Information on EC 1.2.1.27 - methylmalonate-semialdehyde dehydrogenase (CoA-acylating)

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

EC NUMBER
COMMENTARY hide
1.2.1.27
-
RECOMMENDED NAME
GeneOntology No.
methylmalonate-semialdehyde dehydrogenase (CoA-acylating)
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
2-methyl-3-oxopropanoate + CoA + H2O + NAD+ = propanoyl-CoA + HCO3- + NADH
show the reaction diagram
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-
-
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
oxidation
redox reaction
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-
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reduction
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-
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PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
2,4-dinitrotoluene degradation
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L-valine degradation I
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Metabolic pathways
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Propanoate metabolism
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valine metabolism
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Valine, leucine and isoleucine degradation
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SYSTEMATIC NAME
IUBMB Comments
2-methyl-3-oxopropanoate:NAD+ 3-oxidoreductase (CoA-propanoylating)
Also converts 3-oxopropanoate into acetyl-CoA [3]. The reaction occurs in two steps with the decarboxylation process preceding CoA-binding [3]. Bicarbonate rather than CO2 is released as a final product [3].
CAS REGISTRY NUMBER
COMMENTARY hide
37205-49-5
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ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
Oryza sativa Japonica
Japonica
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Manually annotated by BRENDA team
PAO
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-
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
MSDH malfunction can be a reason for 3-hydroxyisobutyric aciduria, which is a disorder of valine metabolism
metabolism
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
2-methyl-3-oxopropanoate + CoA + H2O + NAD+
propanoyl-CoA + HCO3- + NADH
show the reaction diagram
2-methyl-3-oxopropanoate + CoA + NAD+
propanoyl-CoA + CO2 + NADH
show the reaction diagram
2-methylbutyraldehyde + CoA + NAD+
?
show the reaction diagram
-
low activity
-
-
?
acetaldehyde + CoA + NAD+
?
show the reaction diagram
-
low activity
-
-
?
butyraldehyde + CoA + NAD+
?
show the reaction diagram
-
low activity
-
-
?
isobutyraldehyde + CoA + NAD+
?
show the reaction diagram
-
low activity
-
-
?
malonate semialdehyde + CoA + H2O + NAD+
acetyl-CoA + CO2 + NADH
show the reaction diagram
malonate semialdehyde + CoA + NAD+
acetyl-CoA + CO2 + NADH
show the reaction diagram
malondialdehyde + CoA + NAD+
?
show the reaction diagram
-
low activity
-
-
?
methylmalonate semialdehyde + CoA + H2O + NAD+
propanoyl-CoA + HCO3- + NADH
show the reaction diagram
methylmalonate-semialdehyde + CoA + NAD+
propionyl-CoA + NADH + H+ + HCO3-
show the reaction diagram
-
-
-
-
?
p-nitrophenyl acetate + CoA + NAD+
p-nitrophenol + acetyl-CoA + NADH
show the reaction diagram
-
-
-
ir
propanal + 2-mercaptoethanol + NAD+
? + NADH
show the reaction diagram
propanal + CoA + NAD+
propanoyl-CoA + NADH
show the reaction diagram
propanal + NAD+
? + NADH
show the reaction diagram
-
-
-
?
propionaldehyde + CoA + H2O + NAD+
?
show the reaction diagram
no physiological substrate
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-
?
propionaldehyde + CoA + NAD+
? + NADH
show the reaction diagram
highest activity, no physiological substrate for MSDH, it only forms the same thiopropionyl enzyme intermediate as methylmalonate semialdehyde and malonate semialdehyde
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-
?
propionaldehyde + CoA + NAD+
propanoyl-CoA + NADH
show the reaction diagram
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-
-
-
?
succinate semialdehyde + CoA + NAD+
?
show the reaction diagram
-
very low activity
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-
?
additional information
?
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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
2-methyl-3-oxopropanoate + CoA + H2O + NAD+
propanoyl-CoA + HCO3- + NADH
show the reaction diagram
2-methyl-3-oxopropanoate + CoA + NAD+
propanoyl-CoA + CO2 + NADH
show the reaction diagram
malonate semialdehyde + CoA + NAD+
acetyl-CoA + CO2 + NADH
show the reaction diagram
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-
-
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ir
methylmalonate-semialdehyde + CoA + NAD+
propionyl-CoA + NADH + H+ + HCO3-
show the reaction diagram
-
-
-
-
?
additional information
?
