Information on EC 1.1.1.38 - malate dehydrogenase (oxaloacetate-decarboxylating)

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

EC NUMBER
COMMENTARY hide
1.1.1.38
-
RECOMMENDED NAME
GeneOntology No.
malate dehydrogenase (oxaloacetate-decarboxylating)
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
(S)-malate + NAD+ = pyruvate + CO2 + NADH
show the reaction diagram
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
oxidation
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oxidative decarboxylation
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redox reaction
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reduction
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PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
anaerobic energy metabolism (invertebrates, mitochondrial)
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C4 photosynthetic carbon assimilation cycle, NAD-ME type
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chitin degradation to ethanol
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gluconeogenesis I
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L-carnitine degradation III
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L-malate degradation II
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methylgallate degradation
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protocatechuate degradation I (meta-cleavage pathway)
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syringate degradation
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gluconeogenesis
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Pyruvate metabolism
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SYSTEMATIC NAME
IUBMB Comments
(S)-malate:NAD+ oxidoreductase (oxaloacetate-decarboxylating)
Unlike EC 1.1.1.39, malate dehydrogenase (decarboxylating), this enzyme can also decarboxylate oxaloacetate. cf. EC 1.1.1.40, malate dehydrogenase (oxaloacetate-decarboxylating) (NADP+).
CAS REGISTRY NUMBER
COMMENTARY hide
9080-52-8
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ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
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Manually annotated by BRENDA team
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Manually annotated by BRENDA team
Eriochloa borumensis
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Manually annotated by BRENDA team
Erwinia aroidea
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Manually annotated by BRENDA team
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Manually annotated by BRENDA team
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UniProt
Manually annotated by BRENDA team
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-
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Manually annotated by BRENDA team
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UniProt
Manually annotated by BRENDA team
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Manually annotated by BRENDA team
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Manually annotated by BRENDA team
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Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
knockdown of ME2 does not inhibit insulin release stimulated by glucose, pyruvate or 2-aminobicyclo [2,2,1]heptane-2-carboxylic acid-plus-glutamine
additional information
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the molecular basis for the different allosteric properties and quaternary structural stability of m-NAD(P)-ME, EC 1.1.1.38 and c-NADP-ME, EC 1.1.1.40. The structural features near the fumarate binding site and the dimer interface are highly related to the quaternary structural stability of c-NADP-ME and m-NAD(P)-ME. Lys57 plays functional roles in both the allosteric regulation and the subunit-subunit interaction of humanm-NAD(P)-ME
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 + NAD+
CO2 + pyruvate + NADH
show the reaction diagram
(S)-malate + NAD+
pyruvate + CO2 + NADH
show the reaction diagram
(S)-malate + NADP+
CO2 + pyruvate + NADPH
show the reaction diagram
(S)-malate + NADP+
pyruvate + CO2 + NADPH
show the reaction diagram
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-
-
?
Oxaloacetate
CO2 + pyruvate
show the reaction diagram
oxaloacetate + NADH
(S)-malate + NAD+
show the reaction diagram
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divalent metal ions are required
-
?
oxaloacetate + NADH
L-malate + NAD+
show the reaction diagram
-
-
-
?
pyruvate + NADH + H+
(S)-lactate + NAD+
show the reaction diagram
pyruvate + NADH + H+
L-lactate + NAD+
show the reaction diagram
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 + NAD+
CO2 + pyruvate + NADH
show the reaction diagram
(S)-malate + NAD+
pyruvate + CO2 + NADH
show the reaction diagram
(S)-malate + NADP+
CO2 + pyruvate + NADPH
show the reaction diagram
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20% activity compared to cofactor NAD+
-
?
(S)-malate + NADP+
pyruvate + CO2 + NADPH
show the reaction diagram
A0A0G2K502
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-
-
?
Oxaloacetate
CO2 + pyruvate
show the reaction diagram
oxaloacetate + NADH
L-malate + NAD+
show the reaction diagram
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-
-
?
