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Literature summary extracted from

  • Imlay, L.; Armstrong, C.; Masters, M.; Li, T.; Price, K.; Edwards, R.; Mann, K.; Li, L.; Stallings, C.; Berry, N.; O'Neill, P.; Odom, A.
    Plasmodium IspD (2-C-methyl-D-erythritol 4-phosphate cytidyltransferase), an essential and druggable antimalarial target (2016), ACS Infect. Dis., 1, 157-167 .
    View publication on PubMedView publication on EuropePMC

Application

EC Number Application Comment Organism
2.7.7.60 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(Commentary)

EC Number Cloned (Comment) Organism
2.7.7.60 gene ispD, recombinant expression od wild-type enzyme in Escherichia coli Mycobacterium tuberculosis
2.7.7.60 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
2.7.7.60 gene ispD, recombinant expression of His-tagged wild-type and mutant enzymes in Escherichia coli Plasmodium falciparum

Protein Variants

EC Number Protein Variants Comment Organism
2.7.7.60 E688Q site-directed mutagenesis, the mutant shows reduced sensitivity to inhibition by MMV008138 as compared to the wild-type enzyme Plasmodium falciparum
2.7.7.60 L244I site-directed mutagenesis, the mutant shows reduced sensitivity to inhibition by MMV008138 as compared to the wild-type enzyme Plasmodium falciparum

Inhibitors

EC Number Inhibitors Comment Organism Structure
2.7.7.60 (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
2.7.7.60 (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
2.7.7.60 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
2.7.7.60 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

EC Number Metals/Ions Comment Organism Structure
2.7.7.60 Mg2+ required Mycobacterium tuberculosis
2.7.7.60 Mg2+ required Plasmodium vivax
2.7.7.60 Mg2+ required Plasmodium falciparum

Natural Substrates/ Products (Substrates)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
2.7.7.60 CTP + 2-C-methyl-D-erythritol 4-phosphate Mycobacterium tuberculosis
-
 diphosphate + 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol
-
 ?
2.7.7.60 CTP + 2-C-methyl-D-erythritol 4-phosphate Plasmodium vivax
-
 diphosphate + 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol
-
 ?
2.7.7.60 CTP + 2-C-methyl-D-erythritol 4-phosphate Plasmodium falciparum
-
 diphosphate + 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol
-
 ?
2.7.7.60 CTP + 2-C-methyl-D-erythritol 4-phosphate Plasmodium vivax Salvador I
-
 diphosphate + 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol
-
 ?
2.7.7.60 CTP + 2-C-methyl-D-erythritol 4-phosphate Mycobacterium tuberculosis H37Rv
-
 diphosphate + 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol
-
 ?
2.7.7.60 CTP + 2-C-methyl-D-erythritol 4-phosphate Mycobacterium tuberculosis ATCC 25618
-
 diphosphate + 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol
-
 ?

Organism

EC Number Organism UniProt Comment Textmining
2.7.7.60 Mycobacterium tuberculosis P9WKG9
-
-
2.7.7.60 Mycobacterium tuberculosis ATCC 25618 P9WKG9
-
-
2.7.7.60 Mycobacterium tuberculosis H37Rv P9WKG9
-
-
2.7.7.60 Plasmodium falciparum Q8I273
-
-
2.7.7.60 Plasmodium vivax A5K9U5
-
-
2.7.7.60 Plasmodium vivax Salvador I A5K9U5
-
-

Purification (Commentary)

EC Number Purification (Comment) Organism
2.7.7.60 recombinant His-tagged enzyme from Escherichia coli by nickel affinity chromatography and gel filtration Mycobacterium tuberculosis
2.7.7.60 recombinant His-tagged wild-enzyme from Escherichia coli by nickel affinity chromatography Plasmodium vivax
2.7.7.60 recombinant His-tagged wild-type and mutant enzymes from Escherichia coli by nickel affinity chromatography Plasmodium falciparum

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
2.7.7.60 CTP + 2-C-methyl-D-erythritol 4-phosphate
-
 Mycobacterium tuberculosis diphosphate + 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol
-
 ?
2.7.7.60 CTP + 2-C-methyl-D-erythritol 4-phosphate
-
 Plasmodium vivax diphosphate + 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol
-
 ?
2.7.7.60 CTP + 2-C-methyl-D-erythritol 4-phosphate
-
 Plasmodium falciparum diphosphate + 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol
-
 ?
2.7.7.60 CTP + 2-C-methyl-D-erythritol 4-phosphate
-
 Plasmodium vivax Salvador I diphosphate + 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol
-
 ?
2.7.7.60 CTP + 2-C-methyl-D-erythritol 4-phosphate
-
 Mycobacterium tuberculosis H37Rv diphosphate + 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol
-
 ?
2.7.7.60 CTP + 2-C-methyl-D-erythritol 4-phosphate
-
 Mycobacterium tuberculosis ATCC 25618 diphosphate + 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol
-
 ?

Synonyms

EC Number Synonyms Comment Organism
2.7.7.60 IspD
-
 Mycobacterium tuberculosis
2.7.7.60 IspD
-
 Plasmodium vivax
2.7.7.60 IspD
-
 Plasmodium falciparum
2.7.7.60 MEP cytidyltransferase
-
 Mycobacterium tuberculosis
2.7.7.60 MEP cytidyltransferase
-
 Plasmodium vivax
2.7.7.60 MEP cytidyltransferase
-
 Plasmodium falciparum
2.7.7.60 MtIspD
-
 Mycobacterium tuberculosis
2.7.7.60 PF3D7_0106900 locus name Plasmodium falciparum
2.7.7.60 PfIspD
-
 Plasmodium falciparum
2.7.7.60 PvIspD
-
 Plasmodium vivax
2.7.7.60 PVX_081425
-
 Plasmodium vivax
2.7.7.60 Rv3582c
-
 Mycobacterium tuberculosis

Temperature Optimum [°C]

EC Number Temperature Optimum [°C] Temperature Optimum Maximum [°C] Comment Organism
2.7.7.60 37
-
 assay at Mycobacterium tuberculosis
2.7.7.60 37
-
 assay at Plasmodium vivax
2.7.7.60 37
-
 assay at Plasmodium falciparum

pH Optimum

EC Number pH Optimum Minimum pH Optimum Maximum Comment Organism
2.7.7.60 7
-
 assay at Mycobacterium tuberculosis
2.7.7.60 7
-
 assay at Plasmodium vivax
2.7.7.60 7
-
 assay at Plasmodium falciparum

IC50 Value

EC Number IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
2.7.7.60 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
2.7.7.60 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
2.7.7.60 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
2.7.7.60 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

EC Number General Information Comment Organism
2.7.7.60 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
2.7.7.60 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
2.7.7.60 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
2.7.7.60 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
2.7.7.60 physiological function enzyme IspD (MEP cytidyltransferase) catalyzes the cytidylation of MEP to cytidine diphosphate methylerythritol (CDP-ME) Mycobacterium tuberculosis
2.7.7.60 physiological function enzyme IspD (MEP cytidyltransferase) catalyzes the cytidylation of MEP to cytidine diphosphate methylerythritol (CDP-ME) Plasmodium vivax
2.7.7.60 physiological function enzyme IspD (MEP cytidyltransferase) catalyzes the cytidylation of MEP to cytidine diphosphate methylerythritol (CDP-ME) Plasmodium falciparum