Application | Comment | Organism |
---|---|---|
drug development | IspD is a druggable target for the development of additional antimalarial agents. 1R,3S-MMV008138 shows promise as a potential scaffold for target-based antimalarial drug development | Plasmodium falciparum |
Cloned (Comment) | Organism |
---|---|
gene ispD, recombinant expression od wild-type enzyme in Escherichia coli | Mycobacterium tuberculosis |
gene ispD, recombinant expression of a synthetic gene encoding codon-optimized PvISPD (PVX_081425) with a truncated N-terminal apicoplast localization sequence in Escherichia coli | Plasmodium vivax |
gene ispD, recombinant expression of His-tagged wild-type and mutant enzymes in Escherichia coli | Plasmodium falciparum |
Protein Variants | Comment | Organism |
---|---|---|
E688Q | site-directed mutagenesis, the mutant shows reduced sensitivity to inhibition by MMV008138 as compared to the wild-type enzyme | Plasmodium falciparum |
L244I | site-directed mutagenesis, the mutant shows reduced sensitivity to inhibition by MMV008138 as compared to the wild-type enzyme | Plasmodium falciparum |
Inhibitors | Comment | Organism | Structure |
---|---|---|---|
(2,4-dichloro-phenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-2-ium-3-carboxylate | MMV008138, PfIspD is the sole intracellular target of MMV008138, target-based resistance. IspD binding mode analysis, overview. 1R,3S-MMV008138 directly inhibits purified recombinant Plasmodium falciparum IspD (PfIspD), competitively with its CTP substrate. The metabolic effects of 1R,3S-MMV008138 are specific to MEP pathway inhibition, 1R,3S-MMV008138 inhibits malaria parasite growth as a consequence of MEP pathway inhibition. 1R,3S-MMV008138 is also active against Plasmodium vivax but not against bacterial IspD homologues | Plasmodium falciparum | |
(2,4-dichloro-phenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-2-ium-3-carboxylate | MMV008138, Plasmodium vivax IspD (PvIspD) is potently inhibited by 1R,3S-MMV008138. IspD binding mode analysis, overview | Plasmodium vivax | |
additional information | no inhibition of Mycobacetrium tuberculosis IspD by (2,4-dichloro-phenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-2-ium-3-carboxylate, MMV008138 | Mycobacterium tuberculosis | |
additional information | the PfISPD genetic locus is refractory to disruption in malaria parasites, providing independent genetic validation for efforts targeting this enzyme. Phosphonic acid antibiotic fosmidomycin is a substrate mimic and inhibitor of DXR.13 The inhibition of downstream enzyme IspD is also metabolically apparent in fosmidomycin-treated cells, although IspD homologues are not directly inhibited by fosmidomycin in vitro | Plasmodium falciparum |
Metals/Ions | Comment | Organism | Structure |
---|---|---|---|
Mg2+ | required | Mycobacterium tuberculosis | |
Mg2+ | required | Plasmodium vivax | |
Mg2+ | required | Plasmodium falciparum |
Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
---|---|---|---|---|---|---|
CTP + 2-C-methyl-D-erythritol 4-phosphate | Mycobacterium tuberculosis | - |
diphosphate + 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol | - |
? | |
CTP + 2-C-methyl-D-erythritol 4-phosphate | Plasmodium vivax | - |
diphosphate + 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol | - |
? | |
CTP + 2-C-methyl-D-erythritol 4-phosphate | Plasmodium falciparum | - |
diphosphate + 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol | - |
? | |
CTP + 2-C-methyl-D-erythritol 4-phosphate | Plasmodium vivax Salvador I | - |
diphosphate + 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol | - |
? | |
CTP + 2-C-methyl-D-erythritol 4-phosphate | Mycobacterium tuberculosis H37Rv | - |
diphosphate + 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol | - |
? | |
CTP + 2-C-methyl-D-erythritol 4-phosphate | Mycobacterium tuberculosis ATCC 25618 | - |
diphosphate + 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol | - |
? |
Organism | UniProt | Comment | Textmining |
---|---|---|---|
Mycobacterium tuberculosis | P9WKG9 | - |
- |
Mycobacterium tuberculosis ATCC 25618 | P9WKG9 | - |
- |
Mycobacterium tuberculosis H37Rv | P9WKG9 | - |
- |
Plasmodium falciparum | Q8I273 | - |
- |
Plasmodium vivax | A5K9U5 | - |
- |
Plasmodium vivax Salvador I | A5K9U5 | - |
- |
Purification (Comment) | Organism |
---|---|
recombinant His-tagged enzyme from Escherichia coli by nickel affinity chromatography and gel filtration | Mycobacterium tuberculosis |
recombinant His-tagged wild-enzyme from Escherichia coli by nickel affinity chromatography | Plasmodium vivax |
recombinant His-tagged wild-type and mutant enzymes from Escherichia coli by nickel affinity chromatography | Plasmodium falciparum |
Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
---|---|---|---|---|---|---|
CTP + 2-C-methyl-D-erythritol 4-phosphate | - |
