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Information on EC 3.1.2.29 - fluoroacetyl-CoA thioesterase
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3.1.2.29 fluoroacetyl-CoA thioesteraseIUBMB Comments
Fluoroacetate is extremely toxic. It reacts with CoA to form fluoroacetyl-CoA, which substitutes for acetyl CoA and reacts with EC 2.3.3.1 (citrate synthase) to produce fluorocitrate, a metabolite of which binds very tightly to EC 4.2.1.3 (aconitase) and halts the TCA cycle. This enzyme hydrolyses fluoroacetyl-CoA before it can react with citrate synthase, and thus confers fluoroacetate resistance on the organisms that produce it. It has been described in the poisonous plant Dichapetalum cymosum and the bacterium Streptomyces cattleya, both of which are fluoroacetate producers.
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The expected taxonomic range for this enzyme is: Bacteria, Archaea, Eukaryota
Synonyms
fluoroacetyl-coa thioesterase, 
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
FlK
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
fluoroacetyl-CoA + H2O = fluoroacetate + CoA
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SYSTEMATIC NAME
IUBMB Comments
fluoroacetyl-CoA hydrolase
Fluoroacetate is extremely toxic. It reacts with CoA to form fluoroacetyl-CoA, which substitutes for acetyl CoA and reacts with EC 2.3.3.1 (citrate synthase) to produce fluorocitrate, a metabolite of which binds very tightly to EC 4.2.1.3 (aconitase) and halts the TCA cycle. This enzyme hydrolyses fluoroacetyl-CoA before it can react with citrate synthase, and thus confers fluoroacetate resistance on the organisms that produce it. It has been described in the poisonous plant Dichapetalum cymosum and the bacterium Streptomyces cattleya, both of which are fluoroacetate producers.
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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
fluoroacetyl-CoA + H2O
fluoroacetate + CoA
does not accept acetyl-CoA as a substrate
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-
?
fluoroacetyl-CoA + H2O
fluoroacetate + CoA
the enzyme is strongly selective for fluoroacetyl-CoA compared with acetyl-CoA
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?
additional information
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Thr 42, Glu 50, and His 76 are key catalytic residues. FlK minimizes interaction with the thioester carbonyl, leading to selection against acetyl-CoA binding. Fluorinated substrates bind in a hydrophobic binding pocket created by a lid structure, containing Val 23, Leu 26, Phe 33, and Phe 36, that is not found in other structurally characterized members of this superfamily. Water plays a critical role in fluorine specificity. The Phe 36 gate residue functions to exclude water from the active site
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?
additional information
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chemical, kinetic, and structural mechanism for the selectivity for fluoroacetyl-CoA. Following substrate binding, fluoroacetyl-CoA reacts with Glu50 to acylate this side chain. After enzyme acylation, a proton is abstracted by His 76 to generate an enolate that can break down through a proposed ketene intermediate. The pro-R proton of fluoroacetyl-CoA is specifically abstracted. The selectivity for the fluoroacetyl-CoA substrate appears to rely not only on the enhanced polarization provided by the electronegative fluorine substitution but also on molecular recognition of fluorine in both formation and breakdown of the acyl-enzyme intermediate to control active site reactivity
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?
additional information
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chemical, kinetic, and structural mechanism for the selectivity for fluoroacetyl-CoA. Following substrate binding, fluoroacetyl-CoA reacts with Glu50 to acylate this side chain. After enzyme acylation, a proton is abstracted by His 76 to generate an enolate that can break down through a proposed ketene intermediate. The pro-R proton of fluoroacetyl-CoA is specifically abstracted. The selectivity for the fluoroacetyl-CoA substrate appears to rely not only on the enhanced polarization provided by the electronegative fluorine substitution but also on molecular recognition of fluorine in both formation and breakdown of the acyl-enzyme intermediate to control active site reactivity
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additional information
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the high selectivity of fluoroacetyl-CoA thioesterase is achieved through catalysis rather than molecular recognition. Deprotonation at the Calpha position to form a putative ketene intermediate only occurs on the fluorinated substrate, thereby accelerating the rate of hydrolysis 10000fold compared with the nonfluorinated congene. An enzyme-anhydride intermediate is formed for the nonfluorinated substrate
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additional information
?
