Information on EC 4.2.1.2 - fumarate hydratase

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The expected taxonomic range for this enzyme is: Eukaryota, Bacteria, Archaea

EC NUMBER
COMMENTARY hide
4.2.1.2
-
RECOMMENDED NAME
GeneOntology No.
fumarate hydratase
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
(S)-malate = fumarate + H2O
show the reaction diagram
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
C-O bond cleavage by elimination of water
-
-
C-O bond formation
-
-
elimination
-
-
-
-
PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
anaerobic energy metabolism (invertebrates, mitochondrial)
-
-
Biosynthesis of antibiotics
-
-
Biosynthesis of secondary metabolites
-
-
Carbon fixation pathways in prokaryotes
-
-
Citrate cycle (TCA cycle)
-
-
citric acid cycle
-
-
incomplete reductive TCA cycle
-
-
Metabolic pathways
-
-
methylaspartate cycle
-
-
Microbial metabolism in diverse environments
-
-
mixed acid fermentation
-
-
partial TCA cycle (obligate autotrophs)
-
-
pyruvate fermentation to propanoate I
-
-
Pyruvate metabolism
-
-
reductive TCA cycle I
-
-
reductive TCA cycle II
-
-
superpathway of glyoxylate cycle and fatty acid degradation
-
-
TCA cycle I (prokaryotic)
-
-
TCA cycle II (plants and fungi)
-
-
TCA cycle III (animals)
-
-
TCA cycle IV (2-oxoglutarate decarboxylase)
-
-
TCA cycle V (2-oxoglutarate:ferredoxin oxidoreductase)
-
-
TCA cycle VII (acetate-producers)
-
-
TCA cycle VIII (helicobacter)
-
-
SYSTEMATIC NAME
IUBMB Comments
(S)-malate hydro-lyase (fumarate-forming)
-
CAS REGISTRY NUMBER
COMMENTARY hide
9032-88-6
-
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
Uniprot
Manually annotated by BRENDA team
synthrophic propionate-oxidizing bacterium strain MPOB
-
-
Manually annotated by BRENDA team
isolate RMIT 32A; strain ATCC 33559
-
-
Manually annotated by BRENDA team
subsp. fetus ATCC 33246 and subsp. venerealis strain ATCC 19438
-
-
Manually annotated by BRENDA team
-
-
-
Manually annotated by BRENDA team
FumC
-
-
Manually annotated by BRENDA team
var. bacillaris
-
-
Manually annotated by BRENDA team
NU-10
-
-
Manually annotated by BRENDA team
gene HP1325
-
-
Manually annotated by BRENDA team
gene HP1325
-
-
Manually annotated by BRENDA team
-
-
-
Manually annotated by BRENDA team
-
UniProt
Manually annotated by BRENDA team
-
-
-
Manually annotated by BRENDA team
possesses at least two and possibly three fumarases
-
-
Manually annotated by BRENDA team
strain 13525
-
-
Manually annotated by BRENDA team
strain 13525
-
-
Manually annotated by BRENDA team
B1Y931: beta subunit, B1Y932: alpha subunit
B1Y931 and B1Y932
UniProt
Manually annotated by BRENDA team
B1Y931: beta subunit, B1Y932: alpha subunit
B1Y931 and B1Y932
UniProt
Manually annotated by BRENDA team
gene fumR
UniProt
Manually annotated by BRENDA team
-
-
-
Manually annotated by BRENDA team
-
-
-
Manually annotated by BRENDA team
-
-
-
Manually annotated by BRENDA team
strain MT-4 (ATCC 49155)
UniProt
Manually annotated by BRENDA team
X-1
-
-
Manually annotated by BRENDA team
X-1
-
-
Manually annotated by BRENDA team
AS-15-1, class II fumarase
-
-
Manually annotated by BRENDA team
-
-
-
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
metabolism
-
fumarase catalyzes the reversible hydration of fumarate to L-malate and is a key enzyme in the tricarboxylic acid cycle and in amino acid metabolism
physiological function
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
(S)-malate
fumarate + H2O
show the reaction diagram
2(S)-3(S)-tartrate
oxaloacetate
show the reaction diagram
-
-
-
-
acetylene dicarboxylate + H2O
oxaloacetate
show the reaction diagram
alpha-fluorofumarate + H2O
oxaloacetate + ?
show the reaction diagram
bromofumarate + H2O
?
show the reaction diagram
-
-
-
-
?
chlorofumarate + H2O
?
show the reaction diagram
-
-
-
-
?