Mycobacterium tuberculosis | diphosphate + 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol | - |
? | |
CTP + 2-C-methyl-D-erythritol 4-phosphate | - |
Plasmodium vivax | diphosphate + 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol | - |
? | |
CTP + 2-C-methyl-D-erythritol 4-phosphate | - |
Plasmodium falciparum | diphosphate + 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol | - |
? | |
CTP + 2-C-methyl-D-erythritol 4-phosphate | - |
Plasmodium vivax Salvador I | diphosphate + 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol | - |
? | |
CTP + 2-C-methyl-D-erythritol 4-phosphate | - |
Mycobacterium tuberculosis H37Rv | diphosphate + 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol | - |
? | |
CTP + 2-C-methyl-D-erythritol 4-phosphate | - |
Mycobacterium tuberculosis ATCC 25618 | diphosphate + 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol | - |
? |
Synonyms | Comment | Organism |
---|---|---|
IspD | - |
Mycobacterium tuberculosis |
IspD | - |
Plasmodium vivax |
IspD | - |
Plasmodium falciparum |
MEP cytidyltransferase | - |
Mycobacterium tuberculosis |
MEP cytidyltransferase | - |
Plasmodium vivax |
MEP cytidyltransferase | - |
Plasmodium falciparum |
MtIspD | - |
Mycobacterium tuberculosis |
PF3D7_0106900 | locus name | Plasmodium falciparum |
PfIspD | - |
Plasmodium falciparum |
PvIspD | - |
Plasmodium vivax |
PVX_081425 | - |
Plasmodium vivax |
Rv3582c | - |
Mycobacterium tuberculosis |
Temperature Optimum [°C] | Temperature Optimum Maximum [°C] | Comment | Organism |
---|---|---|---|
37 | - |
assay at | Mycobacterium tuberculosis |
37 | - |
assay at | Plasmodium vivax |
37 | - |
assay at | Plasmodium falciparum |
pH Optimum Minimum | pH Optimum Maximum | Comment | Organism |
---|---|---|---|
7 | - |
assay at | Mycobacterium tuberculosis |
7 | - |
assay at | Plasmodium vivax |
7 | - |
assay at | Plasmodium falciparum |
IC50 Value | IC50 Value Maximum | Comment | Organism | Inhibitor | Structure |
---|---|---|---|---|---|
0.000047 | - |
recombinant wild-type enzyme, pH 7.0, 37°C | Plasmodium falciparum | (2,4-dichloro-phenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-2-ium-3-carboxylate | |
0.0001 | - |
recombinant IspD mutant L244I, pH 7.0, 37°C | Plasmodium falciparum | (2,4-dichloro-phenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-2-ium-3-carboxylate | |
0.00031 | - |
recombinant wild-type enzyme, pH 7.0, 37°C | Plasmodium vivax | (2,4-dichloro-phenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-2-ium-3-carboxylate | |
0.00032 | - |
recombinant IspD mutant E688Q, pH 7.0, 37°C | Plasmodium falciparum | (2,4-dichloro-phenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-2-ium-3-carboxylate |
General Information | Comment | Organism |
---|---|---|
malfunction | the inhibition of DXR (EC 1.1.1.267, MEP synthase) dramatically reduces IspD function in cells. Phosphonic acid antibiotic fosmidomycin is a substrate mimic and inhibitor of DXR. The inhibition of downstream enzyme IspD is also metabolically apparent in fosmidomycin-treated cells, although IspD homologues are not directly inhibited by fosmidomycin in vitro | Mycobacterium tuberculosis |
malfunction | the inhibition of DXR (EC 1.1.1.267, MEP synthase) dramatically reduces IspD function in cells. Phosphonic acid antibiotic fosmidomycin is a substrate mimic and inhibitor of DXR. The inhibition of downstream enzyme IspD is also metabolically apparent in fosmidomycin-treated cells, although IspD homologues are not directly inhibited by fosmidomycin in vitro | Plasmodium vivax |
malfunction | the inhibition of DXR (EC 1.1.1.267, MEP synthase) dramatically reduces IspD function in cells. Phosphonic acid antibiotic fosmidomycin is a substrate mimic and inhibitor of DXR.13 The inhibition of downstream enzyme IspD is also metabolically apparent in fosmidomycin-treated cells, although IspD homologues are not directly inhibited by fosmidomycin in vitro. 1R,3S-MMV008138-treated parasites supplemented with 0.2 mM isopentenyl diphosphate (IPP) are viable, but 1R,3S-MMV008138 treatment of such IPP-rescued cells still results in a significant reduction in methylerythritol cyclic diphosphate (MEcPP) levels, the most distal MEP metabolite detected | Plasmodium falciparum |
additional information | the Pf ISPD genetic locus is refractory to disruption in malaria parasites, providing independent genetic validation for efforts targeting this enzyme | Plasmodium falciparum |
physiological function | enzyme IspD (MEP cytidyltransferase) catalyzes the cytidylation of MEP to cytidine diphosphate methylerythritol (CDP-ME) | Mycobacterium tuberculosis |
physiological function | enzyme IspD (MEP cytidyltransferase) catalyzes the cytidylation of MEP to cytidine diphosphate methylerythritol (CDP-ME) | Plasmodium vivax |
physiological function | enzyme IspD (MEP cytidyltransferase) catalyzes the cytidylation of MEP to cytidine diphosphate methylerythritol (CDP-ME) | Plasmodium falciparum |