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Information on EC 1.2.1.47 - 4-trimethylammoniobutyraldehyde dehydrogenase and Organism(s) Homo sapiens and UniProt Accession P49189
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EC Tree
1.2.1.47 4-trimethylammoniobutyraldehyde dehydrogenaseSpecify your search results
Word Map
- 1.2.1.47
- gamma-butyrobetaine
-
proliferator-activated
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dioxygenase
- peroxisome
- l-carnitine
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polyunsaturated
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1.2.1.8
-
badhs
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aldh4a1
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suckling
-
gill
- betaine
- acetaldehyde
- trimethyllysine
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
Reaction Schemes
Synonyms
aldh9a1, tmaba-dh, 4-n-trimethylaminobutyraldehyde dehydrogenase, 4-trimethylaminobutyraldehyde dehydrogenase, gamma-trimethylaminobutyraldehyde dehydrogenase, tmabaldehyde-dh ii, carnitine biosynthesis enzyme, tmabadh, aldehyde dehydrogenase 9a1, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
4-N-trimethylaminobutyraldehyde dehydrogenase
4-trimethylaminobutyraldehyde dehydrogenase
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dehydrogenase, trimethylaminobutyraldehyde
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4-N-trimethylaminobutyraldehyde dehydrogenase
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
redox reaction
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oxidation
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reduction
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SYSTEMATIC NAME
IUBMB Comments
4-trimethylammoniobutanal:NAD+ 1-oxidoreductase
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CAS REGISTRY NUMBER
COMMENTARY
73361-01-0
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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
3-aminopropionaldehyde + NAD+ + H2O
3-aminopropionate + NADH + H+
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-
-
?
3-guanidinopropionaldehyde + NAD+ + H2O
3-guanidinopropionate + NADH + H+
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-
-
?
4-(dimethylamino)butyraldehyde + NAD+ + H2O
4-(dimethylamino)butyrate + NADH + 2 H+
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-
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?
4-(trimethylamino)butyraldehyde + NAD+ + H2O
4-(trimethylamino)butyrate + NADH + 2 H+
preferred substrate
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-
?
4-amino-2-hydroxybutyraldehyde + NAD+ + H2O
4-amino-2-hydroxybutyrate + NADH + H+
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-
-
?
4-guanidinobutyraldehyde + NAD+ + H2O
4-guanidinobutyrate + NADH + H+
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-
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?
4-trimethylammoniobutanal + NAD+ + H2O
4-trimethylammoniobutanoate + NADH + 2 H+
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?
gamma-aminobutyraldehyde + NAD+ + H2O
4-aminobutanoate + NADH + H+
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?
N,N,N-trimethyl-3-aminopropionaldehyde + NAD+ + H2O
N,N,N-trimethyl-3-aminopropionate + NADH + H+
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-
-
?
N,N-dimethyl-3-aminopropionaldehyde + NAD+ + H2O
N,N-dimethyl-3-aminopropionate + NADH + H+
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-
-
?
4-trimethylammoniobutanal + NAD+ + H2O
4-trimethylammoniobutanoate + NADH + 2 H+
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?
3,4-dihydroxyphenylacetaldehyde + NAD+ + H2O
3,4-dihydroxyphenylacetate + NADH + H+
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?
3,4-dihydroxyphenylacetaldehyde + NAD+ + H2O
3,4-dihydroxyphenylacetate + NADH + H+
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?
3,4-dihydroxyphenylacetaldehyde + NAD+ + H2O
3,4-dihydroxyphenylacetate + NADH + H+
a dopamine metabolite
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?
4-trimethylaminobutyraldehyde + NAD+ + H2O
4-N-trimethylaminobutyrate + NADH + H+
strongly preferred substrate
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?
4-trimethylaminobutyraldehyde + NAD+ + H2O
4-N-trimethylaminobutyrate + NADH + H+
a carnitine precursor
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?
aminobutyraldehyde + NAD+ + H2O
aminobutyrate + NADH + H+
a GABA precursor
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?
additional information
?
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ALDH9A1 exhibits wide substrate specificity to aminoaldehydes, aliphatic and aromatic aldehydes with a clear preference for gamma-trimethylaminobutyraldehyde (TMABAL). The enzyme is multifunctional also catalyzing the reactions of EC 1.2.1.3 and EC 1.2.1.19. Substrate specificity, overview
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additional information
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ALDH9A1 exhibits wide substrate specificity to aminoaldehydes, aliphatic and aromatic aldehydes with a clear preference for gamma-trimethylaminobutyraldehyde (TMABAL). The enzyme is multifunctional also catalyzing the reactions of EC 1.2.1.3 and EC 1.2.1.19. Substrate specificity, overview
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additional information
?
