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Information on EC 1.1.1.87 - homoisocitrate dehydrogenase
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EC Tree
1.1.1.87 homoisocitrate dehydrogenaseIUBMB Comments
Forms part of the lysine biosynthesis pathway in fungi .
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Word Map
- 1.1.1.87
- alpha-aminoadipate
- 3-isopropylmalate
- homocitrate
- homoaconitase
-
beta-decarboxylating
- alpha-ketoadipate
- medicine
- synthesis
The enzyme appears in viruses and cellular organisms
Reaction Schemes
Synonyms
lys12, homoisocitrate dehydrogenase, tk0280, schicdh, homoisocitric dehydrogenase, 
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
(-)-1-hydroxy-1,2,4-butanetricarboxylate:NAD+ oxidoreductase (decarboxylating)
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-
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2-hydroxy-3-carboxyadipate dehydrogenase
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-
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3-carboxy-2-hydroxyadipate dehydrogenase
3-carboxy-2-hydroxyadipate:NAD+ oxidoreductase (decarboxylating)
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-
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beta-decarboxylating dehydrogenase
dehydrogenase, homoisocitrate
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EC 1.1.1.155
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formerly
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HIc dehydrogenase
HICDH
homoisocitric dehydrogenase
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LYS12
TK0280
3-carboxy-2-hydroxyadipate dehydrogenase
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-
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
(1R,2S)-1-hydroxybutane-1,2,4-tricarboxylate + NAD+ = 2-oxoadipate + CO2 + NADH + H+
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(1R,2S)-1-hydroxybutane-1,2,4-tricarboxylate + NAD+ = 2-oxoadipate + CO2 + NADH + H+
two enzyme groups act as acid-base catalysts in the reaction. A group with a pKa of 6.5-7 acts as a general base accepting a proton as the beta-hydroxy acid is oxidized to the beta-keto acid, and this residue participates in all three of the chemical steps, acting to shuttle a proton between the C2 hydroxyl and itself. The second group acts as a general acid with a pKa of 9.5 and likely catalyzes the tautomerization step by donating a proton to the enol to give the final product
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(1R,2S)-1-hydroxybutane-1,2,4-tricarboxylate + NAD+ = 2-oxoadipate + CO2 + NADH + H+
there are 2 groups acting as acid-base catalysts in the reaction. One residue with a pKa of 6.5-7.0 serves as the general base to accept a proton as the beta-hydroxy acid is oxidized to the beta-keto acid, and this residue participates in all three of the chemical steps, acting to shuttle a proton between the C2 hydroxyl and itself. The metal ion then acts as a Lewis acid to catalyze the decarboxylation of the beta-ketoacid, with the general base donating a proton to the keto oxygen as the enol of alpha-ketoadipate is formed. A second residue with a pKa of 9.5 likely catalyzes the tautomerization step by donating a proton to the enol to give the final product. Catalytic rapid equilibrium random kinetic mechanism, overview
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
oxidation
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-
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oxidative decarboxylation
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reduction
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reductive carboxylation
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-
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PATHWAY SOURCE
PATHWAYS
BRENDA
KEGG
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SYSTEMATIC NAME
IUBMB Comments
(1R,2S)-1-hydroxybutane-1,2,4-tricarboxylate:NAD+ oxidoreductase (decarboxylating)
Forms part of the lysine biosynthesis pathway in fungi [3].
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CAS REGISTRY NUMBER
COMMENTARY
37250-23-0
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9067-90-7
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
2(R),3(S)-homoisocitrate + NAD+
alpha-ketoadipate + NADH + CO2 + H+
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with homoisocitrate as the substrate, no primary deuterium isotope effect is observed, and a small 13C kinetic isotope effect indicates that the decarboxylation step contributes only slightly to rate limitation
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-
?
homoisocitrate + NADP+
alpha-ketoadipate + NADPH + H+ + CO2
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-
-
-
r
threo-D-isocitric acid + NAD+
?
-
with isocitrate as the substrate, primary deuterium and 13C isotope effects indicate that hydride transfer and decarboxylation steps contribute to rate limitation, and that the decarboxylation step is the more rate-limiting of the two. The multiple-substrate deuterium/13C isotope effects suggest a stepwise mechanism with hydride transfer preceding decarboxylation
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-
?
trisodium (2S,3R)-2-(carboxylatomethoxy)-3-hydroxybutanedioate + NAD+
? + NADH + CO2
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-
-
-
?
trisodium (2S,3R)-2-[(carboxylatomethyl)amino]-3-hydroxybutanedioate + NAD+
? + NADH + CO2
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-
-
-
?
