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Literature summary 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)

EC Number Cloned (Comment) Organism
1.17.7.4 expression in Escherichia coli Aquifex aeolicus

Protein Variants

EC Number Protein Variants Comment Organism
1.17.7.4 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
1.17.7.4 H124A site-directed mutagenesis, the mutant shows an increased Km and a 5fold decreased Vmax compared to the wild-type enzyme Aquifex aeolicus
1.17.7.4 H42A site-directed mutagenesis, the mutant shows a decreased Vmax but unaltered Km compared to the wild-type enzyme Aquifex aeolicus

Inhibitors

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

Natural Substrates/ Products (Substrates)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
1.17.7.4 (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
-
 r
1.17.7.4 (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
-
 r

Organism

EC Number Organism UniProt Comment Textmining
1.17.7.4 Aquifex aeolicus
-
 gene lytB
-
1.17.7.4 no activity in Homo sapiens
-
-
-

Reaction

EC Number Reaction Comment Organism Reaction ID
1.17.7.4 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
a
1.17.7.4 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
a

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
1.17.7.4 (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
-
 r
1.17.7.4 (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
-
 r

Synonyms

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

Ki Value [mM]

EC Number Ki Value [mM] Ki Value maximum [mM] Inhibitor Comment Organism Structure
1.17.7.4 0.97
-
 propargyl diphosphate pH not specified in the publication, temperature not specified in the publication Aquifex aeolicus
1.17.7.4 10
-
 propargyl alcohol above, pH not specified in the publication, temperature not specified in the publication Aquifex aeolicus

General Information

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