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Literature summary extracted from

  • Haymond, A.; Dowdy, T.; Johny, C.; Johnson, C.; Ball, H.; Dailey, A.; Schweibenz, B.; Villarroel, K.; Young, R.; Mantooth, C.J.; Patel, T.; Bases, J.; Dowd, C.S.; Couch, R.D.
    A high-throughput screening campaign to identify inhibitors of DXP reductoisomerase (IspC) and MEP cytidylyltransferase (IspD) (2018), Anal. Biochem., 542, 63-75 .
    View publication on PubMedView publication on EuropePMC

Application

EC Number Application Comment Organism
1.1.1.267 drug development the methyl erythritol phosphate (MEP) pathway represents an attractive series of targets for antibiotic design, considering each enzyme of the pathway is both essential and has no human homologues, including enzymes DXP reductoisomerase (IspC) and MEP cytidylyltransferase (IspD) Mycobacterium tuberculosis
1.1.1.267 drug development the methyl erythritol phosphate (MEP) pathway represents an attractive series of targets for antibiotic design, considering each enzyme of the pathway is both essential and has no human homologues, including enzymes DXP reductoisomerase (IspC) and MEP cytidylyltransferase (IspD) Yersinia pestis
1.1.1.267 drug development the methyl erythritol phosphate (MEP) pathway represents an attractive series of targets for antibiotic design, considering each enzyme of the pathway is both essential and has no human homologues, including enzymes DXP reductoisomerase (IspC) and MEP cytidylyltransferase (IspD) Francisella tularensis subsp. novicida
2.7.7.60 drug development the methyl erythritol phosphate (MEP) pathway, including enzyme MEP cytidylyltransferase (IspD), represents an attractive series of targets for antibiotic design, considering each enzyme of the pathway is both essential and has no human homologues Escherichia coli
2.7.7.60 drug development the methyl erythritol phosphate (MEP) pathway, including enzyme MEP cytidylyltransferase (IspD), represents an attractive series of targets for antibiotic design, considering each enzyme of the pathway is both essential and has no human homologues Francisella tularensis subsp. novicida

Cloned(Commentary)

EC Number Cloned (Comment) Organism
1.1.1.267 gene dxr, recombinant expression of tagged enzyme in Escherichia coli strain BL21 Codon Plus (DE3)-RIL Mycobacterium tuberculosis
1.1.1.267 gene dxr, recombinant expression of tagged enzyme in Escherichia coli strain BL21 Codon Plus (DE3)-RIL Yersinia pestis
1.1.1.267 gene dxr, recombinant expression of tagged enzyme in Escherichia coli strain BL21 Codon Plus (DE3)-RIL Francisella tularensis subsp. novicida
2.7.7.60 gene ispD, recombinant expression of His-tagged enzyme in Escherichia coli strain BL21 Codon Plus (DE3)-RIL Escherichia coli
2.7.7.60 gene ispD, recombinant expression of His-tagged enzyme in Escherichia coli strain BL21 Codon Plus (DE3)-RIL Francisella tularensis subsp. novicida

