Application | Comment | Organism |
---|---|---|
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 |
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 |
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 |
Cloned (Comment) | Organism |
---|---|
gene dxr, recombinant expression of tagged enzyme in Escherichia coli strain BL21 Codon Plus (DE3)-RIL | Mycobacterium tuberculosis |
gene dxr, recombinant expression of tagged enzyme in Escherichia coli strain BL21 Codon Plus (DE3)-RIL | Yersinia pestis |
gene dxr, recombinant expression of tagged enzyme in Escherichia coli strain BL21 Codon Plus (DE3)-RIL | Francisella tularensis subsp. novicida |
Inhibitors | Comment | Organism | Structure |
---|---|---|---|
1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole | i.e. PPT, lead molecule as inhibitor of IspC | Francisella tularensis subsp. novicida | |
1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole | i.e. PPT, lead molecule as inhibitor of IspC | Mycobacterium tuberculosis | |
1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole | i.e. PPT, lead molecule as inhibitor of IspC | Yersinia pestis | |
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 | |
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 | |
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 | |
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 | |
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 | |
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 | |
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 | |
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 | |
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 | |
catechin | - |
Francisella tularensis subsp. novicida | |
catechin | - |
Mycobacterium tuberculosis | |
catechin | 3.35% inhibition | Yersinia pestis | |
EDTA | - |
Francisella tularensis subsp. novicida | |
EDTA | - |
Mycobacterium tuberculosis | |
EDTA | - |
Yersinia pestis | |
fosmidomycin | - |
Francisella tularensis subsp. novicida | |
fosmidomycin | - |
Mycobacterium tuberculosis | |
fosmidomycin | - |
Yersinia pestis | |
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 | |
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 | |
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 | |
quercetin | - |
Francisella tularensis subsp. novicida | |
quercetin | - |
Mycobacterium tuberculosis | |
quercetin | 95.17% inhibition | Yersinia pestis | |
quercetin 3-beta-D-glucoside | - |
Francisella tularensis subsp. novicida | |
quercetin 3-beta-D-glucoside | - |
Mycobacterium tuberculosis | |
quercetin 3-beta-D-glucoside | 23.75% inhibition | Yersinia pestis | |
quercetin 3-D-galactoside | - |
Francisella tularensis subsp. novicida | |
quercetin 3-D-galactoside | - |
Mycobacterium tuberculosis | |
quercetin 3-D-galactoside | 23.21% inhibition | Yersinia pestis | |
quercitrin | - |
Francisella tularensis subsp. novicida | |
quercitrin | - |
Mycobacterium tuberculosis | |
quercitrin | 21.79% inhibition | Yersinia pestis | |
suramin hexasodium | - |
Francisella tularensis subsp. novicida | |
suramin hexasodium | - |
Mycobacterium tuberculosis | |
suramin hexasodium | - |
Yersinia pestis |
Metals/Ions | Comment | Organism | Structure |
---|---|---|---|
Mg2+ | required | Mycobacterium tuberculosis | |
Mg2+ | required | Yersinia pestis | |
Mg2+ | required | Francisella tularensis subsp. novicida |
Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
---|---|---|---|---|---|---|
1-deoxy-D-xylulose 5-phosphate + NADPH + H+ | Mycobacterium tuberculosis | - |
2-C-methyl-D-erythritol 4-phosphate + NADP+ | - |
? | |
1-deoxy-D-xylulose 5-phosphate + NADPH + H+ | Yersinia pestis | - |
2-C-methyl-D-erythritol 4-phosphate + NADP+ | - |
? | |
1-deoxy-D-xylulose 5-phosphate + NADPH + H+ | Francisella tularensis subsp. novicida | - |
2-C-methyl-D-erythritol 4-phosphate + NADP+ | - |
? | |
1-deoxy-D-xylulose 5-phosphate + NADPH + H+ | Francisella tularensis subsp. novicida U112 | - |
2-C-methyl-D-erythritol 4-phosphate + NADP+ | - |
? | |
1-deoxy-D-xylulose 5-phosphate + NADPH + H+ | Yersinia pestis A1122 | - |
2-C-methyl-D-erythritol 4-phosphate + NADP+ | - |
