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Information on EC 2.7.1.148 - 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol kinase and Organism(s) Escherichia coli and UniProt Accession P62615

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IUBMB Comments
The enzyme from Escherichia coli requires Mg2+ or Mn2+. Forms part of an alternative nonmevalonate pathway for terpenoid biosynthesis (for diagram, click here).
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This record set is specific for:
Escherichia coli
UNIPROT: P62615
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The taxonomic range for the selected organisms is: Escherichia coli
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
Synonyms
cdp-me, 4-diphosphocytidyl-2-c-methyl-d-erythritol kinase, 4-diphosphocytidyl-2c-methyl-d-erythritol kinase, cdp-me kinase, twcmk, pvispe, gbcmk1, gbcmk2, cccmk1, 4-(cytidine 5'-diphospho)-2-c-methyl-d-erythritol kinase, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
CDPME kinase
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4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol kinase
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4-(cytidine-5'-diphospho)-2-C-methyl-D-erythritol kinase
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-
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4-diphosphocytidyl-2-C-methyl-D-erythritol kinase
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4-diphosphocytidyl-2-C-methylerythritol 2-kinase
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-
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4-diphosphocytidyl-2C-methyl-D-erythritol 2-kinase
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-
-
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4-diphosphocytidyl-2C-methyl-D-erythritol kinase
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CDP-ME kinase
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-
-
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CDP-methylerythritol kinase
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CDPMEK
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-
-
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Ripening-associated protein pTOM41
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-
-
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additional information
-
the enzyme belongs to the galactose kinase/homoserine kinase/mevalonate kinase phosphomevalonate kinase superfamily
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
ATP + 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol = ADP + 2-phospho-4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol
show the reaction diagram
reaction mechanism
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Phosphorylation
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phospho group transfer
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-
-
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SYSTEMATIC NAME
IUBMB Comments
ATP:4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol 2-phosphotransferase
The enzyme from Escherichia coli requires Mg2+ or Mn2+. Forms part of an alternative nonmevalonate pathway for terpenoid biosynthesis (for diagram, click here).
CAS REGISTRY NUMBER
COMMENTARY hide
263016-77-9
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SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
ATP + 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol
ADP + 2-phospho-4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol
show the reaction diagram
-
-
-
?
ATP + 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol
ADP + 2-phospho-4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol
show the reaction diagram
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
ATP + 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol
ADP + 2-phospho-4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol
show the reaction diagram
-
-
-
?
ATP + 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol
ADP + 2-phospho-4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol
show the reaction diagram
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
(4E)-3-methyl-4-[(5-phenylfuran-2-yl)methylidene]-1,2-oxazol-5(4H)-one
-
-
(4Z)-4-(furan-2-ylmethylidene)-3-phenyl-1,2-oxazol-5(4H)-one
-
-
(4Z)-4-[(5-methylfuran-2-yl)methylidene]-3-phenyl-1,2-oxazol-5(4H)-one
-
-
6-(benzylsulfanyl)-2-(2-hydroxyphenyl)-4-oxo-3,4-dihydro-2H-1,3-thiazine-5-carbonitrile
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at an external concentration of 50 microM, compound is able to inhibit the growth of Escherichia coli in culture for at least six hours
ethyl [4-amino-2-oxo-5-(3-[[(2,2,2-trifluoroethyl)sulfonyl]amino]prop-1-en-1-yl)pyrimidin-1(2H)-yl]acetate
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mixed type
N-[3-(4-amino-1-benzyl-2-oxo-1,2-dihydropyrimidin-5-yl)prop-2-en-1-yl]ethanesulfonamide