Inhibitors

EC Number Inhibitors Comment Organism Structure
1.1.1.267 1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole i.e. PPT, lead molecule as inhibitor of IspC Francisella tularensis subsp. novicida
1.1.1.267 1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole i.e. PPT, lead molecule as inhibitor of IspC Mycobacterium tuberculosis
1.1.1.267 1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole i.e. PPT, lead molecule as inhibitor of IspC Yersinia pestis
1.1.1.267 13-methyl-[1,3]benzodioxolo[5,6-c]-1,3-dioxolo[4,5-i]phenanthridinium chloride i.e. sanguinarine chloride, lead molecule as inhibitor of IspC Francisella tularensis subsp. novicida
1.1.1.267 13-methyl-[1,3]benzodioxolo[5,6-c]-1,3-dioxolo[4,5-i]phenanthridinium chloride i.e. sanguinarine chloride, lead molecule as inhibitor of IspC Mycobacterium tuberculosis
1.1.1.267 13-methyl-[1,3]benzodioxolo[5,6-c]-1,3-dioxolo[4,5-i]phenanthridinium chloride i.e. sanguinarine chloride, lead molecule as inhibitor of IspC Yersinia pestis
1.1.1.267 3'-[(8-cinnamoyl-5,7-dihydroxy-2,2-dimethyl-2H-1-benzopyran-6-yl)methyl]-2',4',6'-trihydroxy-5'-methylacetophenone i.e. rottlerin, lead molecule as inhibitor of IspC Francisella tularensis subsp. novicida
1.1.1.267 3'-[(8-cinnamoyl-5,7-dihydroxy-2,2-dimethyl-2H-1-benzopyran-6-yl)methyl]-2',4',6'-trihydroxy-5'-methylacetophenone i.e. rottlerin, lead molecule as inhibitor of IspC Mycobacterium tuberculosis
1.1.1.267 3'-[(8-cinnamoyl-5,7-dihydroxy-2,2-dimethyl-2H-1-benzopyran-6-yl)methyl]-2',4',6'-trihydroxy-5'-methylacetophenone i.e. rottlerin, lead molecule as inhibitor of IspC Yersinia pestis
1.1.1.267 3-(3,5-dibromo-4-hydroxybenzylidine-5-iodo-1,3-dihydro-indol-2-one) i.e. GW5074, lead molecule as inhibitor of IspC Francisella tularensis subsp. novicida
1.1.1.267 3-(3,5-dibromo-4-hydroxybenzylidine-5-iodo-1,3-dihydro-indol-2-one) i.e. GW5074, lead molecule as inhibitor of IspC Mycobacterium tuberculosis
1.1.1.267 3-(3,5-dibromo-4-hydroxybenzylidine-5-iodo-1,3-dihydro-indol-2-one) i.e. GW5074, lead molecule as inhibitor of IspC Yersinia pestis
1.1.1.267 catechin
-
 Francisella tularensis subsp. novicida
1.1.1.267 catechin
-
 Mycobacterium tuberculosis
1.1.1.267 catechin 3.35% inhibition Yersinia pestis
1.1.1.267 EDTA
-
 Francisella tularensis subsp. novicida
1.1.1.267 EDTA
-
 Mycobacterium tuberculosis
1.1.1.267 EDTA
-
 Yersinia pestis
1.1.1.267 fosmidomycin
-
 Francisella tularensis subsp. novicida
1.1.1.267 fosmidomycin
-
 Mycobacterium tuberculosis
1.1.1.267 fosmidomycin
-
 Yersinia pestis
1.1.1.267 additional information the methyl erythritol phosphate (MEP) pathway represents an attractive series of targets for antibiotic design, considering each enzyme of the pathway is both essential and has no human homologues. MEP pathway inhibitors (collectively called MEPicides) are most often rationally designed on the fosmidomycin scaffold, balancing target specificity with bioavailability. Pilot scale high-throughput screening (HTS) campaign against the first and second committed steps in the pathway, catalyzed by DXP reductoisomerase (IspC) and MEP cytidylyltransferase (IspD), using compounds present in the commercially available LOPAC1280 library as well as in an in-house natural product extract library. Analysis of mechanism of inhibition, most compounds function through aggregation. The method is useful for quickly screening a chemical library, while effectively identifying false positive compounds associated with assay constraints and aggregation. Screening using Yersinia pestis subsp. A1122, Mycobacterium tuberculosis, and Francisella tularensis subsp. novicida strain Utah 112, overview. Inhibition is attenuated in the presence of Triton X-100 for all inhibitors except sanguinarine chloride and suramin hexasodium Francisella tularensis subsp. novicida
