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Information on EC 1.2.1.48 - long-chain-aldehyde dehydrogenase and Organism(s) Homo sapiens and UniProt Accession P51648
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1.2.1.48 long-chain-aldehyde dehydrogenaseIUBMB Comments
The best substrate is dodecylaldehyde.
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Word Map
- 1.2.1.48
- sls
- ichthyosis
- spastic
- faldh
- aldh3a2
-
neurocutaneous
- diplegia
- tetraplegia
-
sjogren-larsson
- amadhs
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phytanic
- aminoaldehyde
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photophobia
-
larsson
- quadriplegia
-
alcohol:nad+
-
glistening
- medicine
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota
Synonyms
fatty aldehyde dehydrogenase, aldh3b2, aldh10, long-chain aldehyde dehydrogenase, aldh3b3, falddh, long-chain fatty aldehyde dehydrogenase, membrane-bound fatty aldehyde dehydrogenase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
ALDH3A2
dehydrogenase, long-chain aliphatic aldehyde
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fatty aldehyde:NAD+ oxidoreductase
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long-chain aldehyde dehydrogenase
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long-chain fatty aldehyde dehydrogenase
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ALDH3A2
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Sjögren-Larsson syndrome is caused by mutations in the ALDH3A2 gene that codes for FALDH
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
a long-chain aldehyde + NAD+ + H2O = a long-chain carboxylate + NADH + 2 H+
the human enzyme FALDH shows a unique reaction mechanism that differs from other ALDHs, modelling giving an alternative model for the reaction mechanism of FALDH, overview. The first step involves the activation of the catalytic Cys241 by deprotonation and subsequent substrate binding. Once Cys241 is deprotonated, it performs a nucleophilic attack on the carbonyl carbon of the fatty aldehyde, which forms a thiohemiacetal. Asn112 supports the orientation of the polar head group by coordinating to the substrate oxygen and subsequently stabilizes a tetrahedral reaction intermediate. In a second step, the collapse of the primarily formed oxyanion then initiates a hydride transfer to the NAD cofactor in a pro-R manner. Subsequently, a water molecule is deprotonated by Glu207 or Glu331 and triggers a nucleophilic attack of the hydroxide anion on the carbonyl carbon. In a final step, a repeated collapse of the oxyanion forms the fatty acid product and releases the covalent bond to Cys241, which remains activated or can be potentially reactivated
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
redox reaction
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oxidation
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reduction
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PATHWAY SOURCE
PATHWAYS
SYSTEMATIC NAME
IUBMB Comments
long-chain-aldehyde:NAD+ oxidoreductase
The best substrate is dodecylaldehyde.
CAS REGISTRY NUMBER
COMMENTARY
59298-89-4
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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
a long-chain aldehyde + NAD+ + H2O
a long-chain carboxylate + NADH + 2 H+
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?
dihydrophytal + NAD+ + H2O
(3R,S,7R,11R)-3,7,11,15-tetramethylhexadecanoic acid + NADH
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?
cis,cis-9,12-octadecadienal + NAD+ + H2O
cis,cis-9,12-octadecadienoic acid + NADH
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?
cis,cis-9,12-octadecadienal + NAD+ + H2O
cis,cis-9,12-octadecadienoic acid + NADH
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major substrate
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?
phytenal + NAD+
phytenic acid + NADH
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the enzyme is involved in the breakdown of phytol
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?
additional information
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the C-terminal gatekeeper helix is important for directing the substrate specificity of FALDH towards long-chain fatty aldehydes. Substrate funnel properties and substrate specificity, overview
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?
additional information
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the C-terminal gatekeeper helix is important for directing the substrate specificity of FALDH towards long-chain fatty aldehydes. Substrate funnel properties and substrate specificity, overview
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?
additional information
?
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poor substrates: acetaldehyde, propionaldehyde, crotonaldehyde, glutaraldehyde, benzaldehyde, retinaldehyde
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?
additional information
?
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Sjögren-Larsson syndrom is an inherited neurocutaneous disease caused by mutations in the ALDH3A2 gene that codes for fatty aldehyde dehydrogenase, an enzyme involved in lipid metabolism. A rich diversity of mutations and haplotype associations is demonstrated in Sjögren-Larsson syndrom
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?
additional information
?
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catalytically important residues to be involved in alcohol and aldehyde oxidation are Gln-120, Glu-207, Cys-241, Phe-333, Tyr-410 and His-411
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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
a long-chain aldehyde + NAD+ + H2O
a long-chain carboxylate + NADH + 2 H+
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?
cis,cis-9,12-octadecadienal + NAD+ + H2O
cis,cis-9,12-octadecadienoic acid + NADH
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major substrate
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?
phytenal + NAD+
phytenic acid + NADH
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the enzyme is involved in the breakdown of phytol
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-
?
additional information
?