(1R,2S)-1-hydroxybutane-1,2,4-tricarboxylate + NAD+
2-oxoadipate + CO2 + NADH + H+
-
strict specificity for homoisocitrate
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-
?
(1R,2S)-1-hydroxybutane-1,2,4-tricarboxylate + NAD+
2-oxoadipate + CO2 + NADH + H+
-
strict specificity for homoisocitrate, the enzyme selectively binds the Mg(II):homoisocitrate complex
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-
?
(1R,2S)-1-hydroxybutane-1,2,4-tricarboxylate + NAD+
2-oxoadipate + CO2 + NADH + H+
-
strict specificity for homoisocitrate
-
-
?
(1R,2S)-1-hydroxybutane-1,2,4-tricarboxylate + NAD+
2-oxoadipate + CO2 + NADH + H+
-
strict specificity for homoisocitrate, the enzyme selectively binds the Mg(II):homoisocitrate complex
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-
?
(1R,2S)-1-hydroxybutane-1,2,4-tricarboxylate + NAD+
2-oxoadipate + CO2 + NADH + H+
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-
-
?
(1R,2S)-1-hydroxybutane-1,2,4-tricarboxylate + NAD+
2-oxoadipate + CO2 + NADH + H+
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-
-
?
(1R,2S)-1-hydroxybutane-1,2,4-tricarboxylate + NAD+
2-oxoadipate + CO2 + NADH + H+
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-
-
?
(1R,2S)-1-hydroxybutane-1,2,4-tricarboxylate + NAD+
2-oxoadipate + CO2 + NADH + H+
i.e. (2R,3S)-homoisocitrate
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-
?
(1R,2S)-1-hydroxybutane-1,2,4-tricarboxylate + NAD+
2-oxoadipate + NADH + H+ + CO2
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?
(1R,2S)-1-hydroxybutane-1,2,4-tricarboxylate + NAD+
2-oxoadipate + NADH + H+ + CO2
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homoisocitrate dehydrogenase catalyzes the Mg2+- and K+-dependent oxidative decarboxylation of homoisocitrate to alpha-ketoadipate using NAD as the oxidant, it utilizes a Lys-Tyr pair to catalyze the acid-base chemistry of the reaction, the active site Lys-Tyr pair consists of lysine 206 and tyrosine 150
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-
?
(1R,2S)-1-hydroxybutane-1,2,4-tricarboxylate + NAD+
2-oxoadipate + NADH + H+ + CO2
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substitution of potassium acetate for KCl changes the kinetic mechanism of HIcDH from a steady state random to a fully ordered mechanism with the binding of Mg-HIc followed by K+ and NAD+
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?
1-hydroxy-1,2,3-propanetricarboxylate + NAD+
?
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more effective substrate than 1-hydroxy-1,2,4-butanetricarboxylate
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?
1-hydroxy-1,2,3-propanetricarboxylate + NAD+
?
Thermus thermophilus HB27 / ATCC BAA-163 / DSM 7039
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more effective substrate than 1-hydroxy-1,2,4-butanetricarboxylate
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?
1-hydroxy-1,2,4-butanetricarboxylate + NAD+
2-oxoadipate + CO2 + NADH
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?
1-hydroxy-1,2,4-butanetricarboxylate + NAD+
2-oxoadipate + CO2 + NADH
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?
1-hydroxy-1,2,4-butanetricarboxylate + NAD+
2-oxoadipate + CO2 + NADH
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?
1-hydroxy-1,2,4-butanetricarboxylate + NAD+
2-oxoadipate + CO2 + NADH
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?
1-hydroxy-1,2,4-butanetricarboxylate + NAD+
2-oxoadipate + CO2 + NADH
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?
1-hydroxy-1,2,4-butanetricarboxylate + NAD+
2-oxoadipate + CO2 + NADH
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r
1-hydroxy-1,2,4-butanetricarboxylate + NAD+
2-oxoadipate + CO2 + NADH
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i.e. homoisocitrate
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r
1-hydroxy-1,2,4-butanetricarboxylate + NAD+
2-oxoadipate + CO2 + NADH
Saccharomycopsis lipolytica
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-
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?
1-hydroxy-1,2,4-butanetricarboxylate + NAD+
2-oxoadipate + CO2 + NADH
Saccharomycopsis lipolytica
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production of 2-oxoadipic acid, a precursor of lysine biosynthesis
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-
?
