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PDBsum entry 1bxs

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protein ligands Protein-protein interface(s) links
Oxidoreductase PDB id
1bxs
Jmol
Contents
Protein chains
494 a.a. *
Ligands
NAD ×4
Waters ×128
* Residue conservation analysis
PDB id:
1bxs
Name: Oxidoreductase
Title: Sheep liver class 1 aldehyde dehydrogenase with NAD bound
Structure: Aldehyde dehydrogenase. Chain: a, b, c, d. Ec: 1.2.1.3
Source: Ovis aries. Sheep. Organism_taxid: 9940. Organ: liver. Cellular_location: cytosol
Biol. unit: Homo-Tetramer (from PDB file)
Resolution:
2.35Å     R-factor:   0.235     R-free:   0.259
Authors: S.A.Moore,H.M.Baker,T.J.Blythe,K.E.Kitson,T.M.Kitson, E.N.Baker
Key ref:
S.A.Moore et al. (1998). Sheep liver cytosolic aldehyde dehydrogenase: the structure reveals the basis for the retinal specificity of class 1 aldehyde dehydrogenases. Structure, 6, 1541-1551. PubMed id: 9862807 DOI: 10.1016/S0969-2126(98)00152-X
Date:
08-Oct-98     Release date:   27-Apr-99    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P51977  (AL1A1_SHEEP) -  Retinal dehydrogenase 1
Seq:
Struc:
501 a.a.
494 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.1.2.1.36  - Retinal dehydrogenase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Retinal + NAD+ + H2O = retinoate + NADH
Retinal
+
NAD(+)
Bound ligand (Het Group name = NAD)
corresponds exactly
+ H(2)O
= retinoate
+ NADH
      Cofactor: FAD
FAD
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cytoplasm   2 terms 
  Biological process     metabolic process   3 terms 
  Biochemical function     oxidoreductase activity     4 terms  

 

 
    reference    
 
 
DOI no: 10.1016/S0969-2126(98)00152-X Structure 6:1541-1551 (1998)
PubMed id: 9862807  
 
 
Sheep liver cytosolic aldehyde dehydrogenase: the structure reveals the basis for the retinal specificity of class 1 aldehyde dehydrogenases.
S.A.Moore, H.M.Baker, T.J.Blythe, K.E.Kitson, T.M.Kitson, E.N.Baker.
 
  ABSTRACT  
 
Background:. Enzymes of the aldehyde dehydrogenase family are required for the clearance of potentially toxic aldehydes, and are essential for the production of key metabolic regulators. The cytosolic, or class 1, aldehyde dehydrogenase (ALDH1) of higher vertebrates has an enhanced specificity for all-trans retinal, oxidising it to the powerful differentiation factor all-trans retinoic acid. Thus, ALDH1 is very likely to have a key role in vertebrate development. Results:. The three-dimensional structure of sheep ALDH1 has been determined by X-ray crystallography to 2.35 A resolution. The overall tertiary and quaternary structures are very similar to those of bovine mitochondrial ALDH (ALDH2), but there are important differences in the entrance tunnel for the substrate. In the ALDH1 structure, the sidechain of the general base Glu268 is disordered and the NAD+ cofactor binds in two distinct modes. Conclusions:. The submicromolar Km of ALDH1 for all-trans retinal, and its 600-fold enhanced affinity for retinal compared to acetaldehyde, are explained by the size and shape of the substrate entrance tunnel in ALDH1. All-trans retinal fits into the active-site pocket of ALDH1, but not into the pocket of ALDH2. Two helices and one surface loop that line the tunnel are likely to have a key role in defining substrate specificity in the wider ALDH family. The relative sizes of the tunnels also suggest why the bulky alcohol aversive drug disulfiram reacts more rapidly with ALDH1 than ALDH2. The disorder of Glu268 and the observation that NAD+ binds in two distinct modes indicate that flexibility is a key facet of the enzyme reaction mechanism.
 
  Selected figure(s)  
 
Figure 4.
Figure 4. A view of ALDH1 showing the 2F[o]-F[c] electron density in blue contoured at 0.9s in the vicinity of Glu268. F[o]-F[c] density for a possible deacylating water molecule is shown in green at 3.0s. (The figure was created using the program TURBO-FRODO [61].)
 