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Sjögren-Larsson syndrom is an inherited neurocutaneous disease caused by mutations in the ALDH3A2 gene that codes for fatty aldehyde dehydrogenase, an enzyme involved in lipid metabolism. A rich diversity of mutations and haplotype associations is demonstrated in Sjögren-Larsson syndrom
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?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
NAD+
a series of ALDHs have been shown to bind NAD in a conformation that results in a pro-R-specific hydride transfer during catalysis. The hydride transfer in FALDH is clearly pro-R specific. Residue Glu331 interacts with the ribose-backbone of NAD and assists correct cofactor binding and orientation
NAD+
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the enzyme has a much greater specificity for NAD+ as cofactor than NADP+
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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
membrane-bound. Membrane interaction of FALDH via its C-terminal transmembrane membrane domain, detailed overview
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
FALDH belongs to the superfamily of ALDHs, which are homooligomeric enzymes characterized by the presence of a cofactor-binding domain, a catalytic domain and a bridging domain involved in oligomerization. The C-terminal gatekeeper feature is conserved across membrane-associated aldehyde dehydrogenases
malfunction
mutations in the gene coding for membrane-bound fatty aldehyde dehydrogenase (FALDH) lead to toxic accumulation of lipid species and development of the Sjoegren-Larsson Syndrome (SLS), a rare disorder characterized by skin defects and mental retardation. Impaired FALDH function alters the metabolic profiles of connected pathways, molecular mechanism of SLS-causing mutations, overview
malfunction
physiological function
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the likely physiological function of ALDH3B1 is to oxidize lipid-derived aldehydes generated in the plasma membrane
additional information
malfunction
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ALDH3B1 does not cause further impairment of the sphingolipid metabolism in the ALDH3A2-deficient cells
malfunction
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deficiency in fatty aldehyde dehydrogenase causes the Sjogren Larsson Syndrome, a rare inherited disorder characterized by ichthyosis, spasticity, and mental retardation
additional information
the dimeric FALDH displays a an element in its C-terminal region, a gatekeeper helix, which extends over the adjacent subunit, controlling the access to the substrate cavity and helping orientate both substrate cavities towards the membrane surface for efficient substrate transit between membranes and catalytic site. The gatekeeper helix is important for directing the substrate specificity of FALDH towards long-chain fatty aldehydes. Cys241 is the catalytic cysteine in the human enzyme
additional information
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the dimeric FALDH displays a an element in its C-terminal region, a gatekeeper helix, which extends over the adjacent subunit, controlling the access to the substrate cavity and helping orientate both substrate cavities towards the membrane surface for efficient substrate transit between membranes and catalytic site. The gatekeeper helix is important for directing the substrate specificity of FALDH towards long-chain fatty aldehydes. Cys241 is the catalytic cysteine in the human enzyme
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). MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
homodimer
human FALDH forms a symmetrical dimer. Each FALDH subunit in the asymmetric unit adopts the canonical aldehyde dehydrogenase fold, including an aminoterminal (N-terminal) cofactor-binding domain (residues 1-79 and 103-208), a catalytic domain (residues 209-419) and an oligomerization domain (residues 82-102 and 420-443) that connects the two subunits of the dimer, and the C-terminal residues 445-460 that form an alpha helix. The recombinant enzyme is truncated and lacks the predicted transmembrane alpha-helical region (residues 464-485) that is not included in the expression constructs, due to incompatibility with the protein production process
additional information
additional information
the dimeric FALDH displays a an element in its C-terminal region, a gatekeeper helix, which extends over the adjacent subunit, controlling the access to the substrate cavity and helping orientate both substrate cavities towards the membrane surface for efficient substrate transit between membranes and catalytic site. Three-dimensional structure analysis and modelling, overview
additional information
-
the dimeric FALDH displays a an element in its C-terminal region, a gatekeeper helix, which extends over the adjacent subunit, controlling the access to the substrate cavity and helping orientate both substrate cavities towards the membrane surface for efficient substrate transit between membranes and catalytic site. Three-dimensional structure analysis and modelling, overview
