Gly678, Glu680, His681, Gln714, Ile717, Lys759, and Ile760. No inhibition by 5-[(6-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-3-yl)amino]cyclohexa-2,4-diene-1-carboxylic acid, 4-[(4-oxo-3,4,5,6,7,8-hexahydroquinazolin-2-yl)amino]benzoic acid, 2-(2-hydroxyanilino)-5,6,7,8-tetrahydroquinazolin-4(3H)-one, 4-[(6-oxo-4-propyl-1,6-dihydropyrimidin-2-yl)amino]benzoic acid, 2-(4-hydroxyanilino)-6-propylpyrimidin-4(3H)-one, 2-(2-hydroxyanilino)-6-propylpyrimidin-4(3H)-one, 2-(4-hydroxy-2-methylanilino)-6-propylpyrimidin-4(3H)-one, 2-(3-hydroxy-4-methylanilino)-6-propylpyrimidin-4(3H)-one, 3-(2-hydroxyanilino)-1,2,4-triazin-5(4H)-one, 3-(4-hydroxyanilino)-1,2,4-triazin-5(4H)-one, and 2-(2-hydroxyanilino)-3,5,6,7-tetrahydro-4H-cyclopenta[d]pyrimidin-4-one Mycobacterium tuberculosis
[4-[(4-oxo-3,4-dihydroquinazolin-2-yl)amino]phenyl]acetic acid residual activity compared to wild-type enzyme is 37% Mycobacterium tuberculosis
[4-[(5-oxo-4,5-dihydro-1,2,4-triazin-3-yl)amino]phenyl]acetic acid residual activity compared to wild-type enzyme is 72% Mycobacterium tuberculosis
[4-[(6-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-3-yl)amino]phenyl]acetic acid residual activity compared to wild-type enzyme is 71% Mycobacterium tuberculosis

Localization

Localization Comment Organism GeneOntology No. Textmining
cytoplasm
-
Homo sapiens 5737
-

Metals/Ions

Metals/Ions Comment Organism Structure
Mg2+ required Homo sapiens

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
ATP + L-leucine + tRNALeu Homo sapiens
-
AMP + diphosphate + L-leucyl-tRNALeu
-
?

Organism

Organism UniProt Comment Textmining
Homo sapiens Q9P2J5
-
-
Mycobacterium tuberculosis P9WFV1
-
-
Mycobacterium tuberculosis ATCC 25618 / H37Rv P9WFV1
-
-

Purification (Commentary)

Purification (Comment) Organism
recombinant His-tagged enzyme from Escherichia coli strain Rosetta (DE3) by nickel affinity chromatography and dialysis, to homogeneity Homo sapiens
recombinant His-tagged enzyme from Escherichia coli strain Rosetta (DE3) by nickel affinity chromatography and dialysis, to homogeneity Mycobacterium tuberculosis

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
ATP + L-leucine + tRNALeu
-
Homo sapiens AMP + diphosphate + L-leucyl-tRNALeu
-
?

Synonyms

Synonyms Comment Organism
LARS
-
Homo sapiens
Leucyl-tRNA synthetase
-
Homo sapiens
Leucyl-tRNA synthetase
-
Mycobacterium tuberculosis
LeuRS
-
Homo sapiens
LeuRS
-
Mycobacterium tuberculosis
leuS
-
Mycobacterium tuberculosis

Temperature Optimum [°C]

Temperature Optimum [°C] Temperature Optimum Maximum [°C] Comment Organism
37
-
assay at Homo sapiens
37
-
assay at Mycobacterium tuberculosis

pH Optimum

pH Optimum Minimum pH Optimum Maximum Comment Organism
8
-
assay at Homo sapiens
8
-
assay at Mycobacterium tuberculosis

Cofactor

Cofactor Comment Organism Structure
ATP
-
Homo sapiens

General Information

General Information Comment Organism
additional information enzyme structure homology modeling using the structure of Thermus thermophilus LeuRS, PDB ID 2V0C, as template Mycobacterium tuberculosis