  The above figure is reprinted by permission from Cell Press: Structure (1998, 6, 1541-1551) copyright 1998.  
  Figure was selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21166653 N.Stiti, I.O.Adewale, J.Petersen, D.Bartels, and H.H.Kirch (2011).
Engineering the nucleotide coenzyme specificity and sulfhydryl redox sensitivity of two stress-responsive aldehyde dehydrogenase isoenzymes of Arabidopsis thaliana.
  Biochem J, 434, 459-471.  
20174634 C.G.Langendorf, T.L.Key, G.Fenalti, W.T.Kan, A.M.Buckle, T.Caradoc-Davies, K.L.Tuck, R.H.Law, and J.C.Whisstock (2010).
The X-ray crystal structure of Escherichia coli succinic semialdehyde dehydrogenase; structural insights into NADP+/enzyme interactions.
  PLoS One, 5, e9280.
PDB code: 3jz4
20133651 D.Srivastava, J.P.Schuermann, T.A.White, N.Krishnan, N.Sanyal, G.L.Hura, A.Tan, M.T.Henzl, D.F.Becker, and J.J.Tanner (2010).
Crystal structure of the bifunctional proline utilization A flavoenzyme from Bradyrhizobium japonicum.
  Proc Natl Acad Sci U S A, 107, 2878-2883.
PDB code: 3haz
20495892 H.F.Lo, and Y.J.Chen (2010).
gene cloning and biochemical characterization of a NAD(P)+ -dependent aldehyde dehydrogenase from Bacillus licheniformis.
  Mol Biotechnol, 46, 157-167.  
19886994 M.Pavan, V.F.Ruiz, F.A.Silva, T.J.Sobreira, R.M.Cravo, M.Vasconcelos, L.P.Marques, S.M.Mesquita, J.E.Krieger, A.A.Lopes, P.S.Oliveira, A.C.Pereira, and J.Xavier-Neto (2009).
ALDH1A2 (RALDH2) genetic variation in human congenital heart disease.
  BMC Med Genet, 10, 113.  
19455414 R.S.Holmes (2009).
Opossum aldehyde dehydrogenases: evidence for four ALDH1A1-like genes on chromosome 6 and ALDH1A2 and ALDH1A3 genes on chromosome 1.
  Biochem Genet, 47, 609-624.  
18848533 S.A.Krupenko (2009).
FDH: an aldehyde dehydrogenase fusion enzyme in folate metabolism.
  Chem Biol Interact, 178, 84-93.  
19300440 Y.G.Kim, S.Lee, O.S.Kwon, S.Y.Park, S.J.Lee, B.J.Park, and K.J.Kim (2009).
Redox-switch modulation of human SSADH by dynamic catalytic loop.
  EMBO J, 28, 959-968.
PDB codes: 2w8n 2w8o 2w8p 2w8q 2w8r
17175089 F.Collard, D.Vertommen, J.Fortpied, G.Duester, and E.Van Schaftingen (2007).
Identification of 3-deoxyglucosone dehydrogenase as aldehyde dehydrogenase 1A1 (retinaldehyde dehydrogenase 1).
  Biochimie, 89, 369-373.  
17884809 H.Donato, N.I.Krupenko, Y.Tsybovsky, and S.A.Krupenko (2007).
10-formyltetrahydrofolate dehydrogenase requires a 4'-phosphopantetheine prosthetic group for catalysis.
  J Biol Chem, 282, 34159-34166.  
17327228 H.N.Larson, J.Zhou, Z.Chen, J.S.Stamler, H.Weiner, and T.D.Hurley (2007).
Structural and functional consequences of coenzyme binding to the inactive asian variant of mitochondrial aldehyde dehydrogenase: roles of residues 475 and 487.
  J Biol Chem, 282, 12940-12950.
PDB codes: 2onm 2onn 2ono 2onp
17173928 L.Di Costanzo, G.A.Gomez, and D.W.Christianson (2007).
Crystal structure of lactaldehyde dehydrogenase from Escherichia coli and inferences regarding substrate and cofactor specificity.
  J Mol Biol, 366, 481-493.
PDB codes: 2hg2 2ilu 2imp
16603817 F.B.Rahman, and K.Yamauchi (2006).
Uncompetitive inhibition of Xenopus laevis aldehyde dehydrogenase 1A1 by divalent cations.
  Zoolog Sci, 23, 239-244.  
17001030 J.D.Larson, J.L.Jenkins, J.P.Schuermann, Y.Zhou, D.F.Becker, and J.J.Tanner (2006).
Crystal structures of the DNA-binding domain of Escherichia coli proline utilization A flavoprotein and analysis of the role of Lys9 in DNA recognition.
  Protein Sci, 15, 2630-2641.
PDB codes: 2ay0 2gpe
16731973 J.S.Rodríguez-Zavala, A.Allali-Hassani, and H.Weiner (2006).
