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Literature summary for 1.1.1.267 extracted from

  • Kesharwani, S.; Sundriyal, S.
    Non-hydroxamate inhibitors of 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) a critical review and future perspective (2021), Eur. J. Med. Chem., 213, 113055 .
    View publication on PubMed

Application

Application Comment Organism
drug development enzyme DXR is an antimicrobial target Escherichia coli
drug development enzyme DXR is an antimicrobial target Plasmodium falciparum
drug development enzyme DXR is an antimicrobial target Mycobacterium tuberculosis

Inhibitors

Inhibitors Comment Organism Structure
(2-[[hydroxy(methyl)carbamoyl]oxy]ethyl)phosphonic acid
-
Escherichia coli
(3-acetamidopropyl)phosphonic acid
-
Escherichia coli
(3-boronopropyl)phosphonic acid MIC90 = 0.053 mg/ml Escherichia coli
(4-hydrazinyl-4-oxobutyl)phosphonic acid
-
Escherichia coli
([[acetyl(hydroxy)amino]methoxy]methyl)phosphonic acid
-
Escherichia coli
([[acetyl(hydroxy)amino]methoxy]methyl)phosphonic acid
-
Plasmodium falciparum
([[formyl(hydroxy)amino]methoxy]methyl)phosphonic acid
-
Escherichia coli
([[formyl(hydroxy)amino]methoxy]methyl)phosphonic acid
-
Plasmodium falciparum
1-hydroxy-5-phenylpyridin-2(1H)-one
-
Escherichia coli
2-[acetyl(hydroxy)amino]ethyl phosphate
-
Escherichia coli
2-[acetyl(hydroxy)amino]ethyl phosphate
-
Mycobacterium tuberculosis
2-[formyl(hydroxy)amino]ethyl phosphate
-
Escherichia coli
2-[formyl(hydroxy)amino]ethyl phosphate
-
Mycobacterium tuberculosis
4-benzylbenzene-1,2-diol
-
Escherichia coli
5-[hydroxy(methyl)amino]-5-oxopentanoic acid
-
Escherichia coli
diethyl (2-[[(furan-2-yl)methyl]amino]-2-oxoethyl)phosphonate
-
Escherichia coli
diethyl [2-(3-hydroxyanilino)-2-oxoethyl]phosphonate 43.9% inhibition at 0.25 mM Escherichia coli
diethyl [2-(3-hydroxyanilino)-2-oxoethyl]phosphonate 45.2% inhibition at 0.25 mM Plasmodium falciparum
diethyl [2-oxo-2-[(1,3-thiazol-2-yl)amino]ethyl]phosphonate
-
Escherichia coli
diethyl [2-oxo-2-[(pyridin-2-yl)amino]ethyl]phosphonate
-
Escherichia coli
diethyl [2-[3-(hydroxymethyl)anilino]-2-oxoethyl]phosphonate 40.4% inhibition at 0.25 mM Escherichia coli
diethyl [2-[3-(hydroxymethyl)anilino]-2-oxoethyl]phosphonate 40.7% inhibition at 0.25 mM Plasmodium falciparum
diethyl [3-(3-hydroxyanilino)-3-oxopropyl]phosphonate 49.2% inhibition at 0.25 mM Escherichia coli
diethyl [3-[3-(hydroxymethyl)anilino]-3-oxopropyl]phosphonate 17.9% inhibition at 0.25 mM Escherichia coli
fosmidomycin a natural product, which forms a chelate with the active site divalent metal ion (Mg2+/Mn2+) through its hydroxamate metal-binding group. Competitive versus 1-deoxy-D-xylulose 5-phosphate, uncompetitive versus NADPH, strong inhibition Escherichia coli
fosmidomycin a natural product, which forms a chelate with the active site divalent metal ion (Mg2+/Mn2+) through its hydroxamate metal-binding group. Competitive versus 1-deoxy-D-xylulose 5-phosphate, uncompetitive versus NADPH Mycobacterium tuberculosis
fosmidomycin a natural product, which forms a chelate with the active site divalent metal ion (Mg2+/Mn2+) through its hydroxamate metal-binding group. Competitive versus 1-deoxy-D-xylulose 5-phosphate, uncompetitive versus NADPH. No or poor inhibition by diethyl [3-[3-(hydroxymethyl)anilino]-3-oxopropyl]phosphonate, diethyl [3-(3-hydroxyanilino)-3-oxopropyl]phosphonate, and [3-(3-methoxyanilino)-3-oxopropyl]phosphonic acid Plasmodium falciparum
FR-900098
-
