spacer
spacer

PDBsum entry 1zum

Go to PDB code: 
protein ligands metals Protein-protein interface(s) links
Oxidoreductase PDB id
1zum
Jmol
Contents
Protein chain
(+ 6 more) 469 a.a. *
Ligands
GAI ×8
EDO ×21
Metals
_NA ×12
Waters ×2649
* Residue conservation analysis
PDB id:
1zum
Name: Oxidoreductase
Title: Human mitochondrial aldehyde dehydrogenase asian variant, aldh2 2, Apo form
Structure: Aldehyde dehydrogenase. Chain: a, b, c, d, e, f, g, h, i, j, k, l. Synonym: aldh class 2, aldhi, aldh-e2, aldh2 2. Engineered: yes. Mutation: yes. Other_details: (does not contain mitochondrial leader sequence)
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: aldh2, aldm. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693.
Biol. unit: Tetramer (from PQS)
Resolution:
2.10Å     R-factor:   0.204     R-free:   0.238
Authors: H.N.Larson,H.Weiner,T.D.Hurley
Key ref:
H.N.Larson et al. (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. PubMed id: 15983043 DOI: 10.1074/jbc.M502345200
Date:
31-May-05     Release date:   28-Jun-05    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P05091  (ALDH2_HUMAN) -  Aldehyde dehydrogenase, mitochondrial
Seq:
Struc:
517 a.a.
469 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: E.C.1.2.1.3  - Aldehyde dehydrogenase (NAD(+)).
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: An aldehyde + NAD+ + H2O = a carboxylate + NADH
aldehyde
Bound ligand (Het Group name = EDO)
matches with 40.00% similarity
+ NAD(+)
+ H(2)O
= carboxylate
+ NADH
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular vesicular exosome   3 terms 
  Biological process     metabolic process   10 terms 
  Biochemical function     electron carrier activity     5 terms  

 

 
    reference    
 
 
DOI no: 10.1074/jbc.M502345200 J Biol Chem 280:30550-30556 (2005)
PubMed id: 15983043  
 
 
Disruption of the coenzyme binding site and dimer interface revealed in the crystal structure of mitochondrial aldehyde dehydrogenase "Asian" variant.
H.N.Larson, H.Weiner, T.D.Hurley.
 
  ABSTRACT  
 
Mitochondrial aldehyde dehydrogenase (ALDH2) is the major enzyme that oxidizes ethanol-derived acetaldehyde. A nearly inactive form of the enzyme, ALDH2*2, is found in about 40% of the East Asian population. This variant enzyme is defined by a glutamate to lysine substitution at residue 487 located within the oligomerization domain. ALDH2*2 has an increased Km for its coenzyme, NAD+, and a decreased kcat, which lead to low activity in vivo. Here we report the 2.1 A crystal structure of ALDH2*2. The structure shows a large disordered region located at the dimer interface that includes much of the coenzyme binding cleft and a loop of residues that form the base of the active site. As a consequence of these structural changes, the variant enzyme exhibits rigid body rotations of its catalytic and coenzyme-binding domains relative to the oligomerization domain. These structural perturbations are the direct result of the inability of lysine 487 to form important stabilizing hydrogen bonds with arginines 264 and 475. Thus, the elevated Km for coenzyme exhibited by this variant probably reflects the energetic penalty for reestablishing this site for productive coenzyme binding, whereas the structural alterations near the active site are consistent with the lowered Vmax.
 
  Selected figure(s)  
 
Figure 1.
FIG. 1. The ALDH2^*2 homotetramer. Blue and violet subunits make one dimer pair (subunits A and B, respectively), and gold and green subunits make the other (subunits C and D, respectively). The remaining two tetramers in the asymmetric unit are composed of subunits E-H and I-L.
Figure 3.
FIG. 3. 2F[O] - F[C] electron density maps contoured at one S.D. of the map. a, for residue Lys487, nearly all atoms are well ordered, with N[ ]and C[ ]being the exceptions in some subunits. b, The 10 strand and G helix. The electron density maps taper at the C-terminal end of the 10 strand. For 11 of the 12 subunits observed, there is no interpretable density for most of the G helix.
 
  The above figures are reprinted from an Open Access publication published by the ASBMB: J Biol Chem (2005, 280, 30550-30556) copyright 2005.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20558439 C.H.Chen, L.Sun, and D.Mochly-Rosen (2010).
Mitochondrial aldehyde dehydrogenase and cardiac diseases.
  Cardiovasc Res, 88, 51-57.  
19922789 K.H.Moon, Y.M.Lee, and B.J.Song (2010).
Inhibition of hepatic mitochondrial aldehyde dehydrogenase by carbon tetrachloride through JNK-mediated phosphorylation.
  Free Radic Biol Med, 48, 391-398.  
19906643 M.Beretta, A.C.Gorren, M.V.Wenzl, R.Weis, M.Russwurm, D.Koesling, K.Schmidt, and B.Mayer (2010).
Characterization of the East Asian variant of aldehyde dehydrogenase-2: bioactivation of nitroglycerin and effects of Alda-1.
  J Biol Chem, 285, 943-952.  
20062057 S.Perez-Miller, H.Younus, R.Vanam, C.H.Chen, D.Mochly-Rosen, and T.D.Hurley (2010).
Alda-1 is an agonist and chemical chaperone for the common human aldehyde dehydrogenase 2 variant.
  Nat Struct Mol Biol, 17, 159-164.
PDB codes: 3inj 3inl
19456322 H.Li, S.Borinskaya, K.Yoshimura, N.Kal'ina, A.Marusin, V.A.Stepanov, Z.Qin, S.Khaliq, M.Y.Lee, Y.Yang, A.Mohyuddin, D.Gurwitz, S.Q.Mehdi, E.Rogaev, L.Jin, N.K.Yankovsky, J.R.Kidd, and K.K.Kidd (2009).
Refined geographic distribution of the oriental ALDH2*504Lys (nee 487Lys) variant.
  Ann Hum Genet, 73, 335-345.  
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
18787169 C.H.Chen, G.R.Budas, E.N.Churchill, M.H.Disatnik, T.D.Hurley, and D.Mochly-Rosen (2008).
Activation of aldehyde dehydrogenase-2 reduces ischemic damage to the heart.
  Science, 321, 1493-1495.  
17885622 G.S.Peng, Y.C.Chen, T.P.Tsao, M.F.Wang, and S.J.Yin (2007).
Pharmacokinetic and pharmacodynamic basis for partial protection against alcoholism in Asians, heterozygous for the variant ALDH2*2 gene allele.
  Pharmacogenet Genomics, 17, 845-855.  
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
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.  
15858425 J.X.Xia, X.W.Chen, S.Y.Cheng, and Z.A.Hu (2005).
Mechanisms of orexin A-evoked changes of intracellular calcium in primary cultured cortical neurons.
  Neuroreport, 16, 783-786.  
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 codes are shown on the right.