Characterization of E. coli tetrameric aldehyde dehydrogenases with atypical properties compared to other aldehyde dehydrogenases.
  Protein Sci, 15, 1387-1396.  
16835232 S.Watanabe, T.Kodaki, and K.Makino (2006).
A novel alpha-ketoglutaric semialdehyde dehydrogenase: evolutionary insight into an alternative pathway of bacterial L-arabinose metabolism.
  J Biol Chem, 281, 28876-28888.  
  16511109 E.Inagaki, H.Takahashi, C.Kuroishi, and T.H.Tahirov (2005).
Crystallization and avoiding the problem of hemihedral twinning in crystals of Delta1-pyrroline-5-carboxylate dehydrogenase from Thermus thermophilus.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 61, 609-611.  
15983043 H.N.Larson, H.Weiner, and T.D.Hurley (2005).
Disruption of the coenzyme binding site and dimer interface revealed in the crystal structure of mitochondrial aldehyde dehydrogenase "Asian" variant.
  J Biol Chem, 280, 30550-30556.
PDB code: 1zum
15299009 T.Bordelon, S.K.Montegudo, S.Pakhomova, M.L.Oldham, and M.E.Newcomer (2004).
A disorder to order transition accompanies catalysis in retinaldehyde dehydrogenase type II.
  J Biol Chem, 279, 43085-43091.  
12808103 X.Fan, A.Molotkov, S.Manabe, C.M.Donmoyer, L.Deltour, M.H.Foglio, A.E.Cuenca, W.S.Blaner, S.A.Lipton, and G.Duester (2003).
Targeted disruption of Aldh1a1 (Raldh1) provides evidence for a complex mechanism of retinoic acid synthesis in the developing retina.
  Mol Cell Biol, 23, 4637-4648.  
11842090 E.Pohl, N.Brunner, M.Wilmanns, and R.Hensel (2002).
The crystal structure of the allosteric non-phosphorylating glyceraldehyde-3-phosphate dehydrogenase from the hyperthermophilic archaeum Thermoproteus tenax.
  J Biol Chem, 277, 19938-19945.
PDB code: 1ky8
11872149 J.Russo, A.Barnes, K.Berger, J.Desgrosellier, J.Henderson, A.Kanters, and L.Merkov (2002).
4-(N,N-dipropylamino)benzaldehyde inhibits the oxidation of all-trans retinal to all-trans retinoic acid by ALDH1A1, but not the differentiation of HL-60 promyelocytic leukemia cells exposed to all-trans retinal.
  BMC Pharmacol, 2, 4.  
12081471 J.S.Rodriguez-Zavala, and H.Weiner (2002).
Structural aspects of aldehyde dehydrogenase that influence dimer-tetramer formation.
  Biochemistry, 41, 8229-8237.  
11985605 K.Yamauchi, and J.Nakajima (2002).
Effect of coenzymes and thyroid hormones on the dual activities of Xenopus cytosolic thyroid-hormone-binding protein (xCTBP) with aldehyde dehydrogenase activity.
  Eur J Biochem, 269, 2257-2264.  
12163495 S.Marchal, and G.Branlant (2002).
Characterization of the amino acids involved in substrate specificity of nonphosphorylating glyceraldehyde-3-phosphate dehydrogenase from Streptococcus mutans.
  J Biol Chem, 277, 39235-39242.  
11882655 V.Montplaisir, N.C.Lan, J.Guimond, C.Savineau, P.V.Bhat, and S.Mader (2002).
Recombinant class I aldehyde dehydrogenases specific for all-trans- or 9-cis-retinal.
  J Biol Chem, 277, 17486-17492.  
11306037 A.Allali-Hassani, and H.Weiner (2001).
Interaction of human aldehyde dehydrogenase with aromatic substrates and ligands.
  Chem Biol Interact, 130, 125-133.  
11306041 B.Wei, and H.Weiner (2001).
Making an Oriental equivalent of the yeast cytosolic aldehyde dehydrogenase as well as making one with positive cooperativity in coenzyme binding by mutations of glutamate 492 and arginine 480.
  Chem Biol Interact, 130, 173-179.  
11306068 G.Duester (2001).
Genetic dissection of retinoid dehydrogenases.
  Chem Biol Interact, 130, 469-480.  
11306030 H.Weiner, B.Wei, and J.Zhou (2001).