Escherichia coli
FR-900098
-
Mycobacterium tuberculosis
FR-900098
-
Plasmodium falciparum
additional information non-hydroxamate inhibitors of 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR), docking study, structure-activity analysis, overview. No inhibiton at 0.02 mM by [3-(3-methoxyanilino)-3-oxopropyl]phosphonic acid or [3-[benzyl(pyridin-2-yl)amino]-3-oxopropyl]phosphonic acid or [3-[benzyl(3-hydroxyphenyl)amino]-3-oxopropyl]phosphonic acid or [2-[(sulfanylcarbonothioyl)amino]ethyl]phosphonic acid or [3-[(sulfanylcarbonothioyl)amino]propyl]phosphonic acid or [3-(2,3-dihydroxyphenyl)propyl]phosphonic acid Escherichia coli
additional information non-hydroxamate inhibitors of 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR), docking study, structure-activity analysis, overview Mycobacterium tuberculosis
additional information non-hydroxamate inhibitors of 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR), docking study, structure-activity analysis, overview Plasmodium falciparum
[(3,4-dichlorophenyl)([2-[hydroxy(methyl)amino]-2-oxoethyl]sulfanyl)methyl]phosphonic acid
-
Escherichia coli
[(3,4-dichlorophenyl)([2-[hydroxy(methyl)amino]-2-oxoethyl]sulfanyl)methyl]phosphonic acid
-
Mycobacterium tuberculosis
[(3,4-dichlorophenyl)([2-[hydroxy(methyl)amino]-2-oxoethyl]sulfanyl)methyl]phosphonic acid
-
Plasmodium falciparum
[(5-phenylpyridin-2-yl)methyl]phosphonic acid
-
Escherichia coli
[(quinolin-2-yl)methyl]phosphonic acid
-
Escherichia coli
[1,1'-biphenyl]-3,4-diol
-
Escherichia coli
[1-(3,4-dichlorophenyl)-3-[formyl(hydroxy)amino]propyl]phosphonic acid
-
Escherichia coli
[1-(3,4-dichlorophenyl)-3-[formyl(hydroxy)amino]propyl]phosphonic acid conformation of inhibitor within the MtDXR active site (PDB ID 2Y1D) Mycobacterium tuberculosis
[1-(3,4-dichlorophenyl)-3-[formyl(hydroxy)amino]propyl]phosphonic acid inhibition of strain D2d Plasmodium falciparum
[2-(1-hydroxy-6-oxo-1,6-dihydropyridin-2-yl)ethyl]phosphonic acid
-
Mycobacterium tuberculosis
[2-(2,3-dihydroxyphenyl)ethyl]phosphonic acid
-
Escherichia coli
[2-(3-hydroxy-4-methylphenyl)ethyl]phosphonic acid
-
Mycobacterium tuberculosis
[2-(3-methoxyanilino)-2-oxoethyl]phosphonic acid 17.8% inhibition at 0.25 mM Escherichia coli
[2-[(hydroxycarbamoyl)oxy]ethyl]phosphonic acid
-
Escherichia coli
[2-[acetyl(hydroxy)amino]ethyl]phosphonic acid 74% inhibition at 0.1 mM Mycobacterium tuberculosis
[3-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)propyl]phosphonic acid MIC90 = 0.063 mg/ml Escherichia coli
[3-oxo-3-[(prop-2-yn-1-yl)amino]propyl]phosphonic acid 6.7% inhibition at 0.020 mM Escherichia coli
[3-[acetyl(hydroxy)amino]-1-(3,4-dichlorophenyl)propyl]phosphonic acid
-
Escherichia coli
[3-[acetyl(hydroxy)amino]-1-(3,4-dichlorophenyl)propyl]phosphonic acid inhibition of strain D2d Plasmodium falciparum
[4-(2-acetylanilino)-4-oxobutyl]phosphonic acid
-
Plasmodium falciparum
[4-(2-fluoroanilino)-4-oxobutyl]phosphonic acid
-
Plasmodium falciparum
[4-(hydroxyamino)-4-oxobutyl]phosphonic acid
-
Escherichia coli
[4-(methoxyamino)-4-oxobutyl]phosphonic acid
-
Escherichia coli
[4-[2-(methanesulfonyl)anilino]-4-oxobutyl]phosphonic acid
-
Plasmodium falciparum
[4-[acetyl(hydroxy)amino]butyl]phosphonic acid 80% inhibition at 0.1 mM Mycobacterium tuberculosis
[4-[hydroxy(methyl)amino]-4-oxobutyl]phosphonic acid
-
Escherichia coli
[4-[methoxy(methyl)amino]-4-oxobutyl]phosphonic acid
-
Escherichia coli
[[(isoquinolin-1-yl)amino]methylene]bis(phosphonic acid)
-
Escherichia coli