1-hydroxy-1,2,4-butanetricarboxylate + NAD+
2-oxoadipate + CO2 + NADH
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?
1-hydroxy-1,2,4-butanetricarboxylate + NAD+
2-oxoadipate + CO2 + NADH
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alpha-aminoadipate pathway for biosynthesis of lysine
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?
1-hydroxy-1,2,4-butanetricarboxylate + NAD+
2-oxoadipate + CO2 + NADH
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?
1-hydroxy-1,2,4-butanetricarboxylate + NAD+
2-oxoadipate + CO2 + NADH
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involved in lysine biosynthesis through alpha-aminoadipate
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?
1-hydroxy-1,2,4-butanetricarboxylate + NAD+
2-oxoadipate + CO2 + NADH
Thermus thermophilus HB27 / ATCC BAA-163 / DSM 7039
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-
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?
1-hydroxy-1,2,4-butanetricarboxylate + NAD+
2-oxoadipate + CO2 + NADH
Thermus thermophilus HB27 / ATCC BAA-163 / DSM 7039
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involved in lysine biosynthesis through alpha-aminoadipate
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?
3-carboxy-2-hydroxyadipate + NAD+
2-oxoadipate + CO2 + NADH
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?
3-carboxy-2-hydroxyadipate + NAD+
2-oxoadipate + CO2 + NADH
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intermediate in lysine biosynthesis
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?
3-isopropylmalate + NAD+
alpha-ketoisocaproate + NADH + H+ + CO2
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the enzyme has low catalytic efficiency toward 3-isopropylmalate
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?
3-isopropylmalate + NAD+
alpha-ketoisocaproate + NADH + H+ + CO2
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the enzyme has low catalytic efficiency toward 3-isopropylmalate
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?
homoisocitrate + NAD+
alpha-ketoadipate + NADH + H+ + CO2
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highest activity
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r
homoisocitrate + NAD+
alpha-ketoadipate + NADH + H+ + CO2
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highest activity
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r
isocitrate + NADP+
2-oxoglutarate + NADPH + H+ + CO2
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?
additional information
?
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retinol dehydrogenase 10 activity is critical for spatiotemporal synthesis of retinoic acid during embrogenesis
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?
additional information
?
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the enzyme is trifunctional performing the activities of 3-isopropylmalate, isocitrate, and homoisocitrate dehydrogenase in one pathway
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?
additional information
?
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the enzyme is trifunctional performing the activities of 3-isopropylmalate, isocitrate, and homoisocitrate dehydrogenase in one pathway
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?
additional information
?
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catalyzes keto-enol tautomerization of tritiated alpha-ketoadipate, not: ethanol, isocitrate, malate, glutamate
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?
additional information
?
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no activity with isocitrate, isopropylmalate, and tartrate
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?
additional information
?
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the wild-type enzyme with isocitrate as the substrate is about 200times slower than with homoisocitrate
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?
additional information
?
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the wild-type enzyme with isocitrate as the substrate is about 200times slower than with homoisocitrate
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?
additional information
?
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no activity with L-tartrate
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-
additional information
?
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substrate binding site structure, the substrate specificity is determined by residue Arg85, no activity with 3-isopropylmalate
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?
additional information
?
-
Thermus thermophilus HB27 / ATCC BAA-163 / DSM 7039
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no activity with 3-isopropylmalate
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-
?
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
(1R,2S)-1-hydroxybutane-1,2,4-tricarboxylate + NAD+
2-oxoadipate + NADH + H+ + CO2
-
-
-
-
?
3-carboxy-2-hydroxyadipate + NAD+
2-oxoadipate + CO2 + NADH
-
intermediate in lysine biosynthesis
-
-
?
(1R,2S)-1-hydroxybutane-1,2,4-tricarboxylate + NAD+
2-oxoadipate + CO2 + NADH + H+
-
strict specificity for homoisocitrate
-
-
?
(1R,2S)-1-hydroxybutane-1,2,4-tricarboxylate + NAD+
2-oxoadipate + CO2 + NADH + H+
-
strict specificity for homoisocitrate
-
-
?
(1R,2S)-1-hydroxybutane-1,2,4-tricarboxylate + NAD+
2-oxoadipate + CO2 + NADH + H+
-
-
-
?
1-hydroxy-1,2,4-butanetricarboxylate + NAD+
2-oxoadipate + CO2 + NADH
-
-
-
?
