BRENDA - Enzyme Database
show all sequences of 5.4.4.2

Stereocontrolled synthesis of a potential transition-state inhibitor of the salicylate synthase MbtI from Mycobacterium tuberculosis

Liu, Z.; Liu, F.; Aldrich, C.C.; J. Org. Chem. 80, 6545-6552 (2015)

Data extracted from this reference:

Application
Application
Commentary
Organism
drug development
enzyme MbtI represents an appealing target for development of inhibitors of mycobactin biosynthesis since it is structurally and biochemically characterized, has no human orthologues, and is conditionally essential under iron-deficient conditions. Inhibitors are designed against the isochorismatase activity of the enzyme (EC 5.4.4.2)
Mycobacterium tuberculosis
Inhibitors
Inhibitors
Commentary
Organism
Structure
(4R,5S,6R)-4-amino-5-(2-carboxyethyl)-6-hydroxycyclohex-1-ene carboxylic acid
transition-state inhibitor
Mycobacterium tuberculosis
(4R,5S,6R)-4-amino-5-(2-carboxyethyl)-6-hydroxycyclohex-1-ene-1-carboxylic acid
-
Mycobacterium tuberculosis
(E)-1-(tert-butyldimethylsilyloxy)-1,3-butadiene
-
Mycobacterium tuberculosis
3-[[(1Z)-1-carboxyprop-1-en-1-yl]oxy]-2-hydroxybenzoic acid
-
Mycobacterium tuberculosis
benzimidazole-2-thione
noncompetitive inhibitor with
Mycobacterium tuberculosis
additional information
design, synthesis and biochemical evaluation of inhibitor 4 based on the putative transition-state (TS) for the isochorismatase partial reaction of MbtI. The inhibitor mimics the hypothesized charge build-up at C-4 of chorismate in the TS as well as C-O bond-formation at C-6. Another important design element of the inhibitor is replacement of the labile pyruvate side-chain in chorismate with a stable C-linked propionate isostere. Development of a stereocontrolled synthesis of the highly functionalized cyclohexene inhibitor that features an asymmetric aldol reaction using a titanium enolate, diastereoselective Grignard addition to a tert-butanesulfinyl aldimine, and ring closing olefin metathesis as key steps
Mycobacterium tuberculosis
oseltamivir
i.e. Tamiflu
Mycobacterium tuberculosis
Metals/Ions
Metals/Ions
Commentary
Organism
Structure
Mg2+
required
Mycobacterium tuberculosis
Natural Substrates/ Products (Substrates)
Natural Substrates
Organism
Commentary (Nat. Sub.)
Natural Products
Commentary (Nat. Pro.)
Organism (Nat. Pro.)
Reversibility
Chorismate
Mycobacterium tuberculosis
-
Isochorismate
-
-
r
Organism
Organism
Primary Accession No. (UniProt)
Commentary
Textmining
Mycobacterium tuberculosis
-
-
-
Reaction
Reaction
Commentary
Organism
chorismate = isochorismate
overall reaction, salicylate sythase converts chorismate into salicylate via an isochorismate intermediate. The isochorismatase activity of bifunctional enzyme MbtI requires Lys205, which nucleophilically activates a water molecule for attack on chorismate at C-6 and Glu252 that polarizes the C-4 hydroxyl-leaving group
Mycobacterium tuberculosis
Substrates and Products (Substrate)
Substrates
Commentary Substrates
Literature (Substrates)
Organism
Products
Commentary (Products)
Literature (Products)
Organism (Products)
Reversibility
Chorismate
-
748448
Mycobacterium tuberculosis
Isochorismate
-
-
-
r
additional information
the bifunctional salicylate synthase converts chorismate into salicylate through a two-step reaction, exhibiting both isochorismate synthase (EC 5.4.4.2) and isochorismate lyase (EC 4.2.99.21) activities
748448
Mycobacterium tuberculosis
?