Metals/Ions

Metals/Ions Comment Organism Structure
Mg2+ active site divalent metal ion Escherichia coli
Mg2+ active site divalent metal ion Plasmodium falciparum
Mg2+ active site divalent metal ion Mycobacterium tuberculosis
Mn2+ active site divalent metal ion Escherichia coli
Mn2+ active site divalent metal ion Plasmodium falciparum
Mn2+ active site divalent metal ion Mycobacterium tuberculosis

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
1-deoxy-D-xylulose 5-phosphate + NADPH + H+ Escherichia coli
-
2-C-methyl-D-erythritol 4-phosphate + NADP+
-
?
1-deoxy-D-xylulose 5-phosphate + NADPH + H+ Plasmodium falciparum
-
2-C-methyl-D-erythritol 4-phosphate + NADP+
-
?
1-deoxy-D-xylulose 5-phosphate + NADPH + H+ Mycobacterium tuberculosis
-
2-C-methyl-D-erythritol 4-phosphate + NADP+
-
?
1-deoxy-D-xylulose 5-phosphate + NADPH + H+ Mycobacterium tuberculosis H37Rv
-
2-C-methyl-D-erythritol 4-phosphate + NADP+
-
?
1-deoxy-D-xylulose 5-phosphate + NADPH + H+ Mycobacterium tuberculosis ATCC 25618
-
2-C-methyl-D-erythritol 4-phosphate + NADP+
-
?

Organism

Organism UniProt Comment Textmining
Escherichia coli P45568
-
-
Mycobacterium tuberculosis P9WNS1
-
-
Mycobacterium tuberculosis ATCC 25618 P9WNS1
-
-
Mycobacterium tuberculosis H37Rv P9WNS1
-
-
Plasmodium falciparum Q8IKG4
-
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
1-deoxy-D-xylulose 5-phosphate + NADPH + H+
-
Escherichia coli 2-C-methyl-D-erythritol 4-phosphate + NADP+
-
?
1-deoxy-D-xylulose 5-phosphate + NADPH + H+
-
Plasmodium falciparum 2-C-methyl-D-erythritol 4-phosphate + NADP+
-
?
1-deoxy-D-xylulose 5-phosphate + NADPH + H+
-
Mycobacterium tuberculosis 2-C-methyl-D-erythritol 4-phosphate + NADP+
-
?
1-deoxy-D-xylulose 5-phosphate + NADPH + H+
-
Mycobacterium tuberculosis H37Rv 2-C-methyl-D-erythritol 4-phosphate + NADP+
-
?
1-deoxy-D-xylulose 5-phosphate + NADPH + H+
-
Mycobacterium tuberculosis ATCC 25618 2-C-methyl-D-erythritol 4-phosphate + NADP+
-
?

