1.1.1.3: homoserine dehydrogenase
This is an abbreviated version!
For detailed information about homoserine dehydrogenase, go to the full flat file.
Word Map on EC 1.1.1.3
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1.1.1.3
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l-threonine
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threonine-sensitive
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corynebacterium
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glutamicum
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l-lysine
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semialdehyde
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dihydrodipicolinate
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l-isoleucine
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brevibacterium
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aspartate-derived
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2.7.2.4
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i-homoserine
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rhodospirillum
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lysine-sensitive
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lactofermentum
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feedback-insensitive
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feedback-resistant
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synthesis
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drug development
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agriculture
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pharmacology
- 1.1.1.3
- l-threonine
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threonine-sensitive
- corynebacterium
- glutamicum
- l-lysine
- semialdehyde
- dihydrodipicolinate
- l-isoleucine
- brevibacterium
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aspartate-derived
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2.7.2.4
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i-homoserine
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rhodospirillum
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lysine-sensitive
- lactofermentum
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feedback-insensitive
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feedback-resistant
- synthesis
- drug development
- agriculture
- pharmacology
Reaction
Synonyms
AK-HDH, AK-HSD-1, AK-HSDH, AK-HseDH, aspartate kinase-homoserine dehydrogenase, aspartokinase-homoserine dehydrogenase I, bifunctional aspartate kinase-homoserine dehydrogenase, BsHSD, HDH, hom, hom-1, Hom6, homoserine dehydrogenase 1, homoserine dehydrogenase 2, HSD, HSDH, HseDH, More, orf19.2951, PbHSD, SACOL1362, StHSD, thrA, TM_0547, TTHA0489, TtHSD
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Inhibitors
Inhibitors on EC 1.1.1.3 - homoserine dehydrogenase
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1-[(1S,2S)-2-(bromomethyl)cyclopropyl]-4-[(trifluoromethyl)sulfanyl]benzene
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2,2'-[thiobis[[2-(1,1-dimethylethyl)-5-methyl-4,1-phenylene]oxy]]bis-acetic acid diethyl ester
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4,4'-[1,2-ethanediylbis(thio)]bis[2,6-bis(1-methylpropyl)]-phenol
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4,4'-[1,2-ethanediylbis(thio)]bis[2-(1,1-dimethylethyl)-6-methyl]-phenol
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4-[[[4-(1,1-dimethylethyl)phenyl]thio]methyl]-2,6-bis(1-methylethyl)-phenol
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5-hydroxy-4-oxo-L-norvaline
HONV, the mechanism of antifungal action of HONV dipeptides (determined against Candida albicans strain ATCC 10231 cells in three different growth media) involves uptake by the oligopeptide transport system, subsequent intracellular cleavage by cytosolic peptidases, and inhibition of homoserine dehydrogenase by the released HONV. Chemical synthesis of HONV and construction of HONV dipeptides as potential antifungal agents, overview. Six dipeptides with L-alanine, L-valine, L-norvaline (Nva), L-leucine, L-isoleucine, and L-phenylalanine as the N-terminal residues are obtained, Gly-HONV and D-Leu-HONV are synthesized and evaluated for comparative purposes. Antifungal in vitro activity and MIC values of HONV and its dipeptides, overview. Activity of HONV strongly depends on growth medium composition. Dipeptide (S)-2-N-[(R)-leucyl]amino-5-hydroxy-4-oxopentanoic acid (D-Leu-HONV) is inactive in all growth media. Antifungal activity of the compounds against different Candida species. Lack of activity of HONV-containing dipeptides against the Candida albicans opt1-opt5DELTA ptr2DELTA ptr22DELTA mutant clearly indicates that these compounds are transported to Candida albicans cells by the oligopeptide transport system, most probably by the di-tripeptide permeases Ptr2p and Ptr22, uptake rates into Candida albicans strain ATCC 10231 cells at pH 5.0 and pH 7.0 are determined, the initial uptake velocities are generally higher at pH 5.0 than at pH 7.0
glycyl-5-hydroxy-4-oxo-L-norvaline
i.e. (S)-2-N-glycylamino-5-hydroxy-4-oxopentanoic acid
L-alanyl-5-hydroxy-4-oxo-L-norvaline