-
-
-
-
Temperature Optimum [°C]
Temperature Optimum [°C]
Temperature Optimum Maximum [°C]
Commentary
Organism
37
-
assay at
Mycobacterium tuberculosis
pH Optimum
pH Optimum Minimum
pH Optimum Maximum
Commentary
Organism
8
-
assay at
Mycobacterium tuberculosis
Ki Value [mM]
Ki Value [mM]
Ki Value maximum [mM]
Inhibitor
Commentary
Organism
Structure
0.0092
-
benzimidazole-2-thione
pH 8.0, 37°C
Mycobacterium tuberculosis
0.011
-
3-[[(1Z)-1-carboxyprop-1-en-1-yl]oxy]-2-hydroxybenzoic acid
pH 8.0, 37°C
Mycobacterium tuberculosis
0.1
-
(4R,5S,6R)-4-amino-5-(2-carboxyethyl)-6-hydroxycyclohex-1-ene-1-carboxylic acid
pH 8.0, 37°C
Mycobacterium tuberculosis
Application (protein specific)
Application
Commentary
Organism
drug development
enzyme MbtI represents an appealing target for development of inhibitors of mycobactin biosynthesis since it is structurally and biochemically characterized, has no human orthologues, and is conditionally essential under iron-deficient conditions. Inhibitors are designed against the isochorismatase activity of the enzyme (EC 5.4.4.2)
Mycobacterium tuberculosis
Inhibitors (protein specific)
Inhibitors
Commentary
Organism
Structure
(4R,5S,6R)-4-amino-5-(2-carboxyethyl)-6-hydroxycyclohex-1-ene carboxylic acid
transition-state inhibitor
Mycobacterium tuberculosis
(4R,5S,6R)-4-amino-5-(2-carboxyethyl)-6-hydroxycyclohex-1-ene-1-carboxylic acid
-
Mycobacterium tuberculosis
(E)-1-(tert-butyldimethylsilyloxy)-1,3-butadiene
-
Mycobacterium tuberculosis
3-[[(1Z)-1-carboxyprop-1-en-1-yl]oxy]-2-hydroxybenzoic acid
-
Mycobacterium tuberculosis
benzimidazole-2-thione
noncompetitive inhibitor with
Mycobacterium tuberculosis
additional information
design, synthesis and biochemical evaluation of inhibitor 4 based on the putative transition-state (TS) for the isochorismatase partial reaction of MbtI. The inhibitor mimics the hypothesized charge build-up at C-4 of chorismate in the TS as well as C-O bond-formation at C-6. Another important design element of the inhibitor is replacement of the labile pyruvate side-chain in chorismate with a stable C-linked propionate isostere. Development of a stereocontrolled synthesis of the highly functionalized cyclohexene inhibitor that features an asymmetric aldol reaction using a titanium enolate, diastereoselective Grignard addition to a tert-butanesulfinyl aldimine, and ring closing olefin metathesis as key steps
Mycobacterium tuberculosis
oseltamivir
i.e. Tamiflu
Mycobacterium tuberculosis
Ki Value [mM] (protein specific)
Ki Value [mM]
Ki Value maximum [mM]
Inhibitor
Commentary
Organism
Structure
0.0092
-
benzimidazole-2-thione
pH 8.0, 37°C
Mycobacterium tuberculosis
0.011
-
3-[[(1Z)-1-carboxyprop-1-en-1-yl]oxy]-2-hydroxybenzoic acid
pH 8.0, 37°C
Mycobacterium tuberculosis
0.1
-
(4R,5S,6R)-4-amino-5-(2-carboxyethyl)-6-hydroxycyclohex-1-ene-1-carboxylic acid
pH 8.0, 37°C
Mycobacterium tuberculosis
Metals/Ions (protein specific)
Metals/Ions
Commentary
Organism
Structure
Mg2+
required
Mycobacterium tuberculosis
Natural Substrates/ Products (Substrates) (protein specific)
Natural Substrates
Organism
Commentary (Nat. Sub.)