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Q6Z4E4
ALDH superfamily represents a group of enzymes that catalyze the oxidation of endogenous and exogenous aldehydes to the corresponding carboxylic acids
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
NADH
-
competitive with NAD+
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.54 - 44
2-mercaptoethanol
0.0025 - 0.06
2-Methyl-3-oxopropanoate
0.021 - 0.62
CoA
0.0045
Malonate semialdehyde
-
-
0.006 - 0.215
methylmalonate semialdehyde
0.033 - 9.44
NAD+
6.1 - 6.4
propanal
9.3 - 9.8
propionaldehyde
additional information
additional information
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Km-value of CoA for R301L mutant enzyme under steady-state conditions with propionaldehyde is above 1 mM at pH 8.2 and 30C
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.003 - 1.1
2-Methyl-3-oxopropanoate
2.8 - 12.6
CoA
0.02
Malonate semialdehyde
Sulfolobus solfataricus
Q97YT9
30C, pH 8.2; pH 8.2, 30C
0.003
methylmalonate semialdehyde
Sulfolobus solfataricus
Q97YT9
30C, pH 8.2
0.02 - 2.2
NAD+
0.03
propionaldehyde
Sulfolobus solfataricus
Q97YT9
30C, pH 8.2; pH 8.2, 30C
additional information
additional information
Bacillus subtilis
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Kcat-value of CoA for R301L mutant enzyme under steady-state conditions with propionaldehyde is above 3 1/sec at pH 8.2 and 30C
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kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
3 - 150
CoA
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0031
NADH
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
8
-
2-methyl-3-oxopropanoate + CoA + NAD+
8.5
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2-methyl-3-oxopropanoate + 2-mercaptoethanol + NAD+; 2-methyl-3-oxopropanoate + CoA + NAD+; propanal + 2-mercaptoethanol + NAD+
pH RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7 - 10
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methylmalonate semialdehyde oxidation, more than 90% of maximal activity
7 - 8.5
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methylmalonate semialdehyde oxidation, less than 90% of maximal activity above and below
8 - 10
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propanal oxidation, less than 50% of maximal activity below, less than 60% of maximal activity above
8 - 9.5
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propanal oxidation, less than 50% of maximal activity above and below
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
pI VALUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
PDB
SCOP
CATH
ORGANISM
UNIPROT
Bacillus subtilis (strain 168)
Rhizobium meliloti (strain 1021)
Rhizobium meliloti (strain 1021)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
54600
calculated from sequence
130000
native molecular weight using gel filtration
132000
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gel filtration
250000
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gel filtration
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
?
x * 53700, 2D-PAGE
dimer
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2 * 58000, SDS-PAGE; 2 * 69000, gel filtration in presence of SDS
homodimer
tetramer
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
phosphoprotein
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side-chain modification
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acylation of active site cysteine residue Cys-285 by long-chain fatty acyl-CoA esters inactivates the enzyme
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
hanging-drop vapour diffusion, crystals diffract to 2.5 A resolution
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methylmalonate semialdehyde dehydrogenase in binary complex with NAD+, showing that the nicotinamide ring is well defined in the electron density due to direct and H2O-mediated hydrogen bonds with the carboxamide and that a conformational isomerization of the NMNH is possible in MSDH
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
on ice, 1 mM NAD+, 20 h, 77% activity remains
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on ice, 10% glycerol, 20 h, 32% activity remains
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on ice, 20 h, 11% activity remains
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Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
; to apparent homogeneity using heat precipitation at 80C for 20 min, ion exchange chromatography and gel filtration
MSDH purified by ammonium sulfate fractionation, 40-80%, and gel filtration on a ACA 34 resin
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recombinant MSDH
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Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
expression in Escherichia coli
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expression in Escherichia coli; SSO1218 expressed in Escherichia coli BL21 (DE3) RIL via isopropyl-b-D-thiogalactopyranoside induction
in Escherichia coli DH5[alpha] transformants containing the pSKmsdbsub plasmid
into the pGEM-T easy vector for sequencing
ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
C49A/C176A/C305A/C369A/C403A
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kinetic parameters similar to the wild-type enzmye
N427L
substitution dramatically alters the catalytic properties of the enzyme, acylation becomes rate-limiting with a decrease of the associated rate constant by at least 10000fold relative to the wild-type MSDH
R124L
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results obtained under pre-steady conditions show that both Arg residues participate not only in methylmalonate semialdehyde binding via stabilizing interactions between the guanidinium groups and the carboxylate but also in the formation of an efficient MSDH-NAD+-methylmalonate semialdehyde ternary complex
R301L
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results obtained under pre-steady conditions show that both Arg residues participate not only in methylmalonate semialdehyde binding via stabilizing interactions between the guanidinium groups and the carboxylate but also in the formation of an efficient MSDH-NAD+-methylmalonate semialdehyde ternary complex
V229G
significant decrease of the rate constant associated with the dissociation of NADH from the NADH-thioacylenzyme complex; together with insertion of glycine at position 225, significant decrease of the rate constant associated with the dissociation of NADH from the NADH/thioacylenzyme complex
V229G/H226P
rate-limiting step changes to acylation instead of deacylation; together with insertion of glycine at position 225, rate-limiting step changes to acylation instead of deacylation
V229G/Y252L/V253I
together with insertion of glycine at position 225, rate-limiting step changes to acylation instead of deacylation
W177F
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NAD-binding followed by fluorescence quenching of methylmalonate semialdehyde dehydrogenase. Only W468 is responsible for time-dependent additional quenching
W28F
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NAD-binding followed by fluorescence quenching of methylmalonate semialdehyde dehydrogenase. Only W468 is responsible for time-dependent additional quenching
W397F
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NAD-binding followed by fluorescence quenching of methylmalonate semialdehyde dehydrogenase. Only W468 is responsible for time-dependent additional quenching
W468F
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NAD-binding followed by fluorescence quenching of methylmalonate semialdehyde dehydrogenase. Only W468 is responsible for time-dependent additional quenching
W76F
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NAD-binding followed by fluorescence quenching of methylmalonate semialdehyde dehydrogenase. Only W468 is responsible for time-dependent additional quenching
P62S
missense mutation in a highly conserved amino acid of MSDH, patient has severe developmental delay associated with development of marked post-natal microcephaly, at 7 years static moderate learning difficulties and borderline microcephaly
S262Y
missense mutation in a highly conserved amino acid of MSDH, patient developed a febrile illness and died from a hepatoencephalopathy at 2 years of age
C285A
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expressed in Escherichia coli, no activity
N251E
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expressed in Escherichia coli, no activity
additional information
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