1-hydroxy-1,2,4-butanetricarboxylate + NAD+
2-oxoadipate + CO2 + NADH
-
-
-
?
1-hydroxy-1,2,4-butanetricarboxylate + NAD+
2-oxoadipate + CO2 + NADH
-
-
-
?
1-hydroxy-1,2,4-butanetricarboxylate + NAD+
2-oxoadipate + CO2 + NADH
-
-
-
?
1-hydroxy-1,2,4-butanetricarboxylate + NAD+
2-oxoadipate + CO2 + NADH
-
-
-
-
?
1-hydroxy-1,2,4-butanetricarboxylate + NAD+
2-oxoadipate + CO2 + NADH
-
-
-
-
r
1-hydroxy-1,2,4-butanetricarboxylate + NAD+
2-oxoadipate + CO2 + NADH
Saccharomycopsis lipolytica
-
production of 2-oxoadipic acid, a precursor of lysine biosynthesis
-
-
?
1-hydroxy-1,2,4-butanetricarboxylate + NAD+
2-oxoadipate + CO2 + NADH
-
alpha-aminoadipate pathway for biosynthesis of lysine
-
?
1-hydroxy-1,2,4-butanetricarboxylate + NAD+
2-oxoadipate + CO2 + NADH
-
involved in lysine biosynthesis through alpha-aminoadipate
-
-
?
1-hydroxy-1,2,4-butanetricarboxylate + NAD+
2-oxoadipate + CO2 + NADH
Thermus thermophilus HB27 / ATCC BAA-163 / DSM 7039
-
involved in lysine biosynthesis through alpha-aminoadipate
-
-
?
additional information
?
-
-
retinol dehydrogenase 10 activity is critical for spatiotemporal synthesis of retinoic acid during embrogenesis
-
-
?
additional information
?
-
the enzyme is trifunctional performing the activities of 3-isopropylmalate, isocitrate, and homoisocitrate dehydrogenase in one pathway
-
-
?
additional information
?
-
-
the enzyme is trifunctional performing the activities of 3-isopropylmalate, isocitrate, and homoisocitrate dehydrogenase in one pathway
-
-
?
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
K+
Mg2+
Mn2+
additional information
-
selectivity of the activator site for monovalent ions, K+ is the best activator, and NH4+ and Rb+ are also activators of the reaction, while Cs+, Li+, and Na+ are not, overview. Substitution of potassium acetate for KCl changes the kinetic mechanism of HIcDH from a steady state random to a fully ordered mechanism with the binding of Mg-HIc followed by K+ and NAD+
K+
the enzyme requires a potassium ion as an activator, for optimal binding of NAD+
Mg2+
-
stimulation of oxidative decarboxylation, required for reductive carboxylation
Mg2+
-
activates, increase in the affinity of enzyme for Mg-HIc as a result of elimination of the inhibitory effect of Cl-
Mg2+
required, three conserved aspartate residues, D243, D267 and D271, coordinate Mg2+, which is also coordinated to the alpha-carboxylate and alpha-hydroxyl of homoisocitrate
Mg2+
-
Mn2+ or Mg2+ is required for this activity, and stronger activity is observed with Mn2+
Mn2+
-
Mn2+ or Mg2+ is required for this activity, and stronger activity is observed with Mn2+
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(2S,3S)-thiahomoisocitrate
interacts through hydrogen bonding to Arg 118, Tyr 125 and Lys 171 in the active site, enzyme binding structure, overview
3-acetylpyridine adenine dinucleotide 3'-phosphate
3-AcPyrADP, competitive versus NAD+
NAD+
-
substrate inhibition at high concentrations and in absence of K+, kinetics, overview
trisodium (2S,3R)-2-[(carboxylatomethyl)amino]-3-hydroxybutanedioate
-
-
trisodium (2S,3S)-2-[(carboxylatomethyl)sulfanyl]-3-hydroxybutanedioate
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-
additional information
-
inhibitor docking study, molecular modeling of CaHIcDH-inhibitor interaction, overview
-
additional information
-
synthesis and inhibition potency of substrate analogue inhibitors derived from 3-hydroxyalkylidene- and 3-carboxyalkylidenemalate derivatives, overview
-
additional information
-
synthesis and inhibition potency of substrate analogue inhibitors derived from 3-hydroxyalkylidene- and 3-carboxyalkylidenemalate derivatives, overview, no inhibition by 3-vinylmalate
-
additional information
-
product and dead-end inhibition studies in the absence of K+
-
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE