Ligand Dichloroacetate

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Basic Ligand Information

Molecular Structure
Picture of Dichloroacetate (click for magnification)
Molecular Formula
BRENDA Name
InChIKey
C2H2ClO2
Dichloroacetate
JXTHNDFMNIQAHM-UHFFFAOYSA-N
Synonyms:
Dichloroacetic acid

Roles as Enzyme Ligand

Substrate in Enzyme-catalyzed Reactions (7 results)

EC NUMBER
LITERATURE
REACTION DIAGRAM
REACTION
ENZYME 3D STRUCTURE
show the reaction diagram
dichloroacetate + H2O = ?
-
show the reaction diagram
dichloroacetate + H2O = ?
-

Product in Enzyme-catalyzed Reactions (7 results)

EC NUMBER
LITERATURE
REACTION DIAGRAM
REACTION
ENZYME 3D STRUCTURE
-
show the reaction diagram
N-dichloroacetyl-L-aspartate + H2O = dichloroacetate + L-aspartate
-
-
show the reaction diagram
N6-dichloroacetyl-L-lysine + H2O = L-lysine + dichloroacetate
-

Activator in Enzyme-catalyzed Reactions (1 result)

COMMENTARY
EC NUMBER
LITERATURE
ENZYME 3D STRUCTURE
together with insulin
-

Inhibitor in Enzyme-catalyzed Reactions (21 results)

COMMENTARY
EC NUMBER
LITERATURE
ENZYME 3D STRUCTURE
i.e. DC, used to treat lactic acidosis and has also been proposed as a novel anticancer agent is both a substrate and a mechanism-based inactivator of GSTZ1-1. Treatment with DCA progressively inactivates GSTZ1-1 and increases the elimination half-life of subsequent doses of DCA. recombinant GSTZ1*A protein is relatively resistant to DCA mediated inactivation when compared with the other isoforms
-
the PDK inhibitor restores pyruvate dehydrogenae activity and enhances glucose oxidation with beneficial molecular effects, i.e. downregulation of FOXO-1 and PDK4, and functional improvement,i.e. enhanced right ventricular function and exercise capacity
synergism with ADP, binding promotes conformational changes at the active-site cleft, structural mechanisms for inhibition of pyruvate dehydrogenase kinase isozymes, binding structure analysis, overview
recombinant homodimers of PDK1 and PDK2 and heterodimers of PDK1 + PDK2, synergism with dichloroacetate; recombinant homodimers of PDK1 and PDK2 and heterodimers of PDK1 + PDK2, synergism with dichloroacetate
binding kinetics
binds at the pyruvate binding site, binding structure, involves e.g. Arg154
R114, S83, I157 and, to some extent, H115 are essential for DCA binding by PDHK, Y80 and D117 are required for the communication between the dichloroacetate-binding site and active site of PDHK2, overview
highly specific
inhibition of isozyme PDK3 is independent of dihydrolipoyl transacetylase, while isozyme PDK2 is more sensitive to inhibition when bound to it
isozyme PDK2: ADP and K+ increase the inhibitory effect; isozyme PDK4: ADP, K+ and Cl- increase the inhibitory effect
noncompetitive to ATP
noncompetitive; pyruvate analog, synergism with ADP, K+ or phosphate, kinetics
potent and highly specific synthetic allosteric inhibitor mimicking pyruvate, inhibition mechanism
weak
-
ATP slightly protects
-
50% inhibition at 1.8 mM
-
DCA
-
the sensitivity to the inhibitor varies between enzyme haplotypes. Three nonsynonymous single-nucleotide polymorphisms of GSTz1/MAAI show different activity toward dichloroacetate and certain other xenobiotic haloacids
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3D Structure of Enzyme-Ligand-Complex (PDB) (2 results)

EC NUMBER
ENZYME 3D STRUCTURE

Enzyme Kinetic Parameters

kcat Value (Turnover Number) (2 results)

COMMENTARY
EC NUMBER
LITERATURE
TURNOVER NUMBER [1/S]
TURNOVER NUMBER MAXIMUM [1/S]
at pH 7.5 and 30°C
82.17
-
isoform Gstz1, at pH 6.5 and 25°C
0.002
-

KM Value (3 results)

COMMENTARY
EC NUMBER
KM VALUE [MM]
KM VALUE MAXIMUM [MM]
LITERATURE
at pH 7.5 and 30°C
0.14
-
isoform Gstz1, at pH 6.5 and 25°C
0.27
-
pH 9.4, 30°C
1.3
-

Ki Value (6 results)

COMMENTARY
EC NUMBER
KI VALUE [MM]
KI VALUE MAXIMUM [MM]
LITERATURE
isozyme PDHK1, 30°C
1
-
isozyme PDHK2, 30°C
0.2
-
isozyme PDHK4, 30°C
0.5
-
kinetic constant from binding study
0.27
-
pH 7.2, 30°C
0.27
-
pH 7.4, 37°C
0.2
-

IC50 Value (19 results)

COMMENTARY
EC NUMBER
IC50 VALUE
IC50 VALUE MAXIMUM
LITERATURE
recombinant isozyme PDHK2 mutant I111A
17.9
-
wild-type enzyme, apparent IC50 for E2p/E3BP-dependent activity
0.48
-
wild-type enzyme, apparent IC50 for basal activity
0.29
-
recombinant wild-type isozyme PDHK2
2.3
-
recombinant isozyme PDHK2 mutant R158A
2
-
recombinant isozyme PDHK2 mutant R154A
1.7
-
recombinant isozyme PDHK2 mutant R112A
1.2
-
recombinant isozyme PDHK2 mutant L53A
17.1
-
recombinant isozyme PDHK2 mutant I161A
2.7
-
recombinant isozyme PDHK2 mutant I157A
0.013
-
mutant D382A/W383A, apparent IC50 for basal activity
37.9
-
recombinant isozyme PDHK2 mutant H115A
8.4
-
mutant Y145F/R149A, apparent IC50 for E2p/E3BP-dependent activity
86.3
-
mutant Y145F/R149A, apparent IC50 for basal activity
102
-
mutant Y145F, apparent IC50 for E2p/E3BP-dependent activity
3.24
-
mutant Y145F, apparent IC50 for basal activity
3.04
-
mutant R149A, apparent IC50 for E2p/E3BP-dependent activity
108
-
mutant R149A, apparent IC50 for basal activity
98.7
-
mutant D382A/W383A, apparent IC50 for E2p/E3BP-dependent activity
35.3
-

References & Links

Links to other databases for Dichloroacetate

ChEBI
PubChem
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PubChem