D-tartrate
?
show the reaction diagram
-
-
-
-
?
Fumarate + H2O
L-Malate
show the reaction diagram
fumaric acid + H2O
(S)-malic acid
show the reaction diagram
-
-
-
-
-
fumaric acid + H2O
L-malic acid
show the reaction diagram
-
-
-
-
-
iodofumarate + H2O
?
show the reaction diagram
-
-
-
-
?
L-malate
fumarate + H2O
show the reaction diagram
-
-
-
-
r
L-tartrate
oxaloacetate + H2O
show the reaction diagram
-
-
-
?
L-threo-chloro-L-malate
chlorofumarate + H2O
show the reaction diagram
-
-
-
?
L-threo-hydroxyaspartate
?
show the reaction diagram
-
-
-
-
?
mesaconate + H2O
?
show the reaction diagram
-
-
-
-
?
S-malate
fumarate + H2O
show the reaction diagram
additional information
?
-
NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
(S)-malate
fumarate + H2O
show the reaction diagram
Fumarate + H2O
L-Malate
show the reaction diagram
additional information
?
-
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Ca2+
has a small stimulatory effect
Fe
-
enzyme contains an oxygen-sensitive [4Fe-4S] cluster
Mn2+
-
cytosolic form gets strongly activated, mitochondrial form only less effectively activated
[3Fe-4S] center
-
10-25% of purified protein contains [3Fe-4S] cluster
additional information
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
(-)-citramalate
-
no inhibition by (+)-citramalate
(2R,3R)-Tartrate
-
-
(R)-malate
mixed-type inhibition
2-hydroxy-3-nitropropionate
-
nitronate form
2-oxoglutarate
-
-
2-propanol
-
15-20% of maximum activity when assayed in 40% (v/v) 2-propanol
4-bromocrotonate
-
-
ammonium persulfate
-
-
bromofumarate
-
-
chlorofumarate
cis-aconitate
-
-
citraconate
-
-
citrate
citrylpolymethylenediamine
-
-
-
CTP
-
-
CuCl2
-
inhibits 37% at 5 mM
Cyanate
-
2 mM ibuprofen and its major metabolites protect by up to 26%. Ibuprofen and the metabolites do not bind to fumarase
D-fructose
-
2 mM ibuprofen and its major metabolites protect by up to 26%. Ibuprofen and the metabolites do not bind to fumarase
D-Tartrate
competitive
dimethylfumarate
-
-
DL-3-phenyllactate
-
-
EDTA
-
inhibits 20% at 2.5 mM
ethanol
-
15-20% of maximum activity when assayed in 40% (v/v) ethanol
FeCl2
-
inhibits 37% at 5 mM
FeCl3
-
inhibits 47.3% at 5 mM
fumarate
the activity of FUMR catalyzing hydration of fumarate to L-malate is completely inhibited by 2 mM fumaric acid
glycerol
-
wild-type enzyme is inhibited due to a viscogenic effect on the recycling rate
GTP
-
-
H2O2
-
causes fibril aggregation and catalytic inactivation of fumarase
hydroxyl radical
-
causes fibril aggregation and catalytic inactivation of fumarase
iodoacetamide
-
-
iodoacetate
-
-
iodofumarate
-
-
isocitrate
-
L-isocitrate
L-Tartrate
-
-
L-threo-hydroxyaspartate
-
-
mesaconate
-
-
meso-tartrate
mesotartaric acid
competitive
methanol
-
94% of maximum activity when assayed in 40% (v/v) methanol
Mg2+
slight inhibition
NaCl
-
in cells cultivated with 200 mM NaCl, the inhibition produced in fumarase is 90%
NEM
-
-
NH4Cl
-
inhibits 23% at 5 mM
phosphate
potassium thiocyanate
-
IC50: 140 mM
Prednisolone
-
2 mM ibuprofen and its major metabolites have no effect on prednisolone-induced inactivation
pyromellilate
-
-
pyromellitate
competitive
pyromellitic acid
-
-
S-2,3-dicarboxyaziridine
-
enzyme form FUMC is inhibited, enzyme form FUMA is not inhibited
-
succinate
-
-
sulfhydryl reagents
trans-aconitate
trans-glutaconate
-
-
UTP
-
-
ZnCl2
-
inhibits 55% at 5 mM
additional information
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
acetate
-
0.2 M, activation
arsenate
-
activates
Borate
-
activates
citrate
-
activates
Cl-
-
activity increases up to 50 mM and remains constant at higher concentrations
phosphate
selenate
-
activates
SO42-
-
activates
additional information
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.3 - 13
(S)-malate
0.145 - 0.9
acetylene dicarboxylate
0.11
bromofumarate
0.7 - 0.8
D-Tartrate
0.027 - 1.7
fluorofumarate
0.005 - 8.8
fumarate
0.12
iodofumarate
-
-
0.025 - 57
L-Malate
1.3
L-Tartrate
-
-
0.02 - 0.14
L-threo-chloromalate
-
-
7.5 - 10
L-threo-hydroxyaspartate
-
-
0.12 - 32
malate
0.51
mesaconate
-
-
0.005 - 12.6
S-malate
additional information
additional information
-
reaction kinetics and thermodynamics, overview
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
25.2 - 460
(S)-malate
1.9 - 1150
fumarate
1 - 620
L-Malate
11.2 - 540
malate
0.55 - 151.4
S-malate
additional information
additional information
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
3 - 12
D-Tartrate
4200 - 4500
fumarate
9.7 - 1600
L-Malate
