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Literature summary for 2.7.7.60 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

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(Commentary)

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

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

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

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

Natural Substrates/ Products (Substrates)

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

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 (Commentary)

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 and Products (Substrate)

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

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

pH Optimum

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 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

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