Structural Modeling Studies of Aldehyde Dehydrogenase X: Insights into Key Interactions in the Tetrameric Assembly of the Isoenzyme

Author(s): Ghosia Lutfullah, Natasha Qaisar Khan, Farhat Amin, Lutfullah Kakakhel, Noreen Azhar.

Journal Name: Protein & Peptide Letters

Volume 18 , Issue 1 , 2011

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Abstract:

Human mitochondrial aldehyde dehydrogenase is a member of superfamily of multisubunit enzymes, catalyzing the conversion of a broad range of aldehydes to corresponding acids via the NAD (P)+-dependent irreversible reaction. They play an important role in the detoxification of acetaldehyde, in the development of alcohol sensitivity and human alcohol- related disorders. The study aimed to understand the role of conserved residues by comparing similarities and differences between the two isoenzymes. A 3D model of the human ALDHX is constructed by molecular modeling based on the crystal structure of human ALDH2 by using MODELLER (8V1) program. Assessment of reliability of the 3D model is carried out by the programs PROCHECK and PROSAII. The ALDHX fold is similar to the previously described ALDH structures. Sequence and structural analyses have highlighted a close structural and functional relationship between the two isoenzymes of human origin. The interfacial residues that are involved in crucial interactions across the interface stabilize the dimer-tetramer interface in the enzyme. Stability factors like salt bonds and hydrogen bonds aid and maintain the tetrameric assembly of the enzyme.

Keywords: Aldehyde dehydrogenase 2, isozymes, tetramer, detoxification, alcoholism, molecular modeling, ALDHX, ALDH2, PROCHECK, PROSAII, Sjogren, –, Larsson syndrome (SLS), hydroxybutyric aciduria, alcohol dehydrogenase (ADH), late-onset Alzheimer's disease (LOAD), local minimum problem, Peptides-based vaccines, peptide-based drugs, SWISS-PROT database, human ALDH2, PHYLIP package, Psi-Phi BLAST program, ALDHX isozyme, 17-residue signal peptide, homotetrameric mammalian Aldehyde Dehydrogenases, cytosolic ALDHs, AGFPPGV, G-factor, ligand-bound model, crab eating macaque, C-terminal hydrophilic tail, Core region, RMSD values, oligomerization domain, stereochemistry of enzyme, Phylogenetic Analysis, betain aldehyde dehydrogenase, retinal dehydrogenase type II, NADP-dependent ALDH, AL1B1_HUMAN, ALDH2_MESAU, ALDH2_RAT, ALDH2_MOUSE, ALDH2_HORSE, ALDH2_HUMAN, AL1A2_HUMAN, AL1A2_MOUSE, AL1A2_RAT, SAAAIQ, Ala7-Ser500, coenzyme/NAD, variant-Rossmann, NAD-dependent dehydrogenases, G helix, a ten-stranded-pleated sheet, Dimer-Tetramer Interfaces, coenzyme-binding (blue), Asp480, Lys142, Glu479-Lys142-Asp480, non-Asian people, A-C Interface, Glu479-His140, His156, Phe468, Thr443, Lys489, Val453, Lys494, Arg475-Val488, Tyr131-Lys138, Subunits A-D Interface, dimer-tetramer, ADH, ALDH, MSA, Nicotinamide Adenine Dinucleotide, NADP, NADH, Nicotinamide Adenine Dinucleotide (reduced form), OTU = Operational taxonomic unit, PDB = Protein databank, TCA = Tricarboxylic acidAldehyde dehydrogenase 2, isozymes, tetramer, detoxification, alcoholism, molecular modeling, ALDHX, ALDH2, PROCHECK, PROSAII, Sjogren, –, Larsson syndrome (SLS), hydroxybutyric aciduria, alcohol dehydrogenase (ADH), late-onset Alzheimer's disease (LOAD), local minimum problem, Peptides-based vaccines, peptide-based drugs, SWISS-PROT database, human ALDH2, PHYLIP package, Psi-Phi BLAST program, ALDHX isozyme, 17-residue signal peptide, homotetrameric mammalian Aldehyde Dehydrogenases, cytosolic ALDHs, AGFPPGV, G-factor, ligand-bound model, crab eating macaque, C-terminal hydrophilic tail, Core region, RMSD values, oligomerization domain, stereochemistry of enzyme, Phylogenetic Analysis, betain aldehyde dehydrogenase, retinal dehydrogenase type II, NADP-dependent ALDH, AL1B1_HUMAN, ALDH2_MESAU, ALDH2_RAT, ALDH2_MOUSE, ALDH2_HORSE, ALDH2_HUMAN, AL1A2_HUMAN, AL1A2_MOUSE, AL1A2_RAT, SAAAIQ, Ala7-Ser500, coenzyme/NAD, variant-Rossmann, NAD-dependent dehydrogenases, G helix, a ten-stranded-pleated sheet, Dimer-Tetramer Interfaces, coenzyme-binding (blue), Asp480, Lys142, Glu479-Lys142-Asp480, non-Asian people, A-C Interface, Glu479-His140, His156, Phe468, Thr443, Lys489, Val453, Lys494, Arg475-Val488, Tyr131-Lys138, Subunits A-D Interface, dimer-tetramer, ADH, ALDH, MSA, Nicotinamide Adenine Dinucleotide, NADP, NADH, Nicotinamide Adenine Dinucleotide (reduced form), OTU = Operational taxonomic unit, PDB = Protein databank, TCA = Tricarboxylic acid

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Article Details

VOLUME: 18
ISSUE: 1
Year: 2011
Page: [41 - 57]
Pages: 17
DOI: 10.2174/092986611794328645

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