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.35
ATP
-
-
0.077
mesotartaric acid
pH 7.3, 30C
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
140
potassium thiocyanate
Campylobacter jejuni
-
IC50: 140 mM
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
173
-
-
205
-
; pH 7.5, 70C
340
-
FUMA
450
-
-
721
-
mitochondrial enzyme
726
-
purified recombinant FumF, pH 8.5, 55C, substrate fumarate
971
-
-
additional information
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
6.8 - 7.5
-
-
7.5 - 8.5
-
-
7.6
-
assay at
8.3
phosphate buffer, substrate: malate
additional information
-
at low concentrations, phosphate, sulfate, borate, selenate, arsenate and citrate activate fumarase and shift somewhat the pH optimum to a more alkaline pH
pH RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
5.5 - 11.5
-
no activity below pH 5.5 and above pH 11.5
5.5 - 9
-
pH 5.5: 43% of maximal activity, pH 9.0: 70% of maximal activity
6.5 - 9.5
-
pH optimum at pH 8.5, the activity is dramatically suppressed below pH 7.0 and above pH 9.0
7 - 10
TEMPERATURE RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
25 - 65
-
70% of maximum activity below 40C, and over 70% of maximum activity between 40-60C, maximal activity at approximately 55C
50 - 100
-
50C: about 30% of maximal activity, 100C: about 80% of maximal activity
85 - 95
-
85C: maximal activity, 95C: 66% of maximal activity, the enzyme is almost inactive at 40C; inactive at 40C, 85C: optimum, 95C: 66% of maximal activity
pI VALUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
6.79
-
sequence calculation
7.1
-
isoelectric focusing
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
-
cells from individuals with hereditary leiomyomatosis and renal cell cancer have lower fumarate hydratase enzyme activity than cells from normal controls
Manually annotated by BRENDA team
-
cells from individuals with hereditary leiomyomatosis and renal cell cancer have lower fumarate hydratase enzyme activity than cells from normal controls
Manually annotated by BRENDA team
-
etiolated
Manually annotated by BRENDA team
-
highest fumarase activity detected
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
-
in thin sections from kidney, liver, heart, adrenal gland and anterior pituitary, strong and specific labeling due to fumarase antibody is only detected in mitochondria. In pancreatic acinar cells, in addition to mitochondria, highly significant labeling is also observed in the zymogen granules and endoplasmic reticulum
Manually annotated by BRENDA team
-
in thin sections from kidney, liver, heart, adrenal gland and anterior pituitary, strong and specific labeling due to fumarase antibody is only detected in mitochondria. In pancreatic acinar cells, in addition to mitochondria, highly significant labeling is also observed in the zymogen granules and endoplasmic reticulum
Manually annotated by BRENDA team
PDB
SCOP
CATH
ORGANISM
UNIPROT
Archaeoglobus fulgidus (strain ATCC 49558 / VC-16 / DSM 4304 / JCM 9628 / NBRC 100126)
Burkholderia pseudomallei (strain 1710b)
Escherichia coli (strain K12)
Escherichia coli (strain K12)
Escherichia coli (strain K12)
Escherichia coli (strain K12)
Escherichia coli (strain K12)
Escherichia coli (strain K12)
Escherichia coli (strain K12)
Mycobacterium smegmatis (strain ATCC 700084 / mc(2)155)
Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
Rhizobium meliloti (strain 1021)
Rickettsia prowazekii (strain Madrid E)
Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
47900
calculated from amino acid sequence
48000
-
mitochondrial fumarate hydratase is translated as an approximately 54000 Da precursor, which is processed upon mitochondrial transport by cleavage of the N-terminal targeting signal, resulting in a mature form of 48000 Da
49000
-
SDS-PAGE
54000
-
mitochondrial fumarate hydratase is translated as an approximately 54000 Da precursor, which is processed upon mitochondrial transport by cleavage of the N-terminal targeting signal, resulting in a mature form of 48000 Da
61100
-
calculated from cDNA
62600
-
calculated from cDNA
64200
-
gel filtration
114000
-
gel filtration
120000
160000
-
sucrose density gradient centrifugation
170000
-
gel filtration
175000
-
gel filtration
180000
190000
-
gel filtration
194000
-
equilibrium sedimentation
195000
-
calculation from amino acid analysis
198000
-
gel filtration
200000
440000
-
oligomer 1, gel filtration
600000
-
oligomer 2, gel filtration
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
homodimer
homotetramer
-