pyruvate + NADH + H+
L-lactate + NAD+
show the reaction diagram
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
NADP+
NADPH
additional information
-
the isoenzyme can also use NADP+ but is more effective with NAD+
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Cs+
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30 mM Na+L-malate instead of K+L-malate reduces enzyme activity to 18% in the presence of 3 mM MnCl2, activity is restored with 5 or 50 mM CsCl
K+
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30 mM Na+L-malate instead of K+L-malate reduces enzyme activity to 18% in the presence of 3 mM MnCl2, activity is restored with 50 mM KCl
Ni2+
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requirement for divalent cation
Zn2+
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requirement for divalent cation
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
1,10-phenanthroline
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0.025 mM, 70% activity lost after 5 min
1-(5-O-phosphono-beta-D-ribofuranosyl)-4-[2-(trifluoromethyl)phenyl]-1H-1,2,3-triazole
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2-methylbutanoate
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5.22 mM, competitive inhibitor, 60% inhibition at pH 7.5, 54% inhibition at pH 7.0
2-methylpentanoate
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5.22 mM, competitive inhibitor, 45% inhibition at pH 7.5, 40% inhibition at pH 7.0
4,4'-dithiodipyridine
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sulfhydryl reagent, rapid and complete loss of activity, presence of Mg2+ or Mn2+ enhances inactivation rate
4-(2-aminophenyl)-1-(5-O-phosphono-beta-D-ribofuranosyl)-1H-1,2,3-triazole
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4-(2-fluorophenyl)-1-(5-O-phosphono-beta-D-ribofuranosyl)-1H-1,2,3-triazole
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4-(2-hydroxyethyl)-1-(5-O-phosphono-beta-D-ribofuranosyl)-1H-1,2,3-triazole
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4-(2-methylphenyl)-1-(5-O-phosphono-beta-D-ribofuranosyl)-1H-1,2,3-triazole
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4-(4-fluorophenyl)-1-(5-O-phosphono-beta-D-ribofuranosyl)-1H-1,2,3-triazole
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4-(4-methoxyphenyl)-1-(5-O-phosphono-beta-D-ribofuranosyl)-1H-1,2,3-triazole
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4-(naphthalen-1-yl)-1-(5-O-phosphono-beta-D-ribofuranosyl)-1H-1,2,3-triazole
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4-phenyl-1-(5-O-phosphono-beta-D-ribofuranosyl)-1H-1,2,3-triazole
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5,5'-dithiobis(2-nitrobenzoic acid)
acetyl-CoA
AgNO3
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inhibition with 20 mM, complete inhibition with 300 mM
Cl-
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competitive vs. malate and NAD+
D-malate
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competitive inhibition
diethyldicarbonate
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80% inactivation after treatment with 5 mM diethyldicarbonate for 25 min, biphasic inactivation, 40-50% inactivation in first phase, 1-2 histidine residues are acylated by diethyldicarbonate, 250 mM malate provides complete protection, 50% protection with 50 mM MgSO4, 55% enzyme activity is restored with 0.5 M hydroxylamine
iodoacetate
malonate
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competitive inhibition
N-acetyl-1-(5-O-phosphono-beta-D-ribofuranosyl)-1H-1,2,3-triazol-4-amine
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N-benzoyl-1-(5-O-phosphono-beta-D-ribofuranosyl)-1H-1,2,3-triazol-4-amine
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N-ethylmaleimide
oxaloacetate
p-(chloromercuri)benzoate
succinate
Tartronate
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competitive inhibition vs. malate, noncompetitve vs. NAD+
tiglic acid
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5.22 mM, competitive inhibitor, 58% inhibition at pH 7.5, 52% inhibition at pH 7.0
Zn2+
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5 mM ZnCl2
additional information
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
5,5'-dithiobis(2-nitrobenzoic acid)
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0.5 mM, 2.7fold increase in oxaloacetate reduction activity
alpha-methyl-DL-aspartate
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1.35fold activation
aspartate
ATP
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68% activation, 2 mM ATP, 0.005 mM CoA, 5 mM malate, 2 mM NAD+, 4 mM Mn2+
beta-methyl-DL-aspartate
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1.34fold activation
D-Aspartate
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2 mM, 1.27fold activation
fumarate
L-aspartate
N-ethylmaleimide
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1 mM, 8.9fold increase in oxaloacetate reduction activity
NH4+
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30 mM Na+L-malate instead of K+L-malate reduces enzyme activity to 18% in the presence of 3 mM MnCl2, activity is restored with 5 or 50 mM NH4Cl
p-chloromercuribenzoate
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0.02 mM, 2.5fold increase in oxaloacetate reduction activity
phosphoenolpyruvate
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0.5 mM
succinate
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UTP
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35% activation, 2 mM UTP, 0.005 mM CoA, 5 mM malate, 2 mM NAD+, 4 mM Mn2+
additional information
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cytosolic NADP+-dependent malic enzyme (c-NADP-ME) is neither a cooperative nor an allosteric enzyme
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.42 - 15.6
(S)-malate
0.19 - 50
L-malate
0.12 - 0.32
Mn2+
0.004 - 0.51
NAD+
0.025 - 1.4
NADH
2.3
NADP+
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2.1 - 5
oxaloacetate
additional information
additional information
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cytosolic NADP+-dependent malic enzyme (c-NADP-ME) is neither a cooperative nor an allosteric enzyme
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
5 - 134.4
(S)-malate
130
L-malate
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native and recombinant enzyme
28 - 30
oxaloacetate
0.06 - 0.09
pyruvate
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
0.017
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water stress plants at daytime or at nighttime
0.036
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control plants at daytime
0.07
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pyruvate reduction
0.107
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control plants at nighttime
0.46
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below, extract from leaves under continuous light conditions
0.58
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below, leaf extract
1.7
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oxaloacetate reduction
30
Erwinia aroidea
