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Literature summary 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 .
    View publication on PubMedView publication on EuropePMC

Cloned(Commentary)

EC Number Cloned (Comment) Organism
1.2.1.48 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)

EC Number Crystallization (Comment) Organism
1.2.1.48 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

EC Number Protein Variants Comment Organism
1.2.1.48 C241S site-directed mutagenesis, inactive active-site mutant Homo sapiens
1.2.1.48 E207Q site-directed mutagenesis, inactive mutant Homo sapiens
1.2.1.48 E331Q site-directed mutagenesis, inactive mutant Homo sapiens
1.2.1.48 N112A site-directed mutagenesis, inactive mutant Homo sapiens
1.2.1.48 Y113F site-directed mutagenesis, the mutant activity is unaltered compared to wild-type Homo sapiens
1.2.1.48 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

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

Natural Substrates/ Products (Substrates)

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

Organism

EC Number Organism UniProt Comment Textmining
1.2.1.48 Homo sapiens P51648
-
-

Purification (Commentary)

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

Reaction

EC Number Reaction Comment Organism Reaction ID
1.2.1.48 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)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
1.2.1.48 a long-chain aldehyde + NAD+ + H2O
-
 Homo sapiens a long-chain carboxylate + NADH + 2 H+
-
 ?
1.2.1.48 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

EC Number Subunits Comment Organism
1.2.1.48 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
1.2.1.48 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

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

Cofactor

EC Number Cofactor Comment Organism Structure
1.2.1.48 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

EC Number General Information Comment Organism
1.2.1.48 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
1.2.1.48 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
1.2.1.48 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