4 * 50000, SDS-PAGE
tetramer
additional information
-
a small but very important conformational change associated with the conversion of dimers to tetramers, finalizing proper orientation of active site residues
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
proteolytic modification
-
the precursor of the mitochondrial enzyme has a larger molecular weight than the mature enzyme, whereas the precursor for the cytosolic enzyme has the same molecular weight as the mature enzyme. These two precursors of fumarase are coded by two different mRNAs
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
free enzyme in which both sites are unoccupied by bound ligand, crystallized from a solution of 50 mM MOPS, pH 7.5, 100 mM LiSO4 and 12% PEG 4000, space group I222, X-ray data are collected between 8 and 2.19 A, unit cell parameters: a = 121.6 A, b = 128 A, c = 62.1 A
-
fumarase C
-
mutant enzyme E315Q
-
crystal structures of Mycobacterium tuberculosis Rv1098c in complex with L-malate, fumarate and the competitive inhibitor meso-tartrate is reported
crystal structure solved at 2.4 A resolution. FumC crystallizes as a homodimer containing two subunits of the normally tetrameric enzyme, in which each chain forms an elongated central four-helix bundle capped by two compact domains at the N- and C-termini
fumarase complex with meso-tartaric acid
-
native and recombinant enzyme, native fumarase is crystallized in the presence of the competitive inhibitor meso-tartrate
-
pH STABILITY
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
3 - 9
purified recombinant enzyme, stable
715093
4.5 - 8.2
-
stable
33769
5 - 9
-
stable in potassium phosphate buffer, above pH 10: dissociation into an inactive form
33728
6 - 10
-
dissociation below pH 6 and above pH 10, Tris-acetate buffer
33728
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
4
-
half-life: 4.6 h, at 0.0438 mg of protein per ml
15 - 70
-
30 min, pH 8.5, activity of FumF is stable with increasing temperature below 58C in the absence of any stabilizer. When the temperature is higher than 60C, FumF protein loses almost 50% of its activity
20
-
half-life: 1.6 h, at 0.0438 mg of protein per ml
45
purified recombinant enzyme, stable below
49
-
5 min, 50% inhibition, enzyme form FUMA
51
-
5 min, 50% inhibition, enzyme form FUMA
56.3
-
melting temperature
57.7
-
melting temperature
70
-
1 h, stable
75
-
24 h, 10% loss of activity
85
-
1 h, stable
100
-
30 min, complete loss of activity
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
(NH4)2SO4, protects enzyme form FUMA from inactivation at 4C
-
0.8 M guanidine hydrochloride, 50% loss of activity after 5 min at 75C, complete inactivation at concentrations above 1.5 M
-
10% glycerol, 0.1 M KCl, 5 mM L-malate or 30% ethyleneglycol, partially protects enzyme form FUMA from inactivation at 4C
-
50% v/v ethanol, 50% v/v methanol, 50% v/v 2-propanol, 4 M urea or 0.1% SDS, stable after treatment for 10 h at room temperature
-
dithiothreitol partially restores from urea and alkaline inactivation
enzyme form FUMA, oxidation and the concomitant release of iron inactivates the enzyme in a reversible manner
-
enzyme form FUMB is extremely unstable
-
enzyme stability is achieved by addition of soy bean protein or bovine serum albumin.
-
exposure to air at room temperature causes 50% loss of activity, reactivation with FeSO4 and 2-mercaptoethanol
-
exposure to air results in 30% decreased activity
-
mitochondrially targeted fumarase harboring a tobacco etch virus protease recognition sequence is efficiently cleaved by the mitochondrial but not by the cytosolic tobacco etch virus protease. Fumarase is readily cleaved by cytosolic tobacco etch virus when its import into mitochondria is slowed down by either disrupting the activity of the TOMcomplex, lowering the growth temperature, or reducing the inner membrane electrochemical potential
-
ORGANIC SOLVENT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
2-propanol
Ethanol
Methanol
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-4C, stable for at least 6 months
-
4C or -20C, stable for several days
-
4C, activity readily decreases to less than 20%
-
4C, crystals in 0.55 saturated ammonium sulfate are stable for several months
-
4C, under N2, stable for at least 1 month
-
Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
affinity chromatography using a column with pyromellitic acid as affinity ligand coupled to the classic Sepharose matrix
-