1.1.1.267 additional information the methyl erythritol phosphate (MEP) pathway represents an attractive series of targets for antibiotic design, considering each enzyme of the pathway is both essential and has no human homologues. MEP pathway inhibitors (collectively called MEPicides) are most often rationally designed on the fosmidomycin scaffold, balancing target specificity with bioavailability. Pilot scale high-throughput screening (HTS) campaign against the first and second committed steps in the pathway, catalyzed by DXP reductoisomerase (IspC) and MEP cytidylyltransferase (IspD), using compounds present in the commercially available LOPAC1280 library as well as in an in-house natural product extract library. Analysis of mechanism of inhibition, most compounds function through aggregation. The method is useful for quickly screening a chemical library, while effectively identifying false positive compounds associated with assay constraints and aggregation. Screening using Yersinia pestis subsp. A1122, Mycobacterium tuberculosis, and Francisella tularensis subsp. novicida strain Utah 112, overview. Inhibition is attenuated in the presence of Triton X-100 for all inhibitors except sanguinarine chloride and suramin hexasodium Mycobacterium tuberculosis
1.1.1.267 additional information the methyl erythritol phosphate (MEP) pathway represents an attractive series of targets for antibiotic design, considering each enzyme of the pathway is both essential and has no human homologues. MEP pathway inhibitors (collectively called MEPicides) are most often rationally designed on the fosmidomycin scaffold, balancing target specificity with bioavailability. Pilot scale high-throughput screening (HTS) campaign against the first and second committed steps in the pathway, catalyzed by DXP reductoisomerase (IspC) and MEP cytidylyltransferase (IspD), using compounds present in the commercially available LOPAC1280 library as well as in an in-house natural product extract library. Analysis of mechanism of inhibition, most compounds function through aggregation. The method is useful for quickly screening a chemical library, while effectively identifying false positive compounds associated with assay constraints and aggregation. Screening using Yersinia pestis strain A1122, Mycobacterium tuberculosis, and Francisella tularensis subsp. novicida strain Utah 112, overview. Inhibition is attenuated in the presence of Triton X-100 for all inhibitors except sanguinarine chloride and suramin hexasodium Yersinia pestis
1.1.1.267 quercetin
-
 Francisella tularensis subsp. novicida
1.1.1.267 quercetin
-
 Mycobacterium tuberculosis
1.1.1.267 quercetin 95.17% inhibition Yersinia pestis
1.1.1.267 quercetin 3-beta-D-glucoside
-
 Francisella tularensis subsp. novicida
1.1.1.267 quercetin 3-beta-D-glucoside
-
 Mycobacterium tuberculosis
1.1.1.267 quercetin 3-beta-D-glucoside 23.75% inhibition Yersinia pestis
1.1.1.267 quercetin 3-D-galactoside
-
 Francisella tularensis subsp. novicida
1.1.1.267 quercetin 3-D-galactoside
-
 Mycobacterium tuberculosis
1.1.1.267 quercetin 3-D-galactoside 23.21% inhibition Yersinia pestis
1.1.1.267 quercitrin
-
 Francisella tularensis subsp. novicida
1.1.1.267 quercitrin
-
 Mycobacterium tuberculosis
1.1.1.267 quercitrin 21.79% inhibition Yersinia pestis
1.1.1.267 suramin hexasodium
-
 Francisella tularensis subsp. novicida
1.1.1.267 suramin hexasodium
-
 Mycobacterium tuberculosis
1.1.1.267 suramin hexasodium
-
 Yersinia pestis
2.7.7.60 6-hydroxy-DL-DOPA
-
 Francisella tularensis subsp. novicida
2.7.7.60 aurintricarboxylic acid
-
 Francisella tularensis subsp. novicida
2.7.7.60 chelerythrine
-
 Francisella tularensis subsp. novicida
2.7.7.60 dequalinium
-
 Francisella tularensis subsp. novicida
2.7.7.60 fosmidomycin
-
 Escherichia coli
2.7.7.60 fosmidomycin
-
 Francisella tularensis subsp. novicida
2.7.7.60 MMV008138
-
 Escherichia coli
2.7.7.60 MMV008138
-
 Francisella tularensis subsp. novicida
2.7.7.60 additional information high-throughput screening to identify inhibitors of MEP cytidylyltransferase (IspD) Escherichia coli
2.7.7.60 additional information bench-scale high-throughput screening to identify inhibitors of MEP cytidylyltransferase (IspD) using purified, recombinant IspD, a commercially available 1280 compound molecular library, and a 150 sample, in-house prepared, natural product extract library. The enzyme activity is not affected by 0.01% Triton X-100, but inhibition is attenuated in the presence of Triton X-100 for all inhibitors, except 6-hydroxy-DL-DOPA Francisella tularensis subsp. novicida
2.7.7.60 quercetin quercetin is retained as a lead molecule for inhibition of IspD, 96% inhibition at 0.1 mM Francisella tularensis subsp. novicida
2.7.7.60 U-74389G maleate
-
 Francisella tularensis subsp. novicida

