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Information on EC 1.1.1.40 - malate dehydrogenase (oxaloacetate-decarboxylating) (NADP+) and Organism(s) Homo sapiens and UniProt Accession P48163

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IUBMB Comments
The enzyme catalyses the oxidative decarboxylation of (S)-malate in the presence of NADP+ and divalent metal ions, and the decarboxylation of oxaloacetate. cf. EC 1.1.1.38, malate dehydrogenase (oxaloacetate-decarboxylating), and EC 1.1.1.39, malate dehydrogenase (decarboxylating).
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This record set is specific for:
Homo sapiens
UNIPROT: P48163
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The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
Reaction Schemes
hide
(S)-malate
+
NADP+
=
pyruvate
+
CO2
+
NADPH
+
H+
+
=
+
+
+
Synonyms
nadp-me, nadp-malate dehydrogenase, nadp-malic enzyme, nadp-mdh, nadp-dependent malic enzyme, nadp-dependent malate dehydrogenase, nadp-me2, malic enzyme 1, nadp malic enzyme, nadp-me1, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
c-NADP-ME
-
cytosolic NADP+-dependent malic enzyme
-
cytosolic malic enzyme
-
-
cytosolic NADP+-dependent malic enzyme
-
-
L-malate:NADP oxidoreductase
-
-
-
-
m-NAD(P)-ME
-
-
malate dehydrogenase (decarboxylating, NADP)
-
-
-
-
malate dehydrogenase (NADP, decarboxylating)
-
-
-
-
malic enzyme
malic enzyme 2
-
-
NADP(+)-dependent mitochondrial malic enzyme 2
-
-
NADP+ dependent malic enzyme
-
-
-
-
NADP-linked decarboxylating malic enzyme
-
-
-
-
NADP-malic enzyme
-
-
-
-
NADP-ME
-
-
-
-
NADP-specific malate dehydrogenase
-
-
-
-
NADP-specific malic enzyme
-
-
-
-
pyruvic-malic carboxylase
-
-
-
-
TME
-
-
-
-
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
(S)-malate + NADP+ = pyruvate + CO2 + NADPH
show the reaction diagram
sequential ordered bi-ter kinetic mechanism with NADP+ as the leading substrate followed by L-malate. The products are released in the order of CO2, pyruvate and NADPH
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
decarboxylation
-
-
-
-
redox reaction
-
-
-
-
oxidation
-
-
-
-
reduction
-
-
-
-
SYSTEMATIC NAME
IUBMB Comments
(S)-malate:NADP+ oxidoreductase (oxaloacetate-decarboxylating)
The enzyme catalyses the oxidative decarboxylation of (S)-malate in the presence of NADP+ and divalent metal ions, and the decarboxylation of oxaloacetate. cf. EC 1.1.1.38, malate dehydrogenase (oxaloacetate-decarboxylating), and EC 1.1.1.39, malate dehydrogenase (decarboxylating).
CAS REGISTRY NUMBER
COMMENTARY hide
9028-47-1
-
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 + NADP+
pyruvate + CO2 + NADPH
show the reaction diagram
-
-
-
r
(S)-malate + NADP+
pyruvate + CO2 + NADPH + H+
show the reaction diagram
-
-
-
?
(S)-malate + NAD+
pyruvate + CO2 + NADH
show the reaction diagram
(S)-malate + NADP+
pyruvate + CO2 + NADPH
show the reaction diagram
(S)-malate + NADP+
pyruvate + CO2 + NADPH + H+
show the reaction diagram
(S)-malate + NADP+
pyruvate + NADPH + H+ + CO2
show the reaction diagram
-
-
-
-
r
Oxaloacetate
Pyruvate + CO2
show the reaction diagram
pyruvate + CO2 + NADPH
(S)-malate + NADP+
show the reaction diagram
-
-
-
-
r
pyruvate + CO2 + NADPH
L-malate + NADP+
show the reaction diagram
pyruvate + CO2 + NADPH + H+
(S)-malate + NADP+
show the reaction diagram
-
-
-
-
r
pyruvate + NADPH
?
show the reaction diagram
-
at 5.4% of the activity of NADP-dependent oxidative decarboxylation of malate
-
-
?
additional information
?