Synonyms

Synonyms Comment Organism
1-deoxy-D-xylulose 5-phosphate reductoisomerase
-
Escherichia coli
1-deoxy-D-xylulose 5-phosphate reductoisomerase
-
Plasmodium falciparum
1-deoxy-D-xylulose 5-phosphate reductoisomerase
-
Mycobacterium tuberculosis
DXR
-
Escherichia coli
DXR
-
Plasmodium falciparum
DXR
-
Mycobacterium tuberculosis
EcDXR
-
Escherichia coli
MtDXR
-
Mycobacterium tuberculosis
PfDXR
-
Plasmodium falciparum

Cofactor

Cofactor Comment Organism Structure
NADP+
-
Escherichia coli
NADP+
-
Plasmodium falciparum
NADP+
-
Mycobacterium tuberculosis
NADPH
-
Escherichia coli
NADPH
-
Plasmodium falciparum
NADPH
-
Mycobacterium tuberculosis

Ki Value [mM]

Ki Value [mM] Ki Value maximum [mM] Inhibitor Comment Organism Structure
6.5
-
(3-acetamidopropyl)phosphonic acid pH and temperature not specified in the publication Escherichia coli

IC50 Value

IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
0.0000045
-
pH and temperature not specified in the publication Plasmodium falciparum [(3,4-dichlorophenyl)([2-[hydroxy(methyl)amino]-2-oxoethyl]sulfanyl)methyl]phosphonic acid
0.0000059
-
pH and temperature not specified in the publication Escherichia coli [(3,4-dichlorophenyl)([2-[hydroxy(methyl)amino]-2-oxoethyl]sulfanyl)methyl]phosphonic acid
0.000008
-
pH and temperature not specified in the publication Escherichia coli fosmidomycin
0.0000092
-
pH and temperature not specified in the publication Mycobacterium tuberculosis [(3,4-dichlorophenyl)([2-[hydroxy(methyl)amino]-2-oxoethyl]sulfanyl)methyl]phosphonic acid
0.000018
-
pH and temperature not specified in the publication Plasmodium falciparum FR-900098
0.000028
-
pH and temperature not specified in the publication Plasmodium falciparum [1-(3,4-dichlorophenyl)-3-[formyl(hydroxy)amino]propyl]phosphonic acid
0.00003
-
pH and temperature not specified in the publication Escherichia coli FR-900098
0.000036
-
pH and temperature not specified in the publication Plasmodium falciparum fosmidomycin
0.000048
-
pH and temperature not specified in the publication Escherichia coli [4-[hydroxy(methyl)amino]-4-oxobutyl]phosphonic acid
0.000059
-
pH and temperature not specified in the publication Escherichia coli [1-(3,4-dichlorophenyl)-3-[formyl(hydroxy)amino]propyl]phosphonic acid
0.000077
-
pH and temperature not specified in the publication Escherichia coli 2-[acetyl(hydroxy)amino]ethyl phosphate
0.00008
-
pH and temperature not specified in the publication Mycobacterium tuberculosis fosmidomycin
0.000087
-
pH and temperature not specified in the publication Escherichia coli ([[acetyl(hydroxy)amino]methoxy]methyl)phosphonic acid
0.00009
-
pH and temperature not specified in the publication Plasmodium falciparum [3-[acetyl(hydroxy)amino]-1-(3,4-dichlorophenyl)propyl]phosphonic acid
0.000119
-
pH and temperature not specified in the publication Escherichia coli [3-[acetyl(hydroxy)amino]-1-(3,4-dichlorophenyl)propyl]phosphonic acid
0.00016
-
pH and temperature not specified in the publication Mycobacterium tuberculosis FR-900098
0.00017
-
pH and temperature not specified in the publication Escherichia coli [4-(hydroxyamino)-4-oxobutyl]phosphonic acid
0.000279
-
pH and temperature not specified in the publication Mycobacterium tuberculosis 2-[acetyl(hydroxy)amino]ethyl phosphate
0.000342
-
pH and temperature not specified in the publication Escherichia coli 2-[formyl(hydroxy)amino]ethyl phosphate
0.00036
-
pH and temperature not specified in the publication Plasmodium falciparum ([[acetyl(hydroxy)amino]methoxy]methyl)phosphonic acid
0.00084
-
pH and temperature not specified in the publication Escherichia coli [(5-phenylpyridin-2-yl)methyl]phosphonic acid
0.0011
-
pH and temperature not specified in the publication Escherichia coli ([[formyl(hydroxy)amino]methoxy]methyl)phosphonic acid
0.0014
-
pH and temperature not specified in the publication Escherichia coli 1-hydroxy-5-phenylpyridin-2(1H)-one
0.0021
-
pH and temperature not specified in the publication Mycobacterium tuberculosis 2-[formyl(hydroxy)amino]ethyl phosphate
0.003
-