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the high selectivity of fluoroacetyl-CoA thioesterase is achieved through catalysis rather than molecular recognition. Deprotonation at the Calpha position to form a putative ketene intermediate only occurs on the fluorinated substrate, thereby accelerating the rate of hydrolysis 10000fold compared with the nonfluorinated congene. An enzyme-anhydride intermediate is formed for the nonfluorinated substrate
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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
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
fluoroacetyl-CoA
substrate inhibition of mutants T42S and E50A above 0.012 and 0.019 mM, respectively; T42S mutant protein: substrate inhibition observed above 0.012 mM, E50A mutant protein: substrate inhibition observed above 0.019 mM
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.015
fluoroacetyl-CoA
mutant T42S, 25°C, pH not specified in the publication
0.015
fluoroacetyl-CoA
T42S mutant protein, pH not specified in the publication, 25°C
0.03
fluoroacetyl-CoA
wild-type, 25°C, pH not specified in the publication
0.03
fluoroacetyl-CoA
wild type protein, pH not specified in the publication, 25°C
0.206
fluoroacetyl-CoA
mutant E50A, 25°C, pH not specified in the publication
0.206
fluoroacetyl-CoA
E50A mutant protein, pH not specified in the publication, 25°C
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.044
fluoroacetyl-CoA
wild-type, 25°C, pH not specified in the publication
0.044
fluoroacetyl-CoA
wild type protein, pH not specified in the publication, 25°C
0.111
fluoroacetyl-CoA
mutant E50A, 25°C, pH not specified in the publication
0.111
fluoroacetyl-CoA
E50A mutant protein, pH not specified in the publication, 25°C
0.409
fluoroacetyl-CoA
mutant T42S, 25°C, pH not specified in the publication
0.409
fluoroacetyl-CoA
T42S mutant protein, pH not specified in the publication, 25°C
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kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.54
fluoroacetyl-CoA
mutant E50A, 25°C, pH not specified in the publication
0.54
fluoroacetyl-CoA
E50A mutant protein, pH not specified in the publication, 25°C
1.47
fluoroacetyl-CoA
wild-type, 25°C, pH not specified in the publication
1.47
fluoroacetyl-CoA
wild type protein, pH not specified in the publication, 25°C
27.3
fluoroacetyl-CoA
mutant T42S, 25°C, pH not specified in the publication
27.3
fluoroacetyl-CoA
T42S mutant protein, pH not specified in the publication, 25°C
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Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
2.8
acetyl-aza(dethia)-CoA
mutant enzyme F36A, with fluoroacetyl-CoA as substrate, at pH 7.6, temperature not specified in the publication
4.7
acetyl-aza(dethia)-CoA
mutant enzyme F36A, with acetyl-CoA as substrate, at pH 7.6, temperature not specified in the publication
8.4
acetyl-aza(dethia)-CoA
wild type enzyme, with acetyl-CoA as substrate, at pH 7.6, temperature not specified in the publication
33
acetyl-aza(dethia)-CoA
wild type enzyme, with fluoroacetyl-CoA as substrate, at pH 7.6, temperature not specified in the publication
2.6
acetyl-carba(dethia)-CoA
wild type enzyme, with acetyl-CoA as substrate, at pH 7.6, temperature not specified in the publication
3.6
acetyl-carba(dethia)-CoA
mutant enzyme F36A, with acetyl-CoA as substrate, at pH 7.6, temperature not specified in the publication
11
acetyl-carba(dethia)-CoA
wild type enzyme, with fluoroacetyl-CoA as substrate, at pH 7.6, temperature not specified in the publication
51
acetyl-carba(dethia)-CoA
mutant enzyme F36A, with fluoroacetyl-CoA as substrate, at pH 7.6, temperature not specified in the publication
0.3
acetyl-oxa(dethia)-CoA
mutant enzyme F36A, with acetyl-CoA as substrate, at pH 7.6, temperature not specified in the publication
0.51
acetyl-oxa(dethia)-CoA
wild type enzyme, with acetyl-CoA as substrate, at pH 7.6, temperature not specified in the publication
1.5
acetyl-oxa(dethia)-CoA
mutant enzyme F36A, with fluoroacetyl-CoA as substrate, at pH 7.6, temperature not specified in the publication
2.5
acetyl-oxa(dethia)-CoA