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diethylaminobenzaldehyde (DEAB) is not a substrate for ALDH9A1
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additional information
?
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diethylaminobenzaldehyde (DEAB) is not a substrate for ALDH9A1
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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
3,4-dihydroxyphenylacetaldehyde + NAD+ + H2O
3,4-dihydroxyphenylacetate + NADH + H+
a dopamine metabolite
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?
4-(trimethylamino)butyraldehyde + NAD+ + H2O
4-(trimethylamino)butyrate + NADH + 2 H+
preferred substrate
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?
4-trimethylaminobutyraldehyde + NAD+ + H2O
4-N-trimethylaminobutyrate + NADH + H+
a carnitine precursor
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?
4-trimethylammoniobutanal + NAD+ + H2O
4-trimethylammoniobutanoate + NADH + 2 H+
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?
aminobutyraldehyde + NAD+ + H2O
aminobutyrate + NADH + H+
a GABA precursor
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?
4-trimethylammoniobutanal + NAD+ + H2O
4-trimethylammoniobutanoate + NADH + 2 H+
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?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
NAD+
enzyme binding structure, enzyme-NAD+ crystal structure analysis, overview. NAD+ binds in the expected site at the C-termini of the beta-strands of the Rossmann fold. NAD+ forms several electrostatic interactions with the protein. The adenine ribose hydrogen bonds with Lys180. The diphosphate interacts with Trp156, Ser233, and Thr236. The nicotinamide ribose of the one complete NAD+ forms a hydrogen bond with Glu391, a residue identically conserved in the ALDH superfamily
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
diethylaminobenzaldehyde
DEAB, the broad-spectrum ALDH inhibitor reversibly inhibits ALDH9A1 in a time-dependent manner by a covalent reversible mechanism of inhibition, mechanism analysis, overview
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
the presence of an aldehyde substrate and NAD+ promotes isomerization of the enzyme into the active conformation
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additional information
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the presence of an aldehyde substrate and NAD+ promotes isomerization of the enzyme into the active conformation
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.011
3,4-dihydroxyphenylacetaldehyde
pH 7.5, temperature not specified in the publication
0.056
3-aminopropionaldehyde
pH 7.5, temperature not specified in the publication
0.021
4-(dimethylamino)butyraldehyde
pH 7.5, temperature not specified in the publication
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0.006
4-(trimethylamino)butyraldehyde
pH 7.5, temperature not specified in the publication
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0.067
4-Aminobutyraldehyde
pH 7.5, temperature not specified in the publication
0.021
4-guanidinobutyraldehyde
pH 7.5, temperature not specified in the publication
0.053
N,N,N-trimethyl-3-aminopropionaldehyde
pH 7.5, temperature not specified in the publication
0.021
N,N-dimethyl-3-aminopropionaldehyde
pH 7.5, temperature not specified in the publication
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additional information
additional information
Michaelis-Menten kinetics
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additional information
additional information
steady-state Michaelis-Menten kinetics
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additional information
additional information
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steady-state Michaelis-Menten kinetics
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Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
10.88
4-(dimethylamino)butyraldehyde
pH 7.5, temperature not specified in the publication
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7.23
4-(trimethylamino)butyraldehyde
pH 7.5, temperature not specified in the publication
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0.021
4-guanidinobutyraldehyde
pH 7.5, temperature not specified in the publication
0.47
N,N,N-trimethyl-3-aminopropionaldehyde
pH 7.5, temperature not specified in the publication
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