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
purified recombinant enzyme, X-ray diffraction structure determination and analysis at 2.1 A resolution, molecular replacement using the human class 3 aldehyde dehydrogenase ALDH3A1, PDB ID 3SZA as search model, and modelling
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Y113F
site-directed mutagenesis, the mutant activity is unaltered compared to wild-type
Y410F
site-directed mutagenesis, the mutant shows normal Vmax/KM levels against octanal and dodecanal and a somewhat reduced but still considerable catalytic capacity for hexadecanal
D245N
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NAD+ cosubstrate binding is occuring but catalytic reduction is diminished
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-20°C, 25 mM potassium phosphate, pH 7.5, 5% glycerol, 0.2 mM NAD+, 3 months, retains more than 80% of its original activity
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4°C, 25 mM potassium phosphate, pH 7.5, 5% glycerol, 0.2 mM NAD+, 1 month, retains 67% of its original activity
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PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant Strep-tagged enzyme from Escherichia coli by affinity chromatography and gel filtration
recombinant His6-FADH purified by anion exchange and metal-chelate chromatography, to 90-95% purity
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using chromatography on columns consisting of omega-aminohexyl-agarose and 5'-AMP-Sepharose 4B
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene ALDH3A2, recombinant expression of Strep-tagged enzyme in Escherichia coli, the enzyme lacks the predicted transmembrane alpha-helical region (residues 464-485) that is not included in the expression constructs, due to incompatibility with the protein production process
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
medicine
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FALDH activity is induced 1.4fold after a 3-day treatment with 0.8 mM bezafibrate in fibroblasts of control subjects. In fibroblasts of two Sjögren-Larsson patients homozygous for the p.R228C substitution, FALDH activity could by induced to 37% of control values by bezafibrate treatment. mRNA analysis in fibroblasts of these patients also reveals a mean 1.8fold induction of FALDH mRNA after bezafibrate treatment. No induction is observed in fibroblasts of patients with mutations that cause instability of FALDH mRNA or that result in a protein without any residual activity
medicine
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direct link between FALDH inactivation and disease pathology of Sjögren-Larsson syndrome caused by accumulation of alcohols
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Kelson, T.L.; Secor McVoy, J.R.; Rizzo, W.B.
Human liver fatty aldehyde dehydrogenase: microsomal localization, purification, and biochemical characterization
Biochim. Biophys. Acta
1335
99-110
1997
Homo sapiens
Carney, G.; Wei, S.; Rizzo, W.B.
Sjogren-Larsson syndrome: seven novel mutations in the fatty aldehyde dehydrogenase gene ALDH3A2
Hum. Mutat.
24
186
2004
Homo sapiens
van den Brink, D.M.; van Miert, J.N.; Dacremont, G.; Rontani, J.F.; Jansen, G.A.; Wanders, R.J.
Identification of fatty aldehyde dehydrogenase in the breakdown of phytol to phytanic acid
Mol. Genet. Metab.
82
33-37
2004
Homo sapiens
Rizzo, W.B.; Carney, G.
Sjoegren-Larsson syndrome: diversity of mutations and polymorphisms in the fatty aldehyde dehydrogenase gene (ALDH3A2)
Hum. Mutat.
26
1-10
2005
Homo sapiens
Gloerich, J.; Ijlst, L.; Wanders, R.J.; Ferdinandusse, S.
Bezafibrate induces FALDH in human fibroblasts; implications for Sjoegren-Larsson syndrome
Mol. Genet. Metab.
89
111-115
2006
Homo sapiens
Rizzo, W.B.
Sjoegren-Larsson syndrome: Molecular genetics and biochemical pathogenesis of fatty aldehyde dehydrogenase deficiency
Mol. Genet. Metab.
90
1-9
2007
Homo sapiens
Lloyd, M.D.; Boardman, K.D.; Smith, A.; van den Brink, D.M.; Wanders, R.J.; Threadgill, M.D.
Characterisation of recombinant human fatty aldehyde dehydrogenase: implications for Sjoegren-Larsson syndrome
J. Enzyme Inhib. Med. Chem.
22
584-590
2007
Homo sapiens
Kitamura, T.; Naganuma, T.; Abe, K.; Nakahara, K.; Ohno, Y.; Kihara, A.
Substrate specificity, plasma membrane localization, and lipid modification of the aldehyde dehydrogenase ALDH3B1
Biochim. Biophys. Acta
1831
1395-1401
2013
Homo sapiens
Keller, M.; Watschinger, K.; Golderer, G.; Maglione, M.; Sarg, B.; Lindner, H.; Werner-Felmayer, G.; Terrinoni, A.; Wanders, R.; Werner, E.
Monitoring of fatty aldehyde dehydrogenase by formation of pyrenedecanoic acid from pyrenedecanal
J. Lipid Res.
51
1554-1559
2010
Homo sapiens, Mus musculus, Rattus norvegicus
Keller, M.A.; Zander, U.; Fuchs, J.E.; Kreutz, C.; Watschinger, K.; Mueller, T.; Golderer, G.; Liedl, K.R.; Ralser, M.; Kraeutler, B.; Werner, E.R.; Marquez, J.A.
A gatekeeper helix determines the substrate specificity of Sjoegren-Larsson Syndrome enzyme fatty aldehyde dehydrogenase
Nat. Commun.
5
4439
2014
Homo sapiens (P51648), Homo sapiens
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