Metals/Ions

EC Number Metals/Ions Comment Organism Structure
1.1.1.267 Mg2+ required Mycobacterium tuberculosis
1.1.1.267 Mg2+ required Yersinia pestis
1.1.1.267 Mg2+ required Francisella tularensis subsp. novicida
2.7.7.60 Mg2+ required Escherichia coli
2.7.7.60 Mg2+ required Francisella tularensis subsp. novicida

Natural Substrates/ Products (Substrates)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
1.1.1.267 1-deoxy-D-xylulose 5-phosphate + NADPH + H+ Mycobacterium tuberculosis
-
 2-C-methyl-D-erythritol 4-phosphate + NADP+
-
 ?
1.1.1.267 1-deoxy-D-xylulose 5-phosphate + NADPH + H+ Yersinia pestis
-
 2-C-methyl-D-erythritol 4-phosphate + NADP+
-
 ?
1.1.1.267 1-deoxy-D-xylulose 5-phosphate + NADPH + H+ Francisella tularensis subsp. novicida
-
 2-C-methyl-D-erythritol 4-phosphate + NADP+
-
 ?
1.1.1.267 1-deoxy-D-xylulose 5-phosphate + NADPH + H+ Francisella tularensis subsp. novicida U112
-
 2-C-methyl-D-erythritol 4-phosphate + NADP+
-
 ?
1.1.1.267 1-deoxy-D-xylulose 5-phosphate + NADPH + H+ Yersinia pestis A1122
-
 2-C-methyl-D-erythritol 4-phosphate + NADP+
-
 ?
1.1.1.267 1-deoxy-D-xylulose 5-phosphate + NADPH + H+ Mycobacterium tuberculosis H37Rv
-
 2-C-methyl-D-erythritol 4-phosphate + NADP+
-
 ?
1.1.1.267 1-deoxy-D-xylulose 5-phosphate + NADPH + H+ Mycobacterium tuberculosis ATCC 25618
-
 2-C-methyl-D-erythritol 4-phosphate + NADP+
-
 ?
2.7.7.60 CTP + 2-C-methyl-D-erythritol 4-phosphate Escherichia coli
-
 diphosphate + 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol
-
 ?
2.7.7.60 CTP + 2-C-methyl-D-erythritol 4-phosphate Francisella tularensis subsp. novicida
-
 diphosphate + 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol
-
 ?
2.7.7.60 CTP + 2-C-methyl-D-erythritol 4-phosphate Francisella tularensis subsp. novicida Utah 112
-
 diphosphate + 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol
-
 ?