aldehyde dehydrogenase 9A1 (ALDH9A1) belongs to the aldehyde dehydrogenase (ALDH) structural superfamily, which is a large group of enzymes that catalyze the NAD+-dependent oxidation of aldehydes to carboxylic acids. The superfamily comprises hundreds of distinct genes, including 19 ALDHs expressed in humans. ALDHs share a common protein fold and catalytic mechanism, but subtle differences in their active sites result in different preferences for the aldehyde substrate. Although ALDH9A1 exhibits the basic ALDH superfamily fold, the structure reveals two remarkable features. First, the final alpha-helix and beta-strand of the Rossmann dinucleotide-binding fold are disordered. Referred to as alphaE-betaE in the closely-related betaine ALDH, these secondary structural elements form extensive interactions with NAD+ in other ALDHs
malfunction
enzyme overexpression causes the Kawasaki disease (KD), an acute vasculitis that preferentially affects coronary arteries. The disease is still the leading cause of acquired heart disease in children. Patients suffering Kawasaki disease show increased TMABADH enzyme protein levels compared to controls
metabolism
the enzyme is involved in the carnitine synthesis pathway, it is abundantly expressed in tissues showing high rates of beta-oxidation such as liver and kidney
physiological function
the major in vivo function of this enzyme is to catalyze the penultimate step of carnitine biosynthesis, the oxidation of TMBAL to 4-N-trimethylaminobutyrate. Carnitine functions in the transport of long-chain fatty acids from the cytosol to the mitochondrial matrix for the synthesis of acyl-CoAs for beta-oxidation. ALDH9A1 functions indirectly in beta-oxidation
additional information
additional information
structure analysis, overview. Structural comparison reveals a position and a unique fold of the interdomain linker of ALDH9A1. This unique difference is not compatible with the presence of a bound substrate and a large conformational rearrangement of the linker up to 30 A has to occur to allow the access of the substrate channel. Moreover, the alphabetaE region consisting of an alpha-helix and a beta-strand of the coenzyme domain at the dimer interface are disordered, likely due to the loss of interactions with the inter-domain linker, which leads to incomplete beta-nicotinamide adenine dinucleotide (NAD+) binding pocket
additional information
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structure analysis, overview. Structural comparison reveals a position and a unique fold of the interdomain linker of ALDH9A1. This unique difference is not compatible with the presence of a bound substrate and a large conformational rearrangement of the linker up to 30 A has to occur to allow the access of the substrate channel. Moreover, the alphabetaE region consisting of an alpha-helix and a beta-strand of the coenzyme domain at the dimer interface are disordered, likely due to the loss of interactions with the inter-domain linker, which leads to incomplete beta-nicotinamide adenine dinucleotide (NAD+) binding pocket
additional information
the active conformation of the enzyme, in which the Rossmann dinucleotide-binding domain is fully ordered and the inter-domain linker adopts the canonical beta-hairpin observed in other ALDH structures. The presence of an aldehyde substrate and NAD+ promotes isomerization of the enzyme into the active conformation
additional information
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the active conformation of the enzyme, in which the Rossmann dinucleotide-binding domain is fully ordered and the inter-domain linker adopts the canonical beta-hairpin observed in other ALDH structures. The presence of an aldehyde substrate and NAD+ promotes isomerization of the enzyme into the active conformation
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). AL9A1_HUMAN
494
0
53802
Swiss-Prot
other Location (Reliability: 5)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
tetramer
additional information
tetramer
4 * 56000, dimer-of-dimers, recombinant His-tagged enzyme, SDS-PAGE
tetramer
enzyme ALDH9A1 forms the classic ALDH superfamily dimer-of-dimers tetramer in solution. Analytical ultracentrifugation, small-angle X-ray scattering (SAXS), and negative stain electron microscopy are used for analysis
additional information
conformation of the inter-domain linker in the P1 ALDH9A1-NAD+ structure, modeling, overview. The in-solution quaternary structure of ALDH9A1 is determined using SAXS
additional information
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conformation of the inter-domain linker in the P1 ALDH9A1-NAD+ structure, modeling, overview. The in-solution quaternary structure of ALDH9A1 is determined using SAXS
additional information