-
-
one may speculate that in vivo the reaction catalyzed by cytosolic enzyme supplies dicarboxylic acids, anaplerotic function, for the formation of neurotransmitters while the mitochondrial enzyme regulates the flux rate via Krebs cycle by disposition of the tricarboxylic acid cycle intermediates, cataplerotic function
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
(S)-malate + NADP+
pyruvate + CO2 + NADPH
show the reaction diagram
-
-
-
r
(S)-malate + NADP+
pyruvate + CO2 + NADPH + H+
show the reaction diagram
-
-
-
?
(S)-malate + NADP+
pyruvate + CO2 + NADPH
show the reaction diagram
-
-
-
-
r
(S)-malate + NADP+
pyruvate + CO2 + NADPH + H+
show the reaction diagram
(S)-malate + NADP+
pyruvate + NADPH + H+ + CO2
show the reaction diagram
-
-
-
-
r
pyruvate + CO2 + NADPH + H+
(S)-malate + NADP+
show the reaction diagram
-
-
-
-
r
additional information
?
-
-
one may speculate that in vivo the reaction catalyzed by cytosolic enzyme supplies dicarboxylic acids, anaplerotic function, for the formation of neurotransmitters while the mitochondrial enzyme regulates the flux rate via Krebs cycle by disposition of the tricarboxylic acid cycle intermediates, cataplerotic function
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
NAD+
-
poor activity with NAD+ compared to NADP+
NADP+
NADPH
additional information
-
nucleotide-binding site of c-NADP-ME, sequence comparisons, overview. A series of E314A-containing c-NADP-ME quadruple mutants are changed to NAD+-utilizing enzymes by abrogating NADP+ binding and increasing NAD+ binding
-
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Mn2+
-
activates
additional information
-
Mg2+ does not influence the thermal stability of the enzyme
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
(NH4)2SO4
-
at high concentrations
embonic acid
-
-
malate
-
excess of malate inhibits the oxidative decarboxylation catalyzed by the cytosolic enzyme at pH 7.0, and below, decarboxylation catalyzed by mitochondrial enzyme is unaffected by the substrate
NaCl
-
at high concentrations
NPD389
-
-
Tartronate
-
noncompetitive inhibitor with respect to L-malate
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
fumarate
succinate
-
increases activity of the mitochondrial enzyme at low malate concentrations, no effect on the activity of the cytosolic enzyme
additional information
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.8 - 1.7
(S)-malate
0.0018 - 0.0125
NADP+
0.0018 - 0.0125
NADPH
0.24 - 36
(S)-malate
13.3 - 27.9
CO2
0.12 - 0.96
L-malate
0.9 - 20
NAD+
0.00139 - 116
NADP+
0.002 - 0.0053
NADPH
4.8 - 7.2
pyruvate
additional information
additional information
-
human m-NAD(P)-ME is a non-cooperative enzyme for substrate L-malate binding, steady-state kinetics of wild-type and mutant enzymes, overview
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
2 - 32
(S)-malate
84.83 - 136.9
(S)-malate
22 - 258
NAD+
1.3 - 149
NADP+
additional information
additional information
-
-
-
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
2.8
NAD+
-
wild-type enzyme, pH 7.4, 30°C
36000
NADP+
-
wild-type enzyme, pH 7.4, 30°C
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.73 - 23.2
ATP
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0014
embonic acid
Homo sapiens
-
pH and temperature not specified in the publication
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
1.92
-
recombinant enzyme in INS-1 832/13 cells, reverse reaction, pH 7.4, temperature not specified in the publication
5.04
-
-
56.35
-
-
90.9
-
mitochondrial enzyme
91.4
-
cytosolic enzyme
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7.4
assay at
7.1
-
NADP+-linked decarboxylation of malate, at 0.2 mM malate
pH RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
6.8 - 8
-
pH 6.8: about 40% of maximal activity, pH 8.0: about 70% of maximal activity, cytosolic enzyme, NADPH-dependent reductive carboxylation of pyruvate
7.1 - 8.6
-
pH 7.1: about 65% of maximal activity, pH 8.6: about 75% of maximal activity, NADP+-dependent decarboxylation of malate, at 10 mM malate, mitochondrial enzyme and cytosolic enzyme
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
30
assay at
37
-
assay at
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
UniProt
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
physiological function
additional information
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION?