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mixed-type
N-[3-[4-amino-2-oxo-1-(1H-pyrazol-5-ylmethyl)-1,2-dihydropyrimidin-5-yl]prop-2-en-1-yl]ethanesulfonamide
-
competitive
N-[3-[4-amino-2-oxo-1-(tetrahydro-2-thienyl)-1,2-dihydropyrimidin-5-yl]prop-2-en-1-yl]-1,1,1-trifluoromethanesulfonamide
-
competitive
N-[3-[4-amino-2-oxo-1-(tetrahydro-2-thienyl)-1,2-dihydropyrimidin-5-yl]prop-2-en-1-yl]-2,2,2-trifluoroethanesulfonamide
-
competitive
N-[3-[4-amino-2-oxo-1-(tetrahydro-2-thienyl)-1,2-dihydropyrimidin-5-yl]prop-2-en-1-yl]benzenesulfonamide
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competitive
N-[3-[4-amino-2-oxo-1-(tetrahydro-2-thienyl)-1,2-dihydropyrimidin-5-yl]prop-2-en-1-yl]cyclopropanesulfonamide
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competitive
N-[3-[4-amino-2-oxo-1-(tetrahydro-2-thienyl)-1,2-dihydropyrimidin-5-yl]prop-2-en-1-yl]ethanesulfonamide
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competitive
N-[3-[4-amino-2-oxo-1-(tetrahydro-2-thienyl)-1,2-dihydropyrimidin-5-yl]prop-2-en-1-yl]methanesulfonamide
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competitive
N-[3-[4-amino-2-oxo-1-(tetrahydro-2-thienyl)-1,2-dihydropyrimidin-5-yl]prop-2-en-1-yl]propane-1-sulfonamide
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mixed-type
N-[3-[4-amino-2-oxo-1-(tetrahydrofuran-2-ylmethyl)-1,2-dihydropyrimidin-5-yl]prop-2-en-1-yl]-2,2,2-trifluoroethanesulfonamide
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competitive
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.2
4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol
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pH not specified in the publication, 22°C
0.02
ATP
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pH not specified in the publication, 22°C
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0042
ethyl [4-amino-2-oxo-5-(3-[[(2,2,2-trifluoroethyl)sulfonyl]amino]prop-1-en-1-yl)pyrimidin-1(2H)-yl]acetate
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competitive inhibition constant
0.0037
N-[3-(4-amino-1-benzyl-2-oxo-1,2-dihydropyrimidin-5-yl)prop-2-en-1-yl]ethanesulfonamide
-
competitive inhibition constant
0.0016
N-[3-[4-amino-2-oxo-1-(1H-pyrazol-5-ylmethyl)-1,2-dihydropyrimidin-5-yl]prop-2-en-1-yl]ethanesulfonamide
-
competitive inhibition constant
0.0012
N-[3-[4-amino-2-oxo-1-(tetrahydro-2-thienyl)-1,2-dihydropyrimidin-5-yl]prop-2-en-1-yl]-1,1,1-trifluoromethanesulfonamide
-
competitive inhibition constant
0.00036
N-[3-[4-amino-2-oxo-1-(tetrahydro-2-thienyl)-1,2-dihydropyrimidin-5-yl]prop-2-en-1-yl]-2,2,2-trifluoroethanesulfonamide
-
competitive inhibition constant
0.0163
N-[3-[4-amino-2-oxo-1-(tetrahydro-2-thienyl)-1,2-dihydropyrimidin-5-yl]prop-2-en-1-yl]benzenesulfonamide
-
competitive inhibition constant
0.00029
N-[3-[4-amino-2-oxo-1-(tetrahydro-2-thienyl)-1,2-dihydropyrimidin-5-yl]prop-2-en-1-yl]cyclopropanesulfonamide
-
competitive inhibition constant
0.00064
N-[3-[4-amino-2-oxo-1-(tetrahydro-2-thienyl)-1,2-dihydropyrimidin-5-yl]prop-2-en-1-yl]ethanesulfonamide
-
competitive inhibition constant
0.0026
N-[3-[4-amino-2-oxo-1-(tetrahydro-2-thienyl)-1,2-dihydropyrimidin-5-yl]prop-2-en-1-yl]methanesulfonamide
-
competitive inhibition constant
0.0082
N-[3-[4-amino-2-oxo-1-(tetrahydro-2-thienyl)-1,2-dihydropyrimidin-5-yl]prop-2-en-1-yl]propane-1-sulfonamide
-
competitive inhibition constant
0.0323
N-[3-[4-amino-2-oxo-1-(tetrahydrofuran-2-ylmethyl)-1,2-dihydropyrimidin-5-yl]prop-2-en-1-yl]-2,2,2-trifluoroethanesulfonamide
-
competitive inhibition constant
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0055
(4E)-3-methyl-4-[(5-phenylfuran-2-yl)methylidene]-1,2-oxazol-5(4H)-one
Escherichia coli
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pH not specified in the publication, 22°C
0.007
(4Z)-4-(furan-2-ylmethylidene)-3-phenyl-1,2-oxazol-5(4H)-one
Escherichia coli
-
pH not specified in the publication, 22°C
0.008
(4Z)-4-[(5-methylfuran-2-yl)methylidene]-3-phenyl-1,2-oxazol-5(4H)-one
Escherichia coli
-
pH not specified in the publication, 22°C
0.018
6-(benzylsulfanyl)-2-(2-hydroxyphenyl)-4-oxo-3,4-dihydro-2H-1,3-thiazine-5-carbonitrile
Escherichia coli
-
pH not specified in the publication, 22°C
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
-
spectrophotometric and HPLC-based assay development for determination of product ADP with use of pyruvate kinase and L-lactate dehydrogenase as auxiliary enzymes
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7.5
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assay at, spectrophotometric assay
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
35 - 37
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assay at
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
metabolism
CDPME kinase (IspE) catalyzes the phosphorylation of CDPME to 4-diphosphocytidyl-2-C-methyl-D-erythritol 2-phosphate (CDPME2P) as part of the MEP pathway, overview. In Escherichia coli, no stable complexes of EcIspD/EcIspE, EcIspE/EcIspF, and EcIspD/EcIspE/EcIspF are observed, only the dual mixture of BsIspE and BsIspF seems to merge into a single band, interaction analysis, overview