Subunit communication in tetrameric class 2 human liver aldehyde dehydrogenase as the basis for half-of-the-site reactivity and the dominance of the oriental subunit in a heterotetramer.
  Chem Biol Interact, 130, 47-56.  
11168411 J.Hempel, I.Kuo, J.Perozich, B.C.Wang, R.Lindahl, and H.Nicholas (2001).
Aldehyde dehydrogenase. Maintaining critical active site geometry at motif 8 in the class 3 enzyme.
  Eur J Biochem, 268, 722-726.  
11306028 L.Zhang, B.Ahvazi, R.Szittner, A.Vrielink, and E.Meighen (2001).
Differences in nucleotide specificity and catalytic mechanism between Vibrio harveyi aldehyde dehydrogenase and other members of the aldehyde dehydrogenase superfamily.
  Chem Biol Interact, 130, 29-38.  
11306026 T.D.Hurley, S.Perez-Miller, and H.Breen (2001).
Order and disorder in mitochondrial aldehyde dehydrogenase.
  Chem Biol Interact, 130, 3.
PDB code: 1o05
11306031 T.M.Kitson, K.E.Kitson, and S.A.Moore (2001).
Interaction of sheep liver cytosolic aldehyde dehydrogenase with quercetin, resveratrol and diethylstilbestrol.
  Chem Biol Interact, 130, 57-69.  
11306044 T.Wymore, H.B.Nicholas, and J.Hempel (2001).
Molecular dynamics simulation of class 3 aldehyde dehydrogenase.
  Chem Biol Interact, 130, 201-207.  
10819999 B.Wei, L.Ni, T.D.Hurley, and H.Weiner (2000).
Cooperativity in nicotinamide adenine dinucleotide binding induced by mutations of arginine 475 located at the subunit interface in the human liver mitochondrial class 2 aldehyde dehydrogenase.
  Biochemistry, 39, 5295-5302.  
10998257 E.C.Kathmann, S.Naylor, and J.J.Lipsky (2000).
Rat liver constitutive and phenobarbital-inducible cytosolic aldehyde dehydrogenases are highly homologous proteins that function as distinct isozymes.
  Biochemistry, 39, 11170-11176.  
10880953 G.Duester (2000).
Families of retinoid dehydrogenases regulating vitamin A function: production of visual pigment and retinoic acid.
  Eur J Biochem, 267, 4315-4324.  
11012673 J.Perozich, I.Kuo, B.C.Wang, J.S.Boesch, R.Lindahl, and J.Hempel (2000).
Shifting the NAD/NADP preference in class 3 aldehyde dehydrogenase.
  Eur J Biochem, 267, 6197-6203.  
11009616 J.Zhou, and H.Weiner (2000).
Basis for half-of-the-site reactivity and the dominance of the K487 oriental subunit over the E487 subunit in heterotetrameric human liver mitochondrial aldehyde dehydrogenase.
  Biochemistry, 39, 12019-12024.  
11087393 L.Zhang, B.Ahvazi, R.Szittner, A.Vrielink, and E.Meighen (2000).
A histidine residue in the catalytic mechanism distinguishes Vibrio harveyi aldehyde dehydrogenase from other members of the aldehyde dehydrogenase superfamily.
  Biochemistry, 39, 14409-14418.  
11018715 T.M.Kitson, and K.E.Kitson (2000).
The effect of quercetin, a widely distributed flavonoid in food and drink, on cytosolic aldehyde dehydrogenase: a comparison with the effect of diethylstilboestrol.
  Biochim Biophys Acta, 1481, 247-254.  
  10548037 C.J.Mann, and H.Weiner (1999).
Differences in the roles of conserved glutamic acid residues in the active site of human class 3 and class 2 aldehyde dehydrogenases.
  Protein Sci, 8, 1922-1929.  
10397277 K.E.Kitson (1999).
Regulation of alcohol and aldehyde dehydrogenase activity: a metabolic balancing act with important social consequences.
  Alcohol Clin Exp Res, 23, 955-957.  
  10631996 L.Ni, J.Zhou, T.D.Hurley, and H.Weiner (1999).
Human liver mitochondrial aldehyde dehydrogenase: three-dimensional structure and the restoration of solubility and activity of chimeric forms.
  Protein Sci, 8, 2784-2790.
PDB code: 1cw3
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.