MAOX_HUMAN
572
0
64150
Swiss-Prot
other Location (Reliability: 5)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
257000
-
gel filtration
63000
-
4 * 63000, SDS-PAGE
64000
-
4 * 64000, SDS-PAGE
65000
-
4 * 65000, SDS-PAGE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
homotetramer
x-ray crystallography
tetramer
a dimer of dimers. The c-NADP-ME monomer is composed of four domains. Domain A (residues 23-130) is predominantly helical and confers the ability to bind fumarate. Domain B (residues 131-277 and 464-535) contains a central five-stranded parallel beta-sheet surrounded by helices on both sides. Domain C (residues 278-463) exhibits a dinucleotide-binding Rossmann fold with a modification: strand beta3 is replaced by a short antiparallel beta-strand. Domain D (residues 536-579) contains one helix followed by a long extended random coil structure protruding away from the ordered portion of the ME monomer. The active site of ME is located at the interface of domains B and C, whereas residues in domains A and D primarily participate in the formation of dimers and tetramers
dimer
-
the dimeric form of c-NADP-ME is as active as tetramers, analytical ultracentrifugation
tetramer
additional information
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
hanging drop vapor diffusion method, using 250 mM LiCl and 19% (w/v) PEG 3350
purified apoenzyme, hanging drop vapor diffusion method, 6 mg/ml protein is crystallized against a reservoir solution containing 250 mM LiCl and 19% w/v PEG 3350, room temperature, 5-7 days, X-ray diffraction structure determination and analysis at 2.55 A resolution, molecular replacement using the structure of pigeon c-NADP-ME in complex with NADP+, Mn2+, and oxalate as search model, modelling
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
K57S/E59N/K73E/D102S
site-directed mutagenesis, the mutant is primarily monomeric with some dimer formation
N59E/E73K
N59E/E73K/S102D
S102D
S57K/N59E/E73K
S57K/N59E/E73K/S102D
S57K/N59E/E73K/S102D/H74K/D78P/D80E/D87G
S57K/N59E/E73K/S102D/H74K/D78P/D80E/D87G/D90E/K106S/Q121S/L125H
S57K/N59E/E73K/S102D/H74K/D78P/D80E/D87G/K106S/Q121S/L125H
D139A
-
dimeric mutant enzyme with reduced activity compared to the wild type enzyme
D568A
-
dimeric or tetrameric mutant enzyme with increased activity compared to the wild type enzyme
D90A
-
dimeric or tetrameric mutant enzyme with reduced activity compared to the wild type enzyme
E314A
-
site-directed mutagenesis
E314A/S346I/K347D/K362H
-
site-directed mutagenesis, the quadruple mutant enzyme is a mainly NAD+-utilizing enzyme by a considerable increase in catalysis using NAD+ as the cofactor, shows increased inhibition by ATP compared to the wild-type enzyme
E314A/S346K
-
site-directed mutagenesis
E314A/S346K/K347Y/K362H
-
site-directed mutagenesis, the quadruple mutant enzyme is a mainly NAD+-utilizing enzyme by a considerable increase in catalysis using NAD+ as the cofactor, shows increased inhibition by ATP compared to the wild-type enzyme
E314A/S346K/K347Y/K362Q
-
site-directed mutagenesis, the quadruple mutant enzyme is a mainly NAD+-utilizing enzyme by a considerable increase in catalysis using NAD+ as the cofactor, shows increased inhibition by ATP compared to the wild-type enzyme
H142A
H142A/D568A
H51A
-
dimeric or tetrameric mutant enzyme with wild type activity
H51A/D139A
H51A/D90A
K347Y
-
site-directed mutagenesis, the mutant enzyme shows a 5fold increased Km for NADP+ compared to the wild-type enzyme