Natural Products
Commentary (Nat. Pro.)
Organism (Nat. Pro.)
Reversibility
Chorismate
Mycobacterium tuberculosis
-
Isochorismate
-
-
r
Substrates and Products (Substrate) (protein specific)
Substrates
Commentary Substrates
Literature (Substrates)
Organism
Products
Commentary (Products)
Literature (Products)
Organism (Products)
Reversibility
Chorismate
-
748448
Mycobacterium tuberculosis
Isochorismate
-
-
-
r
additional information
the bifunctional salicylate synthase converts chorismate into salicylate through a two-step reaction, exhibiting both isochorismate synthase (EC 5.4.4.2) and isochorismate lyase (EC 4.2.99.21) activities
748448
Mycobacterium tuberculosis
?
-
-
-
-
Temperature Optimum [°C] (protein specific)
Temperature Optimum [°C]
Temperature Optimum Maximum [°C]
Commentary
Organism
37
-
assay at
Mycobacterium tuberculosis
pH Optimum (protein specific)
pH Optimum Minimum
pH Optimum Maximum
Commentary
Organism
8
-
assay at
Mycobacterium tuberculosis
General Information
General Information
Commentary
Organism
metabolism
the bifunctional salicylate synthase converts chorismate into salicylate through a two-step reaction, exhibiting both isochorismate synthase (EC 5.4.4.2) and isochorismate lyase (EC 4.2.99.21) activities
Mycobacterium tuberculosis
physiological function
mycobactins are small-molecule iron chelators (siderophores) produced by Mycobacterium tuberculosis (Mtb) for iron mobilization. Siderophores are small-molecule iron chelators that scavenge iron from host tissues and uptake of heme through a specialized heme receptor followed by heme degradation to release the iron. The bifunctional salicylate synthase MbtI catalyzes the first step of mycobactin biosynthesis through the conversion of the primary metabolite chorismate into salicylic acid via isochorismate
Mycobacterium tuberculosis
General Information (protein specific)
General Information
Commentary
Organism
metabolism
the bifunctional salicylate synthase converts chorismate into salicylate through a two-step reaction, exhibiting both isochorismate synthase (EC 5.4.4.2) and isochorismate lyase (EC 4.2.99.21) activities
Mycobacterium tuberculosis
physiological function
mycobactins are small-molecule iron chelators (siderophores) produced by Mycobacterium tuberculosis (Mtb) for iron mobilization. Siderophores are small-molecule iron chelators that scavenge iron from host tissues and uptake of heme through a specialized heme receptor followed by heme degradation to release the iron. The bifunctional salicylate synthase MbtI catalyzes the first step of mycobactin biosynthesis through the conversion of the primary metabolite chorismate into salicylic acid via isochorismate
Mycobacterium tuberculosis
Other publictions for EC 5.4.4.2
No.