each ALDH monomer displays a typical ALDHs fold composed of an oligomerization domain (residues 128-145 and 479-494), a coenzyme domain (residues 1-127, 146-257, 470-478), a catalytic domain (residues 258-448) with the catalytic Cys288, and an interdomain linker highly conserved in amino-acid sequence and folding. Nonetheless, structural comparison reveals a position and a unique fold of the interdomain linker of ALDH9A1. The oligomerization domain wraps over the groove between the catalytic and coenzyme domains of the other monomer forming the dimer
additional information
-
each ALDH monomer displays a typical ALDHs fold composed of an oligomerization domain (residues 128-145 and 479-494), a coenzyme domain (residues 1-127, 146-257, 470-478), a catalytic domain (residues 258-448) with the catalytic Cys288, and an interdomain linker highly conserved in amino-acid sequence and folding. Nonetheless, structural comparison reveals a position and a unique fold of the interdomain linker of ALDH9A1. The oligomerization domain wraps over the groove between the catalytic and coenzyme domains of the other monomer forming the dimer
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
purified human ALDH9A1 in apoform and in complex with NAD+ or 4-(trimethylamino)butyraldehyde, hanging drop vapour diffusion method, mixing of 28 mg/ml protein in 50 mM Tris/HCl, pH 7.5, and 150 mM NaCl, with 50 mM NAD+ and an equal volume of a precipitant solution containing 12% w/v PEG 4000, 0.1 M sodium citrate, pH 5.6, and 2.5% isopropanol, X-ray diffraction structure determination and analysis at 2.3 A, 2.9 A, and 2.5 A resolution, molecular replacement using the structure of BADH from Gadus morhua subsp. callarias liver as a search model (PDB IDs 1BPW and 1A4S), structure modeling
purified recombinant detagged enzyme in complex with NAD+ and inhibitor diethylaminobenzaldehyde, hanging drop vapour diffusion method, mixing of 6 mg/ml protein in 50 mM Tris-HCl, pH 8.0, 600 mM NaCl, 5% glycerol, 0.5 mM TCE, 5 mM DEAB, and 10 mM NAD+, with reservoir solution containing 0.1 M NaCl, 0.05 M Bis-Tris, pH 6.5, 0.1 M ammonium acetate, 0.05 M HEPES, pH 7.5, and 25% w/v PEG 3350, method optimization, X-ray diffraction structure determination and analysis at 2.50-2.64 A resolution, molecular replacement using structures of cod liver betaine ALDH (PDB ID 1A4S) and apo-ALDH9A1 (PDB ID 6QAP) as search models, modeling
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
the enzyme is very sensitive and becomes nearly inactive after two re-freezing cycles. The highest melting temperatures are observed in buffers at pH 7.0 and 7.5
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant FLAG-tagged enzyme TMABA-DH from HEK-293T cells by immunoaffinity chromatography
recombinant His-tagged enzyme from Escherichia coli strain Rosetta2 (DE3) pLysS by cobalt affinity and nickel affinity chromatography, followed by ultrafiltration and gel filtration
recombinant SUMO-His6-tagged ALDH9A1 from Escherichia coli strain BL21(DE3) by nickel affinity chromatography, cleavage of the SUMO-His tag, dialysis, ultrafiltration, and gel filtration
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene ALDH9A1, recombinant expression of His-tagged enzyme in Escherichia coli strain Rosetta2 (DE3) pLysS
recombinant expression of SUMO-His6-tagged ALDH9A1 in Escherichia coli strain BL21(DE3)
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
diagnostics
detection of anti-TMABA-DH autoantibody is a potential strategy for a diagnosis of Kawasaki disease, usefulness of the anti-TMABA-DH antibody as a diagnostic marker
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Marchitti, S.A.; Deitrich, R.A.; Vasiliou, V.
Neurotoxicity and metabolism of the catecholamine-derived 3,4-dihydroxyphenylacetaldehyde and 3,4-dihydroxyphenylglycolaldehyde: the role of aldehyde dehydrogenase
Pharmacol. Rev.
59
125-150
2007
Homo sapiens (P49189)
Matsunaga, A.; Harita, Y.; Shibagaki, Y.; Shimizu, N.; Shibuya, K.; Ono, H.; Kato, H.; Sekine, T.; Sakamoto, N.; Igarashi, T.; Hattori, S.
Identification of 4-trimethylaminobutyraldehyde dehydrogenase (TMABA-DH) as a candidate serum autoantibody target for Kawasaki disease
PLoS ONE
10
e0128189
2015
Homo sapiens (P49189), Homo sapiens, Rattus norvegicus (Q9JLJ3)
Wyatt, J.W.; Korasick, D.A.; Qureshi, I.A.; Campbell, A.C.; Gates, K.S.; Tanner, J.J.
Inhibition, crystal structures, and in-solution oligomeric structure of aldehyde dehydrogenase 9A1
Arch. Biochem. Biophys.
691
108477
2020
Homo sapiens (P49189), Homo sapiens
Koncitikova, R.; Vigouroux, A.; Kopecna, M.; Sebela, M.; Morera, S.; Kopecny, D.
Kinetic and structural analysis of human ALDH9A1
Biosci. Rep.
39
BSR20190558
2019
Homo sapiens (P49189), Homo sapiens
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