K347Y/K362Q
-
site-directed mutagenesis
K362H
-
site-directed mutagenesis
K362Q
-
site-directed mutagenesis, the mutant enzyme displays a significant, over 140fold elevation in Km,NADP value compared with that of wild-type c-NADP-ME but no significant changes in the kcat,NADP value
S346I/K347D/K362H
-
site-directed mutagenesis, the triple c-NADP-ME mutant does not show significant reduction in its Km,NAD values. This mutant exclusively utilizes NAD+ as its cofactor
S346K
-
site-directed mutagenesis, site-directed mutagenesis, the mutant enzyme shows a 3fold increased Km for NADP+ compared to the wild-type enzyme
S346K/K347Y
-
site-directed mutagenesis, the double mutant enzyme shows a 30fold increased Km for NADP+ compared to the wild-type enzyme
S346K/K347Y/K362H
-
site-directed mutagenesis, the triple c-NADP-ME mutant does not show significant reduction in its Km,NAD values, but displays an enhanced value for kcat,NAD
S346K/K347Y/K362Q
-
site-directed mutagenesis, the triple c-NADP-ME mutant does not show significant reduction in its Km,NAD values
S346K/K362Q
-
site-directed mutagenesis
W572A
additional information
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
30
-
completely stable for at least 20 min
52 - 64
-
thermal denaturation of c-NADP-ME wild-type and the interface mutants, overview
additional information
-
Mg2+ does not influence the thermal stability of the enzyme
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
Ni-NTA column chromatography
Ni-NTA-Sepharose column chromatography
-
nickel affinity gel column chromatography
-
recombinant ME1 2229fold from INS-1 832/13 cell cytosolic fractions by 2',5'-ADP affinity chromatography
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expressed in Escherichia coli BL21(DE3) cells
recombinant C-terminally His6-tagged enzyme from Escherichia coli strain BL21(DE3) by nickel affinity chromatography, dialysis, and ultrafiltration
expressed in Escherichia coli BL21 (DE3) cells
-
functional expression of ME1, under the control of cytomegalovirus, which also directs the transcription of GFP from an internal ribosome entry site, in Rattus norvegicus INS-1 832/13 cells and in Mus musculus islets
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
isoform ME2 expression increases as tumor progression and invasion capabilities of cells are increased
-
p53 represses the expression of malic enzyme 1 and malic enzyme 2
-
supplementation by cell permeable exogenous dimethylmalate (DMM) in A-549 cells mimics the ME2 knockdown phenotype
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Mounib, M.S.
NAD- and NADP-malic enzymes in spermatozoa of mammals and fish
FEBS Lett.
48
79-84
1974
Bos taurus, Gadidae, Homo sapiens, salmon
Manually annotated by BRENDA team
Bukato, G.; Kochan, Z.; Swierczynski, J.
Different regulatory properties of the cytosolic and mitochondrial forms of malic enzyme isolated from human brain
Int. J. Biochem. Cell Biol.
27
1003-1008
1995
Homo sapiens
Manually annotated by BRENDA team
Bukato, G.; Kochan, Z.; Swierczynski, J.
Purification and properties of cytosolic and mitochondrial malic enzyme isolated from human brain
Int. J. Biochem. Cell Biol.
27
47-54
1995
Homo sapiens
Manually annotated by BRENDA team
Zelewski, M.; Swierczynski, J.
Malic enzyme in human liver. Intracellular distribution, purification and properties of cytosolic isozyme
Eur. J. Biochem.