physiological function
CDPME kinase (IspE) catalyzes the phosphorylation of CDPME to 4-diphosphocytidyl-2-C-methyl-D-erythritol 2-phosphate (CDPME2P)
metabolism
-
enzyme catalyses the fourth reaction step of the 2C-methylerythritol 4-phosphate (MEP) pathway for the biosynthesis of isopentenyl pyrophosphate and its isomer dimethylallyl pyrophosphate
physiological function
-
the MEP pathway is essential in the malaria parasite Plasmodium falciparum and in most eubacteria, including the causal agents for diverse and serious human diseases like leprosy, bacterial meningitis, various gastrointestinal and sexually transmitted infections, tuberculosis, and certain types of pneumonia
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
62000
-
determined by MALDI-TOF-MS
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
homodimer
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determined by gel filtration, asymmetric unit consists of 2 subunits A and B which assemble with C2 symmetry to form an extended homodimer, but only 4% of the total surface area of the 2 monomers is involved in dimer formation
additional information
-
the enzyme subunit displays the alpha/beta fold characteristic of the galactose kinase/homoserine kinase/mevalonate kinase phosphomevalonate kinase superfamily, arranged into cofactor and substrate-binding domains with the catalytic center positioned in a deep cleft between domains, quarternary structure, overview
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
in complex with ADP, to 2.0 A resolution, and comparison with a monoclinic crystal form of a ternary complex of Escherichia coli 4-diphosphocytidyl-2C-methyl-D-erythritol kinase also with two molecules in the asymmetric unit. The molecular packing is different in the two forms. In the asymmetric unit of the triclinic crystal form the substrate-binding sites are occluded by structural elements of the partner, suggesting that the triclinic dimer is an artefact of the crystal lattice. The surface area of interaction in the triclinic form is almost double that observed in the monoclinic form
purified recombinant enzyme in ternary complex with substrate and non-hydrolyzable ATP analogue adenosine 5'-[beta,gamma-imino]triphosphate, i.e. AMP-PNP, 25 mg/ml protein in 50 mM Tris-HCl, pH 7.7, 50 mM NaCl, 3 mM AMP-PNP, and 2 mM substrate 4-(cytidine 5'-phosphate)-2-C-methyl-D-erythritol, hanging drop vapour diffusion method, 0.001 ml protein solution mixed with equal volume of reservoir solution containing 20% polyethylene glycol 8000, 0.2 M magnesium acetate, 0.1 M sodium cacodylate, pH 6.5, and 0.0002 ml of 0.25 sulfo-betaine, cryoprotection at -173°C by 20% glycerol, X-ray diffraction structure determination and analysis at 2.0 A resolution
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structure-activity relationship studies with inhibitors 6-(benzylsulfanyl)-2-(2-hydroxyphenyl)-4-oxo-3,4-dihydro-2H-1,3-thiazine-5-carbonitrile and (4E)-3-methyl-4-[(5-phenylfuran-2-yl)methylidene]-1,2-oxazol-5(4H)-one
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the structure is resolved by X-ray diffraction at a resolution of 2.01 A
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PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant His6-tagged enzyme from Escherichia coli strain BL21(DE3) by nickel affinity chromatography, tag cleavage through thrombin, followed by anion exchange chromatography, and gel filtration
Hi-trap chelating columns are used for the purification of recombinant 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol kinase
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recombinant His-tagged enzyme from strain BL21(DE3) to homogeneity by nickel affinity and anion exchange chromatography
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recombinant His6-tagged enzyme by nickel affinity chromatography
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene ispE, recombinant expression of C-terminally His6-tagged enzyme in Escherichia coli strain BL21(DE3) from pGEX-6P-1 expression vector
gene ispE, expression of the His-tagged in strain BL21(DE3)
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gene ychB, overexpression of His6-tagged enzyme
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overexpression in Escherichia coli
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
drug development
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enzymes of the MEP pathway represent potential targets for the generation of selective antibacterial, antimalarial and herbicidal molecules
medicine
-
potential target for antimalarial therapy
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Kuzuyama, T.; Takagi, M.; Kaneda, K.; Watanabe, H.; Dairi, T.; Seto, H.
