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Literature summary for 1.17.7.4 extracted from

  • Wang, W.; Wang, K.; Liu, Y.; No, J.; Li, J.; Nilges, M.; Oldfield, E.
    Bioorganometallic mechanism of action, and inhibition, of IspH (2010), Proc. Natl. Acad. Sci. USA, 107, 4522-4527.
    View publication on PubMedView publication on EuropePMC

Cloned(Commentary)

Cloned (Comment) Organism
expression in Escherichia coli Aquifex aeolicus

Protein Variants

Protein Variants Comment Organism
E126A site-directed mutagenesis, the mutant is almost inactive, formation of an organometallic species with HMBPP, a pi/sigma metallacycle or nu2-alkenyl complex, overview Aquifex aeolicus
H124A site-directed mutagenesis, the mutant shows an increased Km and a 5fold decreased Vmax compared to the wild-type enzyme Aquifex aeolicus
H42A site-directed mutagenesis, the mutant shows a decreased Vmax but unaltered Km compared to the wild-type enzyme Aquifex aeolicus

Inhibitors

Inhibitors Comment Organism Structure
additional information alkyne diphosphates are potent IspH inhibitors that form metallacycle complexes. Identification of inhibitors using the metallacycle model Aquifex aeolicus
propargyl alcohol weak inhibition, binding structure, overview Aquifex aeolicus
propargyl diphosphate binding structure, overview Aquifex aeolicus

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
(E)-4-hydroxy-3-methylbut-2-en-1-yl diphosphate + NAD(P)H + H+ Aquifex aeolicus HMBPP reductase catalyzes the 2H+/2e- reduction of (E)-4-hydroxy-3-methylbut-2-en-1-yl diphosphate to form an approximately 5:1 mixture of isopentenyl diphosphate and dimethylallyl diphosphate, insights into IspH catalysis and inhibition, involving organometallic species. Residue E126 is essential for catalytic activity. Residue H124 is not a major contributor to substrate binding, but is essential for catalysis, it is involved in delivering H+ to E126 and the bound (E)-4-hydroxy-3-methylbut-2-en-1-yl diphosphate. Residue H42 forms hydrogen bonds to the bound diphosphate ligand. Ligand binding structure spectral analysis and modelling, overview dimethylallyl diphosphate + NAD(P)+ + H2O
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r
(E)-4-hydroxy-3-methylbut-2-en-1-yl diphosphate + NAD(P)H + H+ Aquifex aeolicus HMBPP reductase catalyzes the 2H+/2e- reduction of (E)-4-hydroxy-3-methylbut-2-en-1-yl diphosphate to form an approximately 5:1 mixture of isopentenyl diphosphate and dimethylallyl diphosphate, insights into IspH catalysis and inhibition, involving organometallic species. Residue E126 is essential for catalytic activity. Residue H124 is not a major contributor to substrate binding, but is essential for catalysis, it is involved in delivering H+ to E126 and the bound (E)-4-hydroxy-3-methylbut-2-en-1-yl diphosphate. Residue H42 forms hydrogen bonds to the bound diphosphate ligand. Ligand binding structure spectral analysis and modelling, overview isopentenyl diphosphate + NAD(P)+ + H2O
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r

Organism

Organism UniProt Comment Textmining
Aquifex aeolicus
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gene lytB
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no activity in Homo sapiens
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-
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Reaction

Reaction Comment Organism Reaction ID
dimethylallyl diphosphate + 2 oxidized ferredoxin [iron-sulfur] cluster + H2O = (E)-4-hydroxy-3-methylbut-2-en-1-yl diphosphate + 2 reduced ferredoxin [iron-sulfur] cluster + 2 H+ reaction mechanism, role of protein residues in the IspH mechanism, detailed overview Aquifex aeolicus
isopentenyl diphosphate + 2 oxidized ferredoxin [iron-sulfur] cluster + H2O = (E)-4-hydroxy-3-methylbut-2-en-1-yl diphosphate + 2 reduced ferredoxin [iron-sulfur] cluster + 2 H+ reaction mechanism, role of protein residues in the IspH mechanism, detailed overview Aquifex aeolicus

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
(E)-4-hydroxy-3-methylbut-2-en-1-yl diphosphate + NAD(P)H + H+ HMBPP reductase catalyzes the 2H+/2e- reduction of (E)-4-hydroxy-3-methylbut-2-en-1-yl diphosphate to form an approximately 5:1 mixture of isopentenyl diphosphate and dimethylallyl diphosphate, insights into IspH catalysis and inhibition, involving organometallic species. Residue E126 is essential for catalytic activity. Residue H124 is not a major contributor to substrate binding, but is essential for catalysis, it is involved in delivering H+ to E126 and the bound (E)-4-hydroxy-3-methylbut-2-en-1-yl diphosphate. Residue H42 forms hydrogen bonds to the bound diphosphate ligand. Ligand binding structure spectral analysis and modelling, overview Aquifex aeolicus dimethylallyl diphosphate + NAD(P)+ + H2O
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r
(E)-4-hydroxy-3-methylbut-2-en-1-yl diphosphate + NAD(P)H + H+ HMBPP reductase catalyzes the 2H+/2e- reduction of (E)-4-hydroxy-3-methylbut-2-en-1-yl diphosphate to form an approximately 5:1 mixture of isopentenyl diphosphate and dimethylallyl diphosphate, insights into IspH catalysis and inhibition, involving organometallic species. Residue E126 is essential for catalytic activity. Residue H124 is not a major contributor to substrate binding, but is essential for catalysis, it is involved in delivering H+ to E126 and the bound (E)-4-hydroxy-3-methylbut-2-en-1-yl diphosphate. Residue H42 forms hydrogen bonds to the bound diphosphate ligand. Ligand binding structure spectral analysis and modelling, overview Aquifex aeolicus isopentenyl diphosphate + NAD(P)+ + H2O
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r

Synonyms

Synonyms Comment Organism
E-4-hydroxy-3-methyl-but-2-enyl diphosphate reductase
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Aquifex aeolicus
HMBPP reductase
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Aquifex aeolicus
ispH
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Aquifex aeolicus
LytB
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Aquifex aeolicus

Ki Value [mM]

Ki Value [mM] Ki Value maximum [mM] Inhibitor Comment Organism Structure
0.97
-
propargyl diphosphate pH not specified in the publication, temperature not specified in the publication Aquifex aeolicus
10
-
propargyl alcohol above, pH not specified in the publication, temperature not specified in the publication Aquifex aeolicus

General Information

General Information Comment Organism
physiological function the enzyme is essential for survival Aquifex aeolicus