201
339-345
1991
Homo sapiens
Manually annotated by BRENDA team
Chang, G.G.; Huang, T.M.; Wang, J.K.; Lee, H.J.; Chou, W.Y.; Meng, C.L.
Kinetic mechanism of the cytosolic malic enzyme from human breast cancer cell line
Arch. Biochem. Biophys.
296
468-473
1992
Homo sapiens
Manually annotated by BRENDA team
Chang, G.G.; Wang, J.K.; Huang, T.M.; Lee, H.J.; Chou, W.Y.; Meng, C.L.
Purification and characterization of the cytosolic NADP+-dependent malic enzyme from human breast cancer cell line
Eur. J. Biochem.
202
681-688
1991
Homo sapiens
Manually annotated by BRENDA team
Hsieh, J.Y.; Liu, G.Y.; Hung, H.C.
Influential factor contributing to the isoform-specific inhibition by ATP of human mitochondrial NAD(P)+-dependent malic enzyme: functional roles of the nucleotide binding site Lys346
FEBS J.
275
5383-5392
2008
Homo sapiens
Manually annotated by BRENDA team
Hsieh, J.Y.; Chen, S.H.; Hung, H.C.
Functional roles of the tetramer organization of malic enzyme
J. Biol. Chem.
284
18096-18105
2009
Homo sapiens
Manually annotated by BRENDA team
Hsieh, J.Y.; Hung, H.C.
Engineering of the cofactor specificities and isoform-specific inhibition of malic enzyme
J. Biol. Chem.
284
4536-4544
2009
Homo sapiens
Manually annotated by BRENDA team
Heart, E.; Cline, G.W.; Collis, L.P.; Pongratz, R.L.; Gray, J.P.; Smith, P.J.
Role for malic enzyme, pyruvate carboxylation, and mitochondrial malate import in glucose-stimulated insulin secretion
Am. J. Physiol. Endocrinol. Metab.
296
E1354-E1362
2009
Homo sapiens
Manually annotated by BRENDA team
Hsieh, J.Y.; Chen, M.C.; Hung, H.C.
Determinants of nucleotide-binding selectivity of malic enzyme
PLoS ONE
6
e25312
2011
Homo sapiens
Manually annotated by BRENDA team
Murugan, S.; Hung, H.C.
Biophysical characterization of the dimer and tetramer interface interactions of the human cytosolic malic enzyme
PLoS ONE
7
e50143
2012
Homo sapiens
Manually annotated by BRENDA team
Hsieh, J.; Li, S.; Chen, M.; Yang, P.; Chen, H.; Chan, N.; Liu, J.; Hung, H.
Structural characteristics of the nonallosteric human cytosolic malic enzyme
Biochim. Biophys. Acta
1844
1773-1783
2014
Homo sapiens (P48163), Homo sapiens
Manually annotated by BRENDA team
Jiang, P.; Du, W.; Mancuso, A.; Wellen, K.E.; Yang, X.
Reciprocal regulation of p53 and malic enzymes modulates metabolism and senescence
Nature
493
689-693
2013
Homo sapiens
Manually annotated by BRENDA team
Ren, J.G.; Seth, P.; Clish, C.B.; Lorkiewicz, P.K.; Higashi, R.M.; Lane, A.N.; Fan, T.W.; Sukhatme, V.P.
Knockdown of malic enzyme 2 suppresses lung tumor growth, induces differentiation and impacts PI3K/AKT signaling
Sci. Rep.
4
5414
2014
Homo sapiens
Manually annotated by BRENDA team
Sarfraz, I.; Rasul, A.; Hussain, G.; Hussain, S.M.; Ahmad, M.; Nageen, B.; Jabeen, F.; Selamoglu, Z.; Ali, M.
Malic enzyme 2 as a potential therapeutic drug target for cancer
IUBMB Life
70
1076-1083
2018
Homo sapiens
Manually annotated by BRENDA team