Organism

EC Number Organism UniProt Comment Textmining
1.1.1.267 Francisella tularensis subsp. novicida A0Q7Y5
-
-
1.1.1.267 Francisella tularensis subsp. novicida U112 A0Q7Y5
-
-
1.1.1.267 Mycobacterium tuberculosis P9WNS1
-
-
1.1.1.267 Mycobacterium tuberculosis ATCC 25618 P9WNS1
-
-
1.1.1.267 Mycobacterium tuberculosis H37Rv P9WNS1
-
-
1.1.1.267 Yersinia pestis Q8ZH62
-
-
1.1.1.267 Yersinia pestis A1122 Q8ZH62
-
-
2.7.7.60 Escherichia coli Q46893
-
-
2.7.7.60 Francisella tularensis subsp. novicida A0Q5K1
-
-
2.7.7.60 Francisella tularensis subsp. novicida Utah 112 A0Q5K1
-
-

Purification (Commentary)

EC Number Purification (Comment) Organism
1.1.1.267 recombinant tagged enzyme from Escherichia coli strain BL21 Codon Plus (DE3)-RIL by metal affinity chromatography and ultrafiltration Mycobacterium tuberculosis
1.1.1.267 recombinant tagged enzyme from Escherichia coli strain BL21 Codon Plus (DE3)-RIL by metal affinity chromatography and ultrafiltration Yersinia pestis
1.1.1.267 recombinant tagged enzyme from Escherichia coli strain BL21 Codon Plus (DE3)-RIL by metal affinity chromatography and ultrafiltration Francisella tularensis subsp. novicida
2.7.7.60 recombinant His-tagged enzyme from Escherichia coli strain BL21 Codon Plus (DE3)-RIL by metal affinity chromatography and ultrafiltration Escherichia coli
2.7.7.60 recombinant His-tagged enzyme from Escherichia coli strain BL21 Codon Plus (DE3)-RIL by metal affinity chromatography and ultrafiltration Francisella tularensis subsp. novicida

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
1.1.1.267 1-deoxy-D-xylulose 5-phosphate + NADPH + H+
-
 Mycobacterium tuberculosis 2-C-methyl-D-erythritol 4-phosphate + NADP+
-
 ?
1.1.1.267 1-deoxy-D-xylulose 5-phosphate + NADPH + H+
-
 Yersinia pestis 2-C-methyl-D-erythritol 4-phosphate + NADP+
-
 ?
1.1.1.267 1-deoxy-D-xylulose 5-phosphate + NADPH + H+
-
 Francisella tularensis subsp. novicida 2-C-methyl-D-erythritol 4-phosphate + NADP+
-
 ?
1.1.1.267 1-deoxy-D-xylulose 5-phosphate + NADPH + H+
-
 Francisella tularensis subsp. novicida U112 2-C-methyl-D-erythritol 4-phosphate + NADP+
-
 ?
1.1.1.267 1-deoxy-D-xylulose 5-phosphate + NADPH + H+
-
 Yersinia pestis A1122 2-C-methyl-D-erythritol 4-phosphate + NADP+
-
 ?
1.1.1.267 1-deoxy-D-xylulose 5-phosphate + NADPH + H+
-
 Mycobacterium tuberculosis H37Rv 2-C-methyl-D-erythritol 4-phosphate + NADP+
-
 ?
1.1.1.267 1-deoxy-D-xylulose 5-phosphate + NADPH + H+
-
 Mycobacterium tuberculosis ATCC 25618 2-C-methyl-D-erythritol 4-phosphate + NADP+
-
 ?
2.7.7.60 CTP + 2-C-methyl-D-erythritol 4-phosphate
-
 Escherichia coli diphosphate + 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol
-
 ?
2.7.7.60 CTP + 2-C-methyl-D-erythritol 4-phosphate
-
 Francisella tularensis subsp. novicida diphosphate + 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol
-
 ?
2.7.7.60 CTP + 2-C-methyl-D-erythritol 4-phosphate
-
 Francisella tularensis subsp. novicida Utah 112 diphosphate + 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol
-
 ?