Studies on the nonmevalonate pathway: conversion of 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol to its 2-phospho derivative by 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol kinase
Tetrahedron Lett.
41
2925-2928
2000
Escherichia coli
-
Manually annotated by BRENDA team
Bernal, C.; Mendez, E.; Terencio, J.; Boronat, A.; Imperial, S.
A spectrophotometric assay for the determination of 4-diphosphocytidyl-2-C-methyl-D-erythritol kinase activity
Anal. Biochem.
340
245-251
2005
Escherichia coli
Manually annotated by BRENDA team
Miallau, L.; Alphey, M.S.; Kemp, L.E.; Leonard, G.A.; McSweeney, S.M.; Hecht, S.; Bacher, A.; Eisenreich, W.; Rohdich, F.; Hunter, W.N.
Biosynthesis of isoprenoids: crystal structure of 4-diphosphocytidyl-2C-methyl-D-erythritol kinase
Proc. Natl. Acad. Sci. USA
100
9173-9178
2003
Escherichia coli
Manually annotated by BRENDA team
Hirsch, A.K.; Lauw, S.; Gersbach, P.; Schweizer, W.B.; Rohdich, F.; Eisenreich, W.; Bacher, A.; Diederich, F.
Nonphosphate inhibitors of IspE protein, a kinase in the non-mevalonate pathway for isoprenoid biosynthesis and a potential target for antimalarial therapy
ChemMedChem
2
806-810
2007
Escherichia coli
Manually annotated by BRENDA team
Gimenez-Oya, V.; Villacanas, O.; Fernandez-Busquets, X.; Rubio-Martinez, J.; Imperial, S.
Mimicking direct protein-protein and solvent-mediated interactions in the CDP-methylerythritol kinase homodimer: a pharmacophore-directed virtual screening approach
J. Mol. Model.
15
997-1007
2009
Escherichia coli
Manually annotated by BRENDA team
Kalinowska-Tluscik, J.; Miallau, L.; Gabrielsen, M.; Leonard, G.A.; McSweeney, S.M.; Hunter, W.N.
A triclinic crystal form of Escherichia coli 4-diphosphocytidyl-2C-methyl-D-erythritol kinase and reassessment of the quaternary structure
Acta Crystallogr. Sect. F
66
237-241
2010
Escherichia coli (P62615), Escherichia coli
Manually annotated by BRENDA team
Tang, M.; Odejinmi, S.I.; Allette, Y.M.; Vankayalapati, H.; Lai, K.
Identification of novel small molecule inhibitors of 4-diphosphocytidyl-2-C-methyl-D-erythritol (CDP-ME) kinase of Gram-negative bacteria
Bioorg. Med. Chem.
19
5886-5895
2011
Escherichia coli, Escherichia coli DH5-alpha, Yersinia pestis
Manually annotated by BRENDA team
Liu, Z.; Jin, Y.; Tao, Y.; Wang, G.
Crystal structure of IspF from Bacillus subtilis and absence of protein complex assembly amongst IspD/IspE/IspF enzymes in the MEP pathway
Biosci. Rep.
38
BSR20171370
2018
Bacillus subtilis (P37550), Bacillus subtilis 168 (P37550), Bacillus subtilis DSM 23778 (P37550), Escherichia coli (P62615)
Manually annotated by BRENDA team