wild type enzyme, with fluoroacetyl-CoA as substrate, at pH 7.6, temperature not specified in the publication
1.2
fluoroacetyl-aza(dethia)-CoA
wild type enzyme, with acetyl-CoA as substrate, at pH 7.6, temperature not specified in the publication
4
fluoroacetyl-aza(dethia)-CoA
mutant enzyme F36A, with fluoroacetyl-CoA as substrate, at pH 7.6, temperature not specified in the publication
4.3
fluoroacetyl-aza(dethia)-CoA
wild type enzyme, with fluoroacetyl-CoA as substrate, at pH 7.6, temperature not specified in the publication
7.5
fluoroacetyl-aza(dethia)-CoA
mutant enzyme F36A, with acetyl-CoA as substrate, at pH 7.6, temperature not specified in the publication
0.46
fluoroacetyl-carba(dethia)-CoA
wild type enzyme, with acetyl-CoA as substrate, at pH 7.6, temperature not specified in the publication
0.9
fluoroacetyl-carba(dethia)-CoA
wild type enzyme, with fluoroacetyl-CoA as substrate, at pH 7.6, temperature not specified in the publication
2.1
fluoroacetyl-carba(dethia)-CoA
mutant enzyme F36A, with fluoroacetyl-CoA as substrate, at pH 7.6, temperature not specified in the publication
4.5
fluoroacetyl-carba(dethia)-CoA
mutant enzyme F36A, with acetyl-CoA as substrate, at pH 7.6, temperature not specified in the publication
0.13
fluoroacetyl-oxa(dethia)-CoA
wild type enzyme, with acetyl-CoA as substrate, at pH 7.6, temperature not specified in the publication
0.26
fluoroacetyl-oxa(dethia)-CoA
mutant enzyme F36A, with fluoroacetyl-CoA as substrate, at pH 7.6, temperature not specified in the publication
0.32
fluoroacetyl-oxa(dethia)-CoA
wild type enzyme, with fluoroacetyl-CoA as substrate, at pH 7.6, temperature not specified in the publication
0.33
fluoroacetyl-oxa(dethia)-CoA
mutant enzyme F36A, with acetyl-CoA as substrate, at pH 7.6, temperature not specified in the publication
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
0.0295
-
crude mitochondrial extract, pH not specified in the publication, temperature not specified in the publication
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
physiological function
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presence of enzyme protects its host from fluoroacetate toxicity in vivo
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UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). A0A6C0QVT2_9BACL
143
0
15830
TrEMBL
-
A0A8A0RIR1_9FIRM
140
0
15198
TrEMBL
-
A0A1J5PUS2_9ZZZZ
135
0
13823
TrEMBL
other Location (Reliability: 4)
A0A1V5MUX8_9BACT
130
0
14180
TrEMBL
-
A0A399F796_9DEIN
152
0
17034
TrEMBL
-
A0A1V6JI54_9BACT
130
0
14137
TrEMBL
-
A0A518B6M3_9BACT
135
0
15217
TrEMBL
-
A0A1V5YAR6_9FIRM
120
1
12988
TrEMBL
-
A0A1V5BH47_9FIRM
133
0
14141
TrEMBL
-
A0A0L6Z727_9CLOT
128
0
14048
TrEMBL
-
A0A645FLE3_9ZZZZ
93
0
10120
TrEMBL
other Location (Reliability: 3)
A0A645AN88_9ZZZZ
122
0
13184
TrEMBL
other Location (Reliability: 1)
A0A8A0RLW9_9FIRM
133
1
14882
TrEMBL
-
A0A1V5M7C5_9FIRM
134
0
14651
TrEMBL
-
A0A0D6JID4_9HYPH
149
0
16116
TrEMBL
-
A0A6L5C2H3_9PSED
151
0
16351
TrEMBL
-
A0A1V5SV66_9BACT
137
0
15188
TrEMBL
-
A0A1V5C0A0_9FIRM
133
0
14051
TrEMBL
-
A0A644TNT9_9ZZZZ
134
0
14470
TrEMBL
other Location (Reliability: 1)
A0A645AR95_9ZZZZ
127
0
13889
TrEMBL
other Location (Reliability: 2)
A0A1V5U2Z5_9FIRM
132
0
13834
TrEMBL
-
A0A1V6JE76_9BACT
128
0
14410
TrEMBL
-
A0A1V5PGA2_9FIRM
129
0
14022
TrEMBL
-
A0A2S6TRS1_9PROT
142
0
15616
TrEMBL
-
A0A7Z0VQQ8_9GAMM
141
0
16159
TrEMBL
-
A0A645H1L4_9ZZZZ
96
0
10939
TrEMBL
other Location (Reliability: 2)
A0A1J5RJ81_9ZZZZ
142
0
15994
TrEMBL
other Location (Reliability: 1)
A0A1J5RJI7_9ZZZZ
144
0
15649
TrEMBL
other Location (Reliability: 3)
A0A1V6CJH3_9BACT
146
0
15856
TrEMBL
-
A0A151ALW2_9CLOT
128
0
14196
TrEMBL
-
A0A1Q9P0R7_HEILC
Heimdallarchaeota archaeon (strain LC_2)
131
0
14486
TrEMBL
-
A0A564ZHG7_9BACT
134
0
15015
TrEMBL
-
A0A1V5RVV6_9CHLR
135
0
14107
TrEMBL
-
A0A2S6TJD6_9PROT
141
0
15855
TrEMBL
-
A0A143ZSI1_9FIRM
132
0
14486
TrEMBL
-
A0A0X8VEK8_ANAPI
133
0
14776
TrEMBL
-
A0A1V6K1E2_9BACT
140
0
14428
TrEMBL
-
A0A143XT29_9FIRM
130
0
13924
TrEMBL
-
A0A1A8XYV5_9RHOO
140
0
15688
TrEMBL
-
A0A1V5JHP8_9BACT
128
0
13899
TrEMBL
-
A0A2U3LLI6_9FIRM
144
0
16237
TrEMBL
-