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Literature summary extracted from
- Stereocontrolled synthesis of a potential transition-state inhibitor of the salicylate synthase MbtI from Mycobacterium tuberculosis (2015), J. Org. Chem., 80, 6545-6552 .
Application
| EC Number | Application | Comment | Organism |
|---|---|---|---|
| 4.2.99.21 | 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 |
| 5.4.4.2 | 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
| EC Number | Inhibitors | Comment | Organism | Structure |
|---|---|---|---|---|
| 5.4.4.2 | (4R,5S,6R)-4-amino-5-(2-carboxyethyl)-6-hydroxycyclohex-1-ene carboxylic acid | transition-state inhibitor | Mycobacterium tuberculosis |  |
| 5.4.4.2 | (4R,5S,6R)-4-amino-5-(2-carboxyethyl)-6-hydroxycyclohex-1-ene-1-carboxylic acid | - |
Mycobacterium tuberculosis | |
| 5.4.4.2 | (E)-1-(tert-butyldimethylsilyloxy)-1,3-butadiene | - |
Mycobacterium tuberculosis | |
| 5.4.4.2 | 3-[[(1Z)-1-carboxyprop-1-en-1-yl]oxy]-2-hydroxybenzoic acid | - |
Mycobacterium tuberculosis | |
| 5.4.4.2 | benzimidazole-2-thione | noncompetitive inhibitor with | Mycobacterium tuberculosis | |
| 5.4.4.2 | 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 | |
| 5.4.4.2 | oseltamivir | i.e. Tamiflu | Mycobacterium tuberculosis | |
Metals/Ions
| EC Number | Metals/Ions | Comment | Organism | Structure |
|---|---|---|---|---|
| 4.2.99.21 | Mg2+ | required | Mycobacterium tuberculosis | |
| 5.4.4.2 | Mg2+ | required | Mycobacterium tuberculosis | |
Natural Substrates/ Products (Substrates)
| EC Number | Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
|---|---|---|---|---|---|---|---|
| 4.2.99.21 | isochorismate | Mycobacterium tuberculosis | - |
salicylate + pyruvate | - |
? | |
| 4.2.99.21 | isochorismate | Mycobacterium tuberculosis ATCC 25618 | - |
salicylate + pyruvate | - |
? | |
| 5.4.4.2 | Chorismate | Mycobacterium tuberculosis | - |
Isochorismate | - |
r | |
Organism
| EC Number | Organism | UniProt | Comment | Textmining |
|---|---|---|---|---|
| 4.2.99.21 | Mycobacterium tuberculosis | P9WFX1 | - |
- |
| 4.2.99.21 | Mycobacterium tuberculosis ATCC 25618 | P9WFX1 | - |
- |
| 5.4.4.2 | Mycobacterium tuberculosis | - |
- |
- |
Reaction
| EC Number | Reaction | Comment | Organism | Reaction ID |
|---|---|---|---|---|
| 4.2.99.21 | isochorismate = salicylate + pyruvate | overall reaction, salicylate sythase converts chorismate into salicylate via an isochorismate intermediate. In the second reaction, pyruvate is eliminated through an intramolecular [3,3]-sigmatropic rearrangement, formerly a retro-Ene reaction, to afford salicylic acid via bicyclic transition state TS2 | Mycobacterium tuberculosis | |
| 5.4.4.2 | 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)
| EC Number | Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
|---|---|---|---|---|---|---|---|
| 4.2.99.21 | isochorismate | - |
Mycobacterium tuberculosis | salicylate + pyruvate | - |
? | |
| 4.2.99.21 | isochorismate | - |
Mycobacterium tuberculosis ATCC 25618 | salicylate + pyruvate | - |
? | |
| 4.2.99.21 | 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 | Mycobacterium tuberculosis | ? | - |
? | |
| 4.2.99.21 | 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 | Mycobacterium tuberculosis ATCC 25618 | ? | - |
? | |
| 5.4.4.2 | Chorismate | - |
Mycobacterium tuberculosis | Isochorismate | - |
r | |
| 5.4.4.2 | 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 | Mycobacterium tuberculosis | ? | - |
? | |
Synonyms
| EC Number | Synonyms | Comment | Organism |
|---|---|---|---|
| 4.2.99.21 | MbtI | - |
Mycobacterium tuberculosis |
| 4.2.99.21 | salicylate synthase | EC 5.4.4.2 and 4.2.99.21 | Mycobacterium tuberculosis |
| 5.4.4.2 | isochorismatase | - |
Mycobacterium tuberculosis |
| 5.4.4.2 | MbtI | - |
Mycobacterium tuberculosis |
| 5.4.4.2 | salicylate synthase | EC 5.4.4.2 and 4.2.99.21 | Mycobacterium tuberculosis |
Temperature Optimum [°C]
| EC Number | Temperature Optimum [°C] | Temperature Optimum Maximum [°C] | Comment | Organism |
|---|---|---|---|---|
| 5.4.4.2 | 37 | - |
assay at | Mycobacterium tuberculosis |
pH Optimum
| EC Number | pH Optimum Minimum | pH Optimum Maximum | Comment | Organism |
|---|---|---|---|---|
| 5.4.4.2 | 8 | - |
assay at | Mycobacterium tuberculosis |
Ki Value [mM]
| EC Number | Ki Value [mM] | Ki Value maximum [mM] | Inhibitor | Comment | Organism | Structure |
|---|---|---|---|---|---|---|
| 5.4.4.2 | 0.0092 | - |
benzimidazole-2-thione | pH 8.0, 37°C | Mycobacterium tuberculosis | |
| 5.4.4.2 | 0.011 | - |
3-[[(1Z)-1-carboxyprop-1-en-1-yl]oxy]-2-hydroxybenzoic acid | pH 8.0, 37°C | Mycobacterium tuberculosis | |
| 5.4.4.2 | 0.1 | - |
(4R,5S,6R)-4-amino-5-(2-carboxyethyl)-6-hydroxycyclohex-1-ene-1-carboxylic acid | pH 8.0, 37°C | Mycobacterium tuberculosis |
General Information
| EC Number | General Information | Comment | Organism |
|---|---|---|---|
| 4.2.99.21 | 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 |
| 4.2.99.21 | 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 |
| 5.4.4.2 | 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 |
| 5.4.4.2 | 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 |
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