affinity chromatography with Sepharose derivatives containing citric acid. The purification is dependent on the length of the spacer arm, but not on the isomeric configuration of the immobilized citrate
-
FUMA and FUMC
-
fumarase A
-
fumarase C
using fractionation by (NH4)2SO4, gel filtration of Sephadex G-25 and ion exchange chromatography of DEAE cellulose
-
using Ni-NTA chromatography
-
Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
a pfl ldhA double mutant Escherichia coli strain NZN11 is used to produce succinic acid by overexpressing the Escherichia coli malic enzyme gene sfcA. This strain, however, produces a large amount of malic acid as well as succinic acid. The fumB gene encoding the anaerobic fumarase of Escherichia coli is co-amplified to solve the problem of malic acid accumulation, and subsequently improve the succinic acid production
-
Cos-1 cells transfected with fumarase constructs, human fumarase with either the native or cytochrome c oxidase subunit VIII mitochondrial targeting sequence is detected exclusively in mitochondria in more than 98% of the cells, while the remainder 1-2% of the cells shows varying amounts of nuclear labeling. When human fumarase is fused to the yeast mitochondrial targeting sequence, more than 50% of the cells show nuclear labeling
entire protein-coding region of fumarase cDNA cloned from Dahl salt-sensitive, SS-13BN, and Brown Norway rats. PCR product inserted into the T-easy vector and propagated in competent Escherichia coli
-
expressed in Escherichia coli
expressed in Escherichia coli as a His-tagged fusion protein
expressed in Escherichia coli as His-tagged fusion proteins
-
expressed in Escherichia coli strain JM109
expressed in HK-2 cells and in skin fibroblasts
-
expressed in yeast FUM1 mutant strain
-
expression in Escherichia coli
B1Y931 and B1Y932
expression in Escherichia coli BL21
expression in Escherichia coli mutant EJ1535
-
FUM1-green fluorescent protein (GFP) expressed driven by the 35S promoter in Arabidopsis thaliana cell cultures; FUM2-red fluorescent protein (RFP) fusions epressed by the 35S promoter, introduced into Arabidopsis thaliana cell cultures
gene fumF, cloned from a plasmid metagenomic library, DNA and amino acid sequence determination and analysis, sequence comparison, and phylogenetic analysis
-
gene fumR, overexpression in Escherichia coli strain BL21 (DE3)
gene HP1325, DNA and amino acid sequence determination and analysis, expression in Escherichia coli strain BL21(DE3)
-
mutant fumarase derivative lacking the MTS expressed in the FUM1 mutant strain, expressing the site-specific HO double-stranded DNA endonuclease
-
plasmid encoding fumarase lacking an MTS transformed into the wild-type, DELTAcit2 and R strains
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
at least 15fold downregulated in presence of acetate, 4-hydroxybutyrate, succinate or pyruvate
fumarate hydratase levels increase 2fold after 24 h of treatment with double-strand breaks. Is overexpressed in response to DNA damage
-
is overexpressed in response to DNA damage
-
knock down of total cellular fumarate hydratase expression using specific shRNA
-
level of FUM2 RNA in rosette leaves is higher in the light than in the dark, but total fumarase activity remains constant throughout the diurnal cycle
level of fumarase mRNA is upregulated both in the DELTacit2 and wild-type plus pCit2 strains. Approximately 2fold higher Fum1 mRNA level in a DELTAcit2 strain when compared with the wild-type strain. Significant increase in fumarase expression and cellular enzymatic activity in the glyoxylate deletion strains: DELTAmls1, DELTAicl1, DELTAaco1and DELTAcit2. Succinic acid in the growth medium affects fumarase dual distribution, succinic acid directly interacts with fumarase and slows down its folding thereby causing more fumarase to be fully imported into mitochondria
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ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
E315Q
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mutation causes about 3% increase in Km-value for S-malate, about 20% increase in Km-value for fumarate. 10fold decrease in turnover number for S-malate, about 11fold decrease in turnover number for fumarate
H129N
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loss of D2O inhibitory effect, product release step is accelerated by glycerol compared to inhibition of wild-type enzyme. 3.1fold reduced maximal velococity in reaction with malate, 1.13fold reduced maximal velocity in reaction with fumarate compared to wild-type enzyme
