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Literature summary for 2.7.7.60 extracted from

  • Saggu, G.S.; Garg, S.; Pala, Z.R.; Kochar, S.K.; Saxena, V.
    Deciphering the role of IspD (2-C-methyl-D-erythritol 4-phosphate cytidyltransferase) enzyme as a potential therapeutic drug target against Plasmodium vivax (2018), Gene, 675, 240-253 .
    View publication on PubMed
Search for more literature for 2.7.7.60

Application

Application Comment Organism
drug development 2-C-methyl-D-erythritol 4-phosphate cytidyltransferase, enzyme IspD, is a potential therapeutic drug target in Plasmodium vivax Plasmodium vivax

Cloned(Commentary)

Cloned (Comment) Organism
gene PvispD, DNA and amino acid sequence determination and analysis, phylogenetic analysis of ispD proteins, recombinant expression of MBP-tagged PvIspD fusion protein in Escherichia coli strain ER2523 from plasmid pMALc2X-PvispD Plasmodium vivax

Inhibitors

Inhibitors Comment Organism Structure
7-hydroxy-[1,2,4] triazolo[1,5-a] pyrimidine azolopyrimidine, docking reveals strong hydrogen bonds with CTP-specific (T326, K406, R431, and K548) and MEP-specific (D428, R431, T525, and K548) amino acid residues of PvIspD protein. A salt-bridge formation is also observed with K406 and D428 residues similar to CTP Plasmodium vivax
cefepime interaction with residues T525 and K548 Plasmodium vivax
domiphen bromide interaction with residue Thr 525 Plasmodium vivax
fosmidomycin Fos, a well-known inhibitor of DXR/IspC enzyme. Strong interaction of Fos with PvIspD enzyme, where hydrogen bonds are observed between Fos and amino acid residues D428, R431, Q493, T523, D524, T525 and K548 of PvIspD enzyme. residues R431 and K548 which form the salt bridge with CTP are observed to form a bridge with the negatively charged phosphate group of Fos Plasmodium vivax
MMV008138 weak inhibition of Plasmodium vivax IspD, the compound is a competitive inhibitor of PvIspD at lower concentrations of CTP, interaction with residues D428, T525, and K548 Plasmodium vivax
additional information docking study Plasmodium vivax
rifampicin a prokaryotic transcription inhibitor, interaction with residues T326, R431, T525, and K548 Plasmodium vivax
tunicamycin interaction with residues V323, T324, T326, D338, L381, L384, K406, and T491 Plasmodium vivax

KM Value [mM]

KM Value [mM] KM Value Maximum [mM] Substrate Comment Organism Structure
0.02305
-
 CTP pH 7.9, 37°C, recombinant enzyme Plasmodium vivax
0.02513
-
 2-C-methyl-D-erythritol 4-phosphate pH 7.9, 37°C, recombinant enzyme Plasmodium vivax

Metals/Ions

Metals/Ions Comment Organism Structure
Mg2+ the PvIspD enzyme is highly specific for Mg2+ ions Plasmodium vivax
additional information poor activity with Mn2+, no activity with Ca2+, Co2+, Cu2+, and Zn2+ Plasmodium vivax

Molecular Weight [Da]

Molecular Weight [Da] Molecular Weight Maximum [Da] Comment Organism
118000
-
 recombinant MBP-tagged enzyme, gel filtration Plasmodium vivax

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 Plasmodium vivax
-
 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
-
 ?

Organism

Organism UniProt Comment Textmining
Plasmodium vivax A5K9U5 obtained from clinical isolates
-
Plasmodium vivax Salvador I A5K9U5 obtained from clinical isolates
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
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 vivax Salvador I diphosphate + 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol
-
 ?
dCTP + 2-C-methyl-D-erythritol 4-phosphate
-
 Plasmodium vivax diphosphate + 4-(deoxycytidine 5'-diphospho)-2-C-methyl-D-erythritol
-
 ?
dCTP + 2-C-methyl-D-erythritol 4-phosphate
-
 Plasmodium vivax Salvador I diphosphate + 4-(deoxycytidine 5'-diphospho)-2-C-methyl-D-erythritol
-
 ?
additional information the PvIspD enzyme is highly specific for CTP, 20% of the activity with CTP is shown with dCTP, and below 10% activity with ATP, dATP, dGTP, and dTTP Plasmodium vivax ?
-
-
additional information the PvIspD enzyme is highly specific for CTP, 20% of the activity with CTP is shown with dCTP, and below 10% activity with ATP, dATP, dGTP, and dTTP Plasmodium vivax Salvador I ?
-
-

Synonyms

Synonyms Comment Organism
IspD
-
 Plasmodium vivax
PvIspD
-
 Plasmodium vivax

Temperature Optimum [°C]

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

pH Optimum

pH Optimum Minimum pH Optimum Maximum Comment Organism
7.9
-
 assay at Plasmodium vivax

Ki Value [mM]

Ki Value [mM] Ki Value maximum [mM] Inhibitor Comment Organism Structure
0.00000233
-
 cefepime pH 7.9, 37°C, recombinant enzyme Plasmodium vivax
0.0000759
-
 rifampicin pH 7.9, 37°C, recombinant enzyme Plasmodium vivax
0.000169
-
 domiphen bromide pH 7.9, 37°C, recombinant enzyme Plasmodium vivax
0.00131
-
 tunicamycin pH 7.9, 37°C, recombinant enzyme Plasmodium vivax
0.0015
-
 fosmidomycin pH 7.9, 37°C, recombinant enzyme Plasmodium vivax

General Information

General Information Comment Organism
additional information molecular dynamics simulation, homology PvIspD structure prediction by comparative modeling technique using the Escherichia coli IspD crystal structure (PDB ID 1I52) as template, and three-dimensional modeling of PvIspD. The conserved domain (NCBI) analysis of translated sequences (619 a.a.) shows the presence of Glycosyl transferase family A (GT-A) domain spanning the amino acid residues 191-558. The two signature motifs of the IspD proteins in this domain viz. GXG and [IVT]-[LIVMC]-[IVT]-[HS]-D-[SGAV]-[AV]-R are also observed in PVX_081425 and all Indian PvIspD sequences by PROSITE as 199GXG201 and 424ILVHDGAR431. Key residues R431 and K548 form the salt bridge with CTP Plasmodium vivax