? | |
1-deoxy-D-xylulose 5-phosphate + NADPH + H+ | Mycobacterium tuberculosis H37Rv | - |
2-C-methyl-D-erythritol 4-phosphate + NADP+ | - |
? | |
1-deoxy-D-xylulose 5-phosphate + NADPH + H+ | Mycobacterium tuberculosis ATCC 25618 | - |
2-C-methyl-D-erythritol 4-phosphate + NADP+ | - |
? |
Organism | UniProt | Comment | Textmining |
---|---|---|---|
Francisella tularensis subsp. novicida | A0Q7Y5 | - |
- |
Francisella tularensis subsp. novicida U112 | A0Q7Y5 | - |
- |
Mycobacterium tuberculosis | P9WNS1 | - |
- |
Mycobacterium tuberculosis ATCC 25618 | P9WNS1 | - |
- |
Mycobacterium tuberculosis H37Rv | P9WNS1 | - |
- |
Yersinia pestis | Q8ZH62 | - |
- |
Yersinia pestis A1122 | Q8ZH62 | - |
- |
Purification (Comment) | Organism |
---|---|
recombinant tagged enzyme from Escherichia coli strain BL21 Codon Plus (DE3)-RIL by metal affinity chromatography and ultrafiltration | Mycobacterium tuberculosis |
recombinant tagged enzyme from Escherichia coli strain BL21 Codon Plus (DE3)-RIL by metal affinity chromatography and ultrafiltration | Yersinia pestis |
recombinant tagged enzyme from Escherichia coli strain BL21 Codon Plus (DE3)-RIL by metal affinity chromatography and ultrafiltration | Francisella tularensis subsp. novicida |
Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
---|---|---|---|---|---|---|
1-deoxy-D-xylulose 5-phosphate + NADPH + H+ | - |
Mycobacterium tuberculosis | 2-C-methyl-D-erythritol 4-phosphate + NADP+ | - |
? | |
1-deoxy-D-xylulose 5-phosphate + NADPH + H+ | - |
Yersinia pestis | 2-C-methyl-D-erythritol 4-phosphate + NADP+ | - |
? | |
1-deoxy-D-xylulose 5-phosphate + NADPH + H+ | - |
Francisella tularensis subsp. novicida | 2-C-methyl-D-erythritol 4-phosphate + NADP+ | - |
? | |
1-deoxy-D-xylulose 5-phosphate + NADPH + H+ | - |
Francisella tularensis subsp. novicida U112 | 2-C-methyl-D-erythritol 4-phosphate + NADP+ | - |
? | |
1-deoxy-D-xylulose 5-phosphate + NADPH + H+ | - |
Yersinia pestis A1122 | 2-C-methyl-D-erythritol 4-phosphate + NADP+ | - |
? | |
1-deoxy-D-xylulose 5-phosphate + NADPH + H+ | - |
Mycobacterium tuberculosis H37Rv | 2-C-methyl-D-erythritol 4-phosphate + NADP+ | - |
? | |
1-deoxy-D-xylulose 5-phosphate + NADPH + H+ | - |
Mycobacterium tuberculosis ATCC 25618 | 2-C-methyl-D-erythritol 4-phosphate + NADP+ | - |
? |
Synonyms | Comment | Organism |
---|---|---|
DXP reductoisomerase | - |
Mycobacterium tuberculosis |
DXP reductoisomerase | - |
Yersinia pestis |
DXP reductoisomerase | - |
Francisella tularensis subsp. novicida |
DXR | - |
Mycobacterium tuberculosis |
DXR | - |
Yersinia pestis |
DXR | - |
Francisella tularensis subsp. novicida |
FtIspC | - |
Francisella tularensis subsp. novicida |
IspC | - |
Mycobacterium tuberculosis |
IspC | - |
Yersinia pestis |
IspC | - |
Francisella tularensis subsp. novicida |
MtbIspC | - |
Mycobacterium tuberculosis |
YpIspC | - |
Yersinia pestis |
Temperature Optimum [°C] | Temperature Optimum Maximum [°C] | Comment | Organism |
---|---|---|---|
37 | - |
assay at | Mycobacterium tuberculosis |
37 | - |
assay at | Yersinia pestis |
37 | - |
assay at | Francisella tularensis subsp. novicida |
pH Optimum Minimum | pH Optimum Maximum | Comment | Organism |
---|---|---|---|
7.8 | - |
assay at | Mycobacterium tuberculosis |
7.8 | - |
assay at | Yersinia pestis |
7.8 | - |
assay at | Francisella tularensis subsp. novicida |
Cofactor | Comment | Organism | Structure |
---|---|---|---|
NADP+ | - |
Mycobacterium tuberculosis | |
NADP+ | - |
Yersinia pestis | |
NADP+ | - |
Francisella tularensis subsp. novicida | |
NADPH | - |
Mycobacterium tuberculosis | |
NADPH | - |
Yersinia pestis | |
NADPH | - |
Francisella tularensis subsp. novicida |
General Information | Comment | Organism |
---|---|---|
metabolism | the enzyme catalyzes the first comitted step in the methyl erythritol phosphate (MEP) pathway | Mycobacterium tuberculosis |
metabolism | the enzyme catalyzes the first comitted step in the methyl erythritol phosphate (MEP) pathway | Yersinia pestis |
metabolism | the enzyme catalyzes the first comitted step in the methyl erythritol phosphate (MEP) pathway | Francisella tularensis subsp. novicida |