K127D
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mutant enzyme behaves like wild-type enzyme
R126A
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loss of D2O inhibitory effect, product release step is accelerated by glycerol compared to inhibition of wild-type enzyme. 4.3fold reduced maximal velococity in reaction with malate, 2.7fold reduced maximal velocity in reaction with fumarate compared to wild-type enzyme
R126A/H129N
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great loss of D2O inhibitory effect, product release step is accelerated by glycerol compared to inhibition of wild-type enzyme. 8.6fold reduced maximal velococity in reaction with malate, 7.1fold reduced maximal velocity in reaction with fumarate compared to wild-type enzyme
H129N
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loss of D2O inhibitory effect, product release step is accelerated by glycerol compared to inhibition of wild-type enzyme. 3.1fold reduced maximal velococity in reaction with malate, 1.13fold reduced maximal velocity in reaction with fumarate compared to wild-type enzyme
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K127D
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mutant enzyme behaves like wild-type enzyme
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R126A
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loss of D2O inhibitory effect, product release step is accelerated by glycerol compared to inhibition of wild-type enzyme. 4.3fold reduced maximal velococity in reaction with malate, 2.7fold reduced maximal velocity in reaction with fumarate compared to wild-type enzyme
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R126A/H129N
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great loss of D2O inhibitory effect, product release step is accelerated by glycerol compared to inhibition of wild-type enzyme. 8.6fold reduced maximal velococity in reaction with malate, 7.1fold reduced maximal velocity in reaction with fumarate compared to wild-type enzyme
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A117P
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missense mutation
A239T
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missense mutation
A274T
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missense mutation
A308Y
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the mutation is associated with fumarase deficiency
A385D
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missense mutation
C333Y
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missense mutation
D425V
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the mutation is associated with fumarase deficiency
E319Q
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mutant with strongly reduced activity
E355K
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missense mutation
E362Q
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the mutation is associated with fumarase deficiency
F312C
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the mutation is associated with fumarase deficiency
G282V
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missense mutation
G397R
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missense mutation
H135R
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missense mutation
H180R
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missense mutation
H318L
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the mutation is associated with fumarase deficiency
H402C
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the mutation is associated with fumarase deficiency
I229T
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missense mutation
I77V
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the mutant enzyme shows increased activity
K230R
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missense mutation
K467R
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missense mutation
L335P
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missense mutation
L507P
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missense mutation
M195T
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missense mutation
M368T
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the mutation is associated with hereditarymultiplecutaneous leiomyoma
M454I
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missense mutation
N107T
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missense mutation
N188S
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missense mutation