i.e. (S)-2-N-[(S)-alanyl]amino-5-hydroxy-4-oxopentanoic acid
L-isoleucyl-5-hydroxy-4-oxo-L-norvaline
i.e. (S)-2-N-[(S)-isoleucyl]amino-5-hydroxy-4-oxopentanoic acid
L-leucyl-5-hydroxy-4-oxo-L-norvaline
i.e. (S)-2-N-[(S)-leucyl]amino-5-hydroxy-4-oxopentanoic acid
L-lysine
allosteric regulation of recombinant engineered homoserine dehydrogenase by nonnatural inhibitor L-lysine
L-norvalyl-5-hydroxy-4-oxo-L-norvaline
i.e. (S)-2-N-[(S)-norvalyl]amino-5-hydroxy-4-oxopentanoic acid
L-phenylalanyl-5-hydroxy-4-oxo-L-norvaline
i.e. (S)-2-N-[(S)-phenylalanyl]amino-5-hydroxy-4-oxopentanoic acid
L-valyl-5-hydroxy-4-oxo-L-norvaline
i.e. (S)-2-N-[(S)-valyl]amino-5-hydroxy-4-oxopentanoic acid
NADH
acts as a competitive inhibitor of NAD+, product inhibition, non-competitive inhibition versus L-homoserine
[2-(1,1-dimethylethyl)-4-[[5-(1,1-dimethylethyl)-4-hydroxy-2-methylphenyl]thio]-5-methylphenoxy]-acetic acid ethyl ester
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competitive to L-aspartate 4-semialdehyde, enzyme binding structure anaysis from crystal structure, overview
MIC value against strain Pb18 is 0.12 mg/ml
MIC value against strain Pb18 is 0.007 mg/ml
L-cysteine
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slight inhibition of chloroplast isozyme, strong inhibition of cytoplasmic isozyme
L-cysteine
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slight inhibition of chloroplast isozyme, strong inhibition of cytoplasmic isozyme
L-cysteine
competitive versus L-homoserine, uncompetitive versus cofactors NAD+ and NADP+. 95% inhibition at 10 mM. The feedback inhibition of StHSD by cysteine occurs through the formation of an enzyme-NAD-cysteine complex. Cysteine situates within the homoserine binding site, formation of a covalent bond between cysteine and the nicotinamide ring. Cysteine interacts with six residues (Gly156, Thr157, Tyr183, Glu185, Asp191, and Lys200) in the StHSD active site, binding structure analysis, overview
strong inhibition of both enzyme activities, aspartate dehydrogenase and aspartate kinase activity, by decreasing the affinity of the enzyme for substrate and cofactors, kinetic effects
L-threonine
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the regulatory domain of the enzyme contains 2 binding sites, interaction with Gln443 leads to inhibition of the aspartate kinase activity and facilitates the binding of a second threonine on Gln524 leading to inhibition of the homoserine dehydrogenase activity, inhibition of the forward reactions
L-threonine
the enzyme activity is subjected to feedback regulation by L-threonine
L-threonine
the natural threonine binding sites of the enzyme are predicted and verified by mutagenesis experiments
L-threonine
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degree of inhibition depends on age of plant; sensitive and insensitive isozymes
L-threonine
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degree of inhibition depends on age of plant; sensitive and insensitive isozymes
L-threonine
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degree of inhibition depends on age of plant; sensitive and insensitive isozymes
NADP+
NADP+ does not act as a cofactor for this enzyme, but as a strong inhibitor of NAD+-dependent oxidation of Hse, evaluation of the factors responsible for the NADP+-mediated inhibition
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feedback inhibition, one isozyme is resistant and another is sensitive to threonine inhibition, 46.9% inhibition at 1 mM, 63.9% at 5 mM
threonine
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the methionine-producing strain contains a deregulated homoserine dehydrogenase that is not sensitive to feedback inhibition as the wild-type enzyme
Zinc273730
MIC value is 0.064. Zinc273730 makes important contacts with Gly215, Tyr216, Thr217, and Glu218
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Lys, Met, and S-2-aminoethyl-L-cysteine do not affect HSDH activity at 1-5 mM
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additional information
the natural threonine binding sites of the enzyme are engineered to a lysine binding pocket. The reengineered enzyme only responds to lysine inhibition but not to threonine
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additional information
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the natural threonine binding sites of the enzyme are engineered to a lysine binding pocket. The reengineered enzyme only responds to lysine inhibition but not to threonine
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additional information
L-homoserine inhibits the activity of aspartokinase encoded by metL
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additional information
enzyme is not inhibited by other aspartate-derived amino acids than threonine
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additional information
enzyme is not inhibited by other aspartate-derived amino acids than threonine
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additional information
enzyme is not inhibited by other aspartate-derived amino acids than threonine
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additional information
