Literature summary for 1.2.1.48 extracted from

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 (2014), Nat. Commun., 5, 4439 .

Search for more literature for 1.2.1.48

Cloned(Commentary)

Cloned (Comment)	Organism
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	Homo sapiens

Crystallization (Commentary)

Crystallization (Comment)	Organism
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	Homo sapiens

Protein Variants

Protein Variants	Comment	Organism
C241S	site-directed mutagenesis, inactive active-site mutant	Homo sapiens
E207Q	site-directed mutagenesis, inactive mutant	Homo sapiens
E331Q	site-directed mutagenesis, inactive mutant	Homo sapiens
N112A	site-directed mutagenesis, inactive mutant	Homo sapiens
Y113F	site-directed mutagenesis, the mutant activity is unaltered compared to wild-type	Homo sapiens
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	Homo sapiens

Localization

Localization	Comment	Organism	GeneOntology No.	Textmining
membrane	membrane-bound. Membrane interaction of FALDH via its C-terminal transmembrane membrane domain, detailed overview	Homo sapiens	16020	-
peroxisomal membrane	-	Homo sapiens	5778	-
plasma membrane	-	Homo sapiens	5886	-

Natural Substrates/ Products (Substrates)

Natural Substrates	Organism	Comment (Nat. Sub.)	Natural Products	Comment (Nat. Pro.)	Rev.	Reac.
a long-chain aldehyde + NAD+ + H2O	Homo sapiens	-	a long-chain carboxylate + NADH + 2 H+	-	?

Organism

Organism	UniProt	Comment	Textmining
Homo sapiens	P51648	-	-

Purification (Commentary)

Purification (Comment)	Organism
recombinant Strep-tagged enzyme from Escherichia coli by affinity chromatography and gel filtration	Homo sapiens

Reaction

Reaction	Comment	Organism	Reaction ID
a long-chain aldehyde + NAD+ + H2O = a long-chain carboxylate + NADH + 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	Homo sapiens	a

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.	Reac.
a long-chain aldehyde + NAD+ + H2O	-	Homo sapiens	a long-chain carboxylate + NADH + 2 H+	-	?
additional information	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	Homo sapiens	?	-	?

Subunits

Subunits	Comment	Organism
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	Homo sapiens
More	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	Homo sapiens

Synonyms

Synonyms	Comment	Organism
ALDH3A2	-	Homo sapiens
FALDH	-	Homo sapiens
fatty aldehyde dehydrogenase	-	Homo sapiens
membrane-bound fatty aldehyde dehydrogenase	-	Homo sapiens

Cofactor

Cofactor	Comment	Organism	Structure
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	Homo sapiens

General Information

General Information	Comment	Organism
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	Homo sapiens
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	Homo sapiens
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	Homo sapiens

Use of this online version of BRENDA is free under the CC BY 4.0 license. See terms of use for full details.

Release 2023.1 (January 2023)