Synonyms

EC Number Synonyms Comment Organism
1.1.1.267 DXP reductoisomerase
-
 Mycobacterium tuberculosis
1.1.1.267 DXP reductoisomerase
-
 Yersinia pestis
1.1.1.267 DXP reductoisomerase
-
 Francisella tularensis subsp. novicida
1.1.1.267 DXR
-
 Mycobacterium tuberculosis
1.1.1.267 DXR
-
 Yersinia pestis
1.1.1.267 DXR
-
 Francisella tularensis subsp. novicida
1.1.1.267 FtIspC
-
 Francisella tularensis subsp. novicida
1.1.1.267 IspC
-
 Mycobacterium tuberculosis
1.1.1.267 IspC
-
 Yersinia pestis
1.1.1.267 IspC
-
 Francisella tularensis subsp. novicida
1.1.1.267 MtbIspC
-
 Mycobacterium tuberculosis
1.1.1.267 YpIspC
-
 Yersinia pestis
2.7.7.60 EcIspD
-
 Escherichia coli
2.7.7.60 FtIspD
-
 Francisella tularensis subsp. novicida
2.7.7.60 IspD
-
 Escherichia coli
2.7.7.60 IspD
-
 Francisella tularensis subsp. novicida
2.7.7.60 MEP cytidylyltransferase
-
 Escherichia coli
2.7.7.60 MEP cytidylyltransferase
-
 Francisella tularensis subsp. novicida

Temperature Optimum [°C]

EC Number Temperature Optimum [°C] Temperature Optimum Maximum [°C] Comment Organism
1.1.1.267 37
-
 assay at Mycobacterium tuberculosis
1.1.1.267 37
-
 assay at Yersinia pestis
1.1.1.267 37
-
 assay at Francisella tularensis subsp. novicida
2.7.7.60 37
-
 assay at Escherichia coli
2.7.7.60 37
-
 assay at Francisella tularensis subsp. novicida

pH Optimum

EC Number pH Optimum Minimum pH Optimum Maximum Comment Organism
1.1.1.267 7.8
-
 assay at Mycobacterium tuberculosis
1.1.1.267 7.8
-
 assay at Yersinia pestis
1.1.1.267 7.8
-
 assay at Francisella tularensis subsp. novicida
2.7.7.60 8.2
-
 assay at Escherichia coli
2.7.7.60 8.2
-
 assay at Francisella tularensis subsp. novicida

Cofactor

EC Number Cofactor Comment Organism Structure
1.1.1.267 NADP+
-
 Mycobacterium tuberculosis
1.1.1.267 NADP+
-
 Yersinia pestis
1.1.1.267 NADP+
-
 Francisella tularensis subsp. novicida
1.1.1.267 NADPH
-
 Mycobacterium tuberculosis
1.1.1.267 NADPH
-
 Yersinia pestis
1.1.1.267 NADPH
-
 Francisella tularensis subsp. novicida

General Information

EC Number General Information Comment Organism
1.1.1.267 metabolism the enzyme catalyzes the first comitted step in the methyl erythritol phosphate (MEP) pathway Mycobacterium tuberculosis
1.1.1.267 metabolism the enzyme catalyzes the first comitted step in the methyl erythritol phosphate (MEP) pathway Yersinia pestis
1.1.1.267 metabolism the enzyme catalyzes the first comitted step in the methyl erythritol phosphate (MEP) pathway Francisella tularensis subsp. novicida
2.7.7.60 metabolism the MEP cytidylyltransferase, or IspD catalyzes the second committed step of the methyl erythritol phosphate (MEP) pathway. The MEP pathway is essential for the production of isoprenoids Escherichia coli
2.7.7.60 metabolism the MEP cytidylyltransferase, or IspD catalyzes the second committed step of the methyl erythritol phosphate (MEP) pathway. The MEP pathway is essential for the production of isoprenoids Francisella tularensis subsp. novicida