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Information on EC 5.4.4.2 - isochorismate synthase and Organism(s) Mycobacterium tuberculosis and UniProt Accession P9WFX1
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5.4.4.2 isochorismate synthaseIUBMB Comments
Requires Mg2+. The reaction is reversible.
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Word Map
- 5.4.4.2
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corticosteroid
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inhaled
- asthma
- children
- pulmonary
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long-acting
- airway
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labas
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asthmatic
- agonist
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bronchodilator
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placebo
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fluticasone
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eosinophil
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expiratory
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prescript
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short-acting
-
double-blind
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physician
- bronchial
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beta2-agonists
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budesonide
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spirometry
- montelukast
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add-on
-
wheezing
-
randomised
- ketanserin
- 5-hydroxytryptamine
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leukotriene
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once-daily
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muscarinic
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monotherapy
- salmeterol
- sputum
-
5-ht-induced
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urodynamic
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parallel-group
- methysergide
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intercostal
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fixed-dose
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immunochromatographic
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self-management
- ondansetron
- incontinence
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real-life
- drug development
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8-oh-dpat
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datalink
- agriculture
-
airflow
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run-in
The taxonomic range for the selected organisms is: Mycobacterium tuberculosis
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
Synonyms
ics, isochorismate synthase, amonabactin, salicylate synthase, isochorismate synthase 1, eds16, atics1, isochorismate hydroxymutase, menaquinone-specific isochorismate synthase, atics2, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
Amonabactin
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-
-
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Eds16
-
-
-
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IcsI
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-
-
-
isochorismate mutase
-
-
-
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Isochorismic synthase
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-
-
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Sid2
-
-
-
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Synthase, isochorismate
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-
-
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
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
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
isomerization
-
-
-
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PATHWAY SOURCE
PATHWAYS
KEGG
-
-, -, -, -
SYSTEMATIC NAME
IUBMB Comments
isochorismate hydroxymutase
Requires Mg2+. The reaction is reversible.
CAS REGISTRY NUMBER
COMMENTARY
37318-53-9
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
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
-
-
?
additional information
?
-
-
the enzyme is essential for siderohore biosynthesis, first step in salicylate production
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-
?
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
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-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
additional information
?
-
-
the enzyme is essential for siderohore biosynthesis, first step in salicylate production
-
-
?
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(4R,5R)-5-[(1-carboxyethenyl)oxy]-4-hydroxycyclohex-1-ene-1-carboxylic acid
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(4R,5S,6R)-4-amino-5-(2-carboxyethyl)-6-hydroxycyclohex-1-ene carboxylic acid
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transition-state inhibitor
(4R,5S,6R)-4-amino-5-(2-carboxyethyl)-6-hydroxycyclohex-1-ene-1-carboxylic acid
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-
-
additional information
inhibitor structure-function realtionship and molecular docking
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additional information
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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
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Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.1
(4R,5S,6R)-4-amino-5-(2-carboxyethyl)-6-hydroxycyclohex-1-ene-1-carboxylic acid
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pH 8.0, 37°C
-
0.011
3-[[(1Z)-1-carboxyprop-1-en-1-yl]oxy]-2-hydroxybenzoic acid
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pH 8.0, 37°C
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
metabolism
the first committed step during the biosynthesis of siderophores, which are small molecules capable of chelating iron from the host organism, is the conversion of chorismate into isochorismate by isochorismate synthase (EC 5.4.4.2) and consequently to salicylate by isochorismate pyruvate-lyase (EC 4.2.99.21). 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
physiological function
the enzyme is involved in the biosynthesis of the siderophore mycobactin. Chorismate-utilizing enzymes (CUE) such as chorismate mutase, anthranilate synthase, chorismate pyruvate-lyase, 4-amino-4-deoxychorismate synthase, isochorismate synthase and salicylate synthase are responsible for converting chorismate into various products necessary for the survival of bacteria
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
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
PDB
SCOP
CATH
UNIPROT
ORGANISM
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
sitting-drop vapur diffusion, crystals diffrect to a maximum resolution of 1.8 A. They belong to space group O2(1)2(1)2(1) with unit-cell parameters a = 51.8 A, b = 163.4 A, c = 194.9 A
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PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
drug development
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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)
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Harrison, A.J.; Ramsay, R.J.; Baker, E.N.; Lott, J.S.
Crystallization and preliminary x-ray crystallographic analysis of MbtI, a protein essential for siderophore biosynthesis in Mycobacterium tuberculosis
Acta Crystallogr. Sect. F
F61
121-123
2005
Mycobacterium tuberculosis
Svarcova, M.; Kratky, M.; Vinsova, J.
Investigation of potential inhibitors of chorismate-utilizing enzymes
Curr. Med. Chem.
22
1383-1399
2015
no activity in Homo sapiens, Yersinia pestis, Yersinia enterocolitica, Escherichia coli (P38051), Mycobacterium tuberculosis (P9WFX1), Pseudomonas aeruginosa (Q51508)
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