1st author
Pub Med
title
organims
journal
volume
pages
year
Activating Compound
Application
Cloned(Commentary)
Crystallization (Commentary)
Engineering
General Stability
Inhibitors
KM Value [mM]
Localization
Metals/Ions
Molecular Weight [Da]
Natural Substrates/ Products (Substrates)
Organic Solvent Stability
Organism
Oxidation Stability
Posttranslational Modification
Purification (Commentary)
Reaction
Renatured (Commentary)
Source Tissue
Specific Activity [micromol/min/mg]
Storage Stability
Substrates and Products (Substrate)
Subunits
Temperature Optimum [°C]
Temperature Range [°C]
Temperature Stability [°C]
Turnover Number [1/s]
pH Optimum
pH Range
pH Stability
Cofactor
Ki Value [mM]
pI Value
IC50 Value
Activating Compound (protein specific)
Application (protein specific)
Cloned(Commentary) (protein specific)
Cofactor (protein specific)
Crystallization (Commentary) (protein specific)
Engineering (protein specific)
General Stability (protein specific)
IC50 Value (protein specific)
Inhibitors (protein specific)
Ki Value [mM] (protein specific)
KM Value [mM] (protein specific)
Localization (protein specific)
Metals/Ions (protein specific)
Molecular Weight [Da] (protein specific)
Natural Substrates/ Products (Substrates) (protein specific)
Organic Solvent Stability (protein specific)
Oxidation Stability (protein specific)
Posttranslational Modification (protein specific)
Purification (Commentary) (protein specific)
Renatured (Commentary) (protein specific)
Source Tissue (protein specific)
Specific Activity [micromol/min/mg] (protein specific)
Storage Stability (protein specific)
Substrates and Products (Substrate) (protein specific)
Subunits (protein specific)
Temperature Optimum [°C] (protein specific)
Temperature Range [°C] (protein specific)
Temperature Stability [°C] (protein specific)
Turnover Number [1/s] (protein specific)
pH Optimum (protein specific)
pH Range (protein specific)
pH Stability (protein specific)
pI Value (protein specific)
Expression
General Information
General Information (protein specific)
Expression (protein specific)
KCat/KM [mM/s]
KCat/KM [mM/s] (protein specific)
749121
Su
Endogenous salicylic acid sho ...
Scutellaria baicalensis
PLoS ONE
13
e0192114
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747030
Macaulay
The biochemical properties of ...
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Biochem. J.
474
1579-1590
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8
2
2
2
747617
Svarcova
Investigation of potential in ...
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Curr. Med. Chem.
22
1383-1399
2015
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748448
Liu
Stereocontrolled synthesis of ...
Mycobacterium tuberculosis
J. Org. Chem.
80
6545-6552
2015
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748946
Wang
TCP transcription factors are ...
Arabidopsis thaliana, Arabidopsis thaliana Col-0
Plant J.
82
151-162
2015
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748944
Villajuana-Bonequi
Elevated salicylic acid level ...
Arabidopsis thaliana
Plant J.
79
206-219
2014
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726636
Domagalski
Structure of isochorismate syn ...
Bacillus anthracis, Bacillus anthracis Ames
Acta Crystallogr. Sect. F
69
956-961
2013
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726817
Meneely
Lysine221 is the general base ...
Pseudomonas aeruginosa
Arch. Biochem. Biophys.
538
49-56
2013
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4
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1
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2
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4
4
728058
Gawronski
Isochorismate synthase 1 is re ...
Arabidopsis thaliana, Arabidopsis thaliana Col-0
J. Exp. Bot.
64
3669-3679
2013
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728533
Sadeghi
Isolation and characterization ...
Carthamus tinctorius
Plant Signal. Behav.
8
e27335 1-9
2013
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726963
Lamb
Pericyclic reactions catalyzed ...
Pseudomonas aeruginosa
Biochemistry
50
7476-7483
2011
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705184
Sridharan
Crystal structure of Escherich ...
Escherichia coli
J. Mol. Biol.
397
290-300
2010
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14
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705370
Zhang
Nuclear localization of NPR1 i ...
Arabidopsis thaliana
J. Plant Physiol.
167
144-148
2010
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716034
Simoh
Metabolic changes of Brassica ...
Escherichia coli
J. Plant Physiol.
167
1525-1532
2010
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706037
Payne
Synthesis and evaluation of 2, ...
Escherichia coli
Org. Biomol. Chem.
7
2421-2429
2009
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706530
Yuan
Alternative splicing and gene ...
Arabidopsis thaliana, Populus fremontii x Populus angustifolia, Populus tremuloides
Proc. Natl. Acad. Sci. USA
106
22020-22025
2009
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3
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690238
Parsons
Structure of isochorismate syn ...
Escherichia coli
Acta Crystallogr. Sect. D
64
607-610
2008
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