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38.5
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recombinant enzyme
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
4
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oxaloacetate reduction
5
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pyruvate reduction
7.3 - 7.6
7.3
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assay at
7.3 - 7.6
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pH RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
6.9 - 8
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over 70% of maximal activity within this range
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
65000
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monomeric recombinant His6-tagged enzyme, native PAGE
84000
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gel filtration
140000
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gel filtration
180000
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gel filtration
190000
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gel filtration
198000
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low speed sedimentation equilibrium
200000
203000
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sucrose density gradient centrifugation
220000
240000
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gel filtration
260000
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tetrameric recombinant His6-tagged enzyme, native PAGE
500000
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octameric recombinant His6-tagged enzyme, native PAGE
580000
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gel filtration
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
dimer and tetramer
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oligomer
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x * 65000, recombinant His6-tagged enzyme, SDS-PAGE, monomer, homotetramer, and homooctamer enzyme fomrs exist in solution
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
50
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22% activity left after 4 min, 80% activity left in the presence of 10 mM L-aspartate and 1 mM MnCl2, 78% activity left in the presence of 0.7 mM CoA
OXIDATION STABILITY
ORGANISM
UNIPROT
LITERATURE
enzyme is reversibly inhibited by air oxidation, activity is completely restored in 30 min by the addition of 2 mM dithiotreitol
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286697
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-20°C, 15 mM triethanolamine-maleate, pH 7.5, 1 mM EDTA, 10 mM dithiotreitol, 5% glycerol, several months, no loss of activity
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4°C, 50 mM Tris-HCl, pH 7.4, 1 mM EDTA, 10 mM 2-mercaptoethanol, 10 mM MgCl2, 5 mM L-aspartate, 2 months, 10% activity lost
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4°C, 50 mM Tris-HCl, pH 7.4, 1 mM EDTA, 10 mM 2-mercaptoethanol, 2 months, 15% activity lost
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4°C, 50 mM Tris-HCl, pH 7.4, 1 month, 90% activity lost
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Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
38-40°c treatment, ammonium sulfate, protamine sulfate precipitation, calcium phosphate gel, ammonium sulfate
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ammonium sulfate, DEAE-cellulose, Blue-B agarose, Orange-A agarose
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DEAE Sepharose CL-6B column chromatography, and Q Sepharose column chromatography
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MnCl2 precipitation, protaminsulfate precipitation, Sephadex G-25, hydroxylapatite
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MnCl2 precipitation, protaminsulfate precipitation, Sephadex G-25, Sephadex G-200, hydroxylapatite
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protamine sulfate precipitation, ammonium sulfate precipitation, DEAE-cellulose
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recombinant C-terminally His6-tagged enzyme from Escherichia coli strain BL21(DE3) by nickel affinity chromatography, dialysis, and ultrafiltration
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recombinant His6-tagged enzyme from strain BL21(DE3) by nickel affinity chromatography and ultrafiltration to 95% purity
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streptomycin sulfate ammonium sulfate, Phenyl-sepharose, Orange-A-Sepharose
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streptomycin, ammonium sulfate, heat treatment, acid treatment, calcium phosphate gel, DEAE-sephadex, hydroxylapatite, Sepharose 6B
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Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
expressed in Escherichia coli
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expression of His6-tagged enzyme in strain BL21(DE3) as mainly soluble protein
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gene ME2, quantitative RT-PCR expression analysis of isozymes Me1, Me2, and Me3 in wild-type strain and mutant Me2 strains
overexpressed in Escherichia coli
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recombinant expression of C-terminally His6-tagged enzyme in Escherichia coli strain BL21(DE3)
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ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
N434A
with N434A, the interaction of the residue with malate is lost, causing the malate to reorient itself, leading to a slower decarboxylation step
N479Q
the Kmalate value for the N479Q mutant enzyme increases by 2.2fold compared to the wild type enzyme, the KNAD value for the N479Q mutant enzyme increases by 1.1fold compared to the wild type enzyme
N479S
the Kmalate value for the N479Q mutant enzyme increases by 2.1fold compared to the wild type enzyme, the KNAD value for the N479Q mutant enzyme increases by 1.8fold compared to the wild type enzyme
S433A
the KNAD value for the S433A mutant enzyme increases by 80fold compared to the wild type enzyme, indicating that this residue provides significant binding affinity for the dinucleotide
K57S/E59N/K73E/D102S
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site-directed mutagenesis
G444A
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inactive enzyme
additional information
generation of Me2 single and double knockdown cell lines, thereby generating cel lines Me2–2124(H)/Me2–2124(P) and Me2–2124(H)/Me2-654(P), overview. Me2 mRNA and ME2 enzyme activity are drastically reduced in the double-knockdown cell lines Me2-2124(H)/Me2-2124(P) and Me2-2124(H)/Me2-456(P). Me3 mRNA is slightly reduced in these two cell lines, whereas Me1 mRNA and ME1 enzyme activity are not affected. Resident siRNA might interfere with the expression of the siRNA expressed from the second vector. Knockdown of isozyme ME3, EC 1.1.1.40, but not ME1 or ME2 (both EC 1.1.1.39) alone or together, inhibits insulin release stimulated by glucose, pyruvate or 2-aminobicyclo [2,2,1]heptane-2-carboxylic acid-plus-glutamine
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