above, pH and temperature not specified in the publication Escherichia coli (2-[[hydroxy(methyl)carbamoyl]oxy]ethyl)phosphonic acid
0.003
-
above, pH and temperature not specified in the publication Escherichia coli [2-[(hydroxycarbamoyl)oxy]ethyl]phosphonic acid
0.004
-
pH and temperature not specified in the publication Escherichia coli [[(isoquinolin-1-yl)amino]methylene]bis(phosphonic acid)
0.0049
-
pH and temperature not specified in the publication Plasmodium falciparum ([[formyl(hydroxy)amino]methoxy]methyl)phosphonic acid
0.0159
-
pH and temperature not specified in the publication Escherichia coli [(quinolin-2-yl)methyl]phosphonic acid
0.0224
-
pH and temperature not specified in the publication Escherichia coli 4-benzylbenzene-1,2-diol
0.025
-
pH and temperature not specified in the publication Escherichia coli 5-[hydroxy(methyl)amino]-5-oxopentanoic acid
0.041
-
pH and temperature not specified in the publication Mycobacterium tuberculosis [2-(3-hydroxy-4-methylphenyl)ethyl]phosphonic acid
0.0447
-
pH and temperature not specified in the publication Escherichia coli [1,1'-biphenyl]-3,4-diol
0.053
-
pH and temperature not specified in the publication Mycobacterium tuberculosis [2-(1-hydroxy-6-oxo-1,6-dihydropyridin-2-yl)ethyl]phosphonic acid
0.064
-
above, pH and temperature not specified in the publication Plasmodium falciparum [4-(2-acetylanilino)-4-oxobutyl]phosphonic acid
0.064
-
above, pH and temperature not specified in the publication Plasmodium falciparum [4-(2-fluoroanilino)-4-oxobutyl]phosphonic acid
0.064
-
above, pH and temperature not specified in the publication Plasmodium falciparum [4-[2-(methanesulfonyl)anilino]-4-oxobutyl]phosphonic acid
0.408
-
pH and temperature not specified in the publication Escherichia coli diethyl (2-[[(furan-2-yl)methyl]amino]-2-oxoethyl)phosphonate
0.472
-
pH and temperature not specified in the publication Escherichia coli diethyl [2-oxo-2-[(pyridin-2-yl)amino]ethyl]phosphonate
0.73
-
pH and temperature not specified in the publication Escherichia coli diethyl [2-oxo-2-[(1,3-thiazol-2-yl)amino]ethyl]phosphonate
0.93
-
pH and temperature not specified in the publication Escherichia coli [4-(methoxyamino)-4-oxobutyl]phosphonic acid
1
-
pH and temperature not specified in the publication Escherichia coli (4-hydrazinyl-4-oxobutyl)phosphonic acid
1.2
-
pH and temperature not specified in the publication Escherichia coli [2-(2,3-dihydroxyphenyl)ethyl]phosphonic acid
3.8
-
pH and temperature not specified in the publication Escherichia coli [4-[methoxy(methyl)amino]-4-oxobutyl]phosphonic acid

General Information

General Information Comment Organism
malfunction DXR is essential for the survival of the pathogen, and its inhibition leads to the antimalarial action Plasmodium falciparum
malfunction DXR is essential for the survival of the pathogen, and its inhibition leads to the antitubercular action Mycobacterium tuberculosis
metabolism 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR) catalyzes the second step of the nonmevalonate (or MEP) pathway that functions in several organisms and plants for the synthesis of isoprenoids Escherichia coli
metabolism 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR) catalyzes the second step of the nonmevalonate (or MEP) pathway that functions in several organisms and plants for the synthesis of isoprenoids Plasmodium falciparum
metabolism 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR) catalyzes the second step of the nonmevalonate (or MEP) pathway that functions in several organisms and plants for the synthesis of isoprenoids Mycobacterium tuberculosis
physiological function DXR is essential for the survival of multiple pathogenic bacteria/parasites Escherichia coli
physiological function DXR is essential for the survival of multiple pathogenic bacteria/parasites, including those that cause tuberculosis and malaria in humans Plasmodium falciparum
physiological function DXR is essential for the survival of multiple pathogenic bacteria/parasites, including those that cause tuberculosis and malaria in humans Mycobacterium tuberculosis