N310Y
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missense mutation
N330S
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missense mutation detected in a patient with a bilateral renal cell cancer
N340K
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missense mutation
N362K
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the mutation is associated with renal cell cancer
P174R
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missense mutation
P192L
-
missense mutation
P369S
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the mutation is associated with fumarase deficiency
Q142K
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missense mutation
Q185R
-
missense mutation
Q376P
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the mutation is associated with fumarase deficiency
Q439P
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the mutation is associated with renal cell cancer
R101P
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the mutation is associated with renal cell cancer
R101X
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the mutation is associated with renal cell cancer
R160G
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missense mutation
R233C
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the mutation is associated with renal cell cancer
R233H
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the mutation is associated with renal cell cancer
R233L
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the mutation is associated with renal cell cancer
R343X
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the mutation is associated with renal cell cancer
R51E
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missense mutation
S158I
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missense mutation
S187L
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missense mutation
S334R
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the mutation is associated with hereditarymultiplecutaneous leiomyoma
S365G
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missense mutation
S365N
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missense mutation
S41P
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the mutation is associated with renal cell cancer
T330P
-
missense mutation
V322D
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missense mutation
V394L
-
missense mutation
Y465C
-
missense mutation
S318A
mutant shows no activity
S318C
mutant shows no activity
S318A
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mutant shows no activity
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S318C
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mutant shows no activity
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H153R
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is catalytically inactive since it does not complement a fumarase knockout strain with respect to its TCA cycle function. Yeast strains expressing the mutant protein do not grow on glycerol as the sole energy and carbon source
A347S
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mutation results in an increase in optimum temperature of 10C and a fourfold enhancement in specific activity
G163R
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mutation results in an increase in optimum temperature of 5C
G163R/G170E
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mutant is more thermostable than wild-type scFUMC. Mutation results in an increase in optimum temperature of 5C
G163R/G170E/A347S
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mutant is more thermostable than wild-type scFUMC. Mutation results in an increase in optimum temperature of 5C
G170E
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mutation results in an increase in optimum temperature of 5C
G170E/A347S
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mutation results in an increase in optimum temperature of 5C
additional information
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
analysis
-
fumarate hydratase activity can be useful in the diagnosis of hereditary leiomyomatosis and renal cell cancer in cases with atypical presentation and undetectable fumarate hydratase mutations. Furthermore, fumarate hydratase activity testing is of value in laboratory investigations to elucidate the mechanism of hereditary leiomyomatosis and renal cell cancer
industry
medicine
synthesis
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