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enzyme is not inhibited by other aspartate-derived amino acids than threonine
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additional information
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Thr does not inhibit homoserine dehydrogenase 1
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additional information
molecular docking simulations and inhibitor screening, virtual screening simulations with 187841 molecules purchasable from the Zinc database. 14 molecules are selected and analyzed by the use of absorption, distribution, metabolism, excretion, and toxicity criteria, resulting in four compounds for in vitro assays. Synergistic effects of HS1 and HS2 in combination with itraconazole against Paracoccidioides brasiliensis. Zinc1531037 and Zinc52986906 are not inhibitory
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additional information
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molecular docking simulations and inhibitor screening, virtual screening simulations with 187841 molecules purchasable from the Zinc database. 14 molecules are selected and analyzed by the use of absorption, distribution, metabolism, excretion, and toxicity criteria, resulting in four compounds for in vitro assays. Synergistic effects of HS1 and HS2 in combination with itraconazole against Paracoccidioides brasiliensis. Zinc1531037 and Zinc52986906 are not inhibitory
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additional information
PbHSD inhibitor screening using the Zinc library, molecular dynamics simulations of PbHSD and ligand docking, electrostatic contacts between protein residues and the respective ligand atoms, overview. The selected ligands remain bound to the protein by a common mechanism throughout the simulation. Cytotoxicity evaluation in HeLa and Vero cells
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additional information
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PbHSD inhibitor screening using the Zinc library, molecular dynamics simulations of PbHSD and ligand docking, electrostatic contacts between protein residues and the respective ligand atoms, overview. The selected ligands remain bound to the protein by a common mechanism throughout the simulation. Cytotoxicity evaluation in HeLa and Vero cells
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additional information
molecular docking simulations and inhibitor screening, virtual screening simulations with 187841 molecules purchasable from the Zinc database. 14 Molecules are selected and analyzed by the use of absorption, distribution, metabolism, excretion, and toxicity criteria, resulting in four compounds for in vitro assays. Zinc1531037 and Zinc52986906 are not inhibitory
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additional information
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molecular docking simulations and inhibitor screening, virtual screening simulations with 187841 molecules purchasable from the Zinc database. 14 Molecules are selected and analyzed by the use of absorption, distribution, metabolism, excretion, and toxicity criteria, resulting in four compounds for in vitro assays. Zinc1531037 and Zinc52986906 are not inhibitory
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additional information
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no inhibition by [2-(1,1-dimethylethyl)-4-[[5-(1,1-dimethylethyl)-4-hydroxy-2-methylphenyl]thio]-5-methylphenoxy]-acetic acid and 4-amino-butyric acid 2-tert-butyl-4-(3-tert-butyl-4-hydroxy-phenylsulfanyl)-phenyl ester
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additional information
tHSD is poorly inhibited by less than 5% by 10 mM L-methionine, L-isoleucine, or L-threonine, all of which are final products in the aspartate pathway, and by L-lysine
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additional information
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tHSD is poorly inhibited by less than 5% by 10 mM L-methionine, L-isoleucine, or L-threonine, all of which are final products in the aspartate pathway, and by L-lysine
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additional information
L-homoserine oxidation of the Thermotoga maritima enzyme is almost impervious to inhibition by L-threonine, while L-threonine inhibits AK activity in a cooperative manner. The distinctive sequence of the regulatory domain in Thermotoga maritima AK-HseDH is likely responsible for the unique sensitivity to L-threonine. The quaternary structure of this enzyme is not affected by L-threonine
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additional information
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L-homoserine oxidation of the Thermotoga maritima enzyme is almost impervious to inhibition by L-threonine, while L-threonine inhibits AK activity in a cooperative manner. The distinctive sequence of the regulatory domain in Thermotoga maritima AK-HseDH is likely responsible for the unique sensitivity to L-threonine. The quaternary structure of this enzyme is not affected by L-threonine
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