 |
PDBsum entry 1a4z
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Oxidoreductase
|
PDB id
|
|
|
|
1a4z
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
* Residue conservation analysis
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Structure of mitochondrial aldehyde dehydrogenase: the genetic component of ethanol aversion.
|
|
|
Authors
|
|
C.G.Steinmetz,
P.Xie,
H.Weiner,
T.D.Hurley.
|
|
|
Ref.
|
|
Structure, 1997,
5,
701-711.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
BACKGROUND: The single genetic factor most strongly correlated with reduced
alcohol consumption and incidence of alcoholism is a naturally occurring variant
of mitochondrial aldehyde dehydrogenase (ALDH2). This variant contains a
glutamate to lysine substitution at position 487 (E487K). The E487K variant of
ALDH2 is found in approximately 50% of the Asian population, and is associated
with a phenotypic loss of ALDH2 activity in both heterozygotes and homozygotes.
ALDH2-deficient individuals exhibit an averse response to ethanol consumption,
which is probably caused by elevated levels of blood acetaldehyde. The structure
of ALDH2 is important for the elucidation of its catalytic mechanism, to gain a
clear understanding of the contribution of ALDH2 to the genetic component of
alcoholism and for the development of specific ALDH2 inhibitors as potential
drugs for use in the treatment of alcoholism. RESULTS: The X-ray structure of
bovine ALDH2 has been solved to 2.65 A in its free form and to 2.75 A in a
complex with NAD+. The enzyme structure contains three domains; two
dinucleotide-binding domains and a small three-stranded beta-sheet domain, which
is involved in subunit interactions in this tetrameric enzyme. The E487K
mutation occurs in this small oligomerization domain and is located at a key
interface between subunits immediately below the active site of another monomer.
The active site of ALDH2 is divided into two halves by the nicotinamide ring of
NAD+. Adjacent to the A-side (Pro-R) of the nicotinamide ring is a cluster of
three cysteines (Cys301, Cys302 and Cys303) and adjacent to the B-side (Pro-S)
are Thr244, Glu268, Glu476 and an ordered water molecule bound to Thr244 and
Glu476. CONCLUSIONS: Although there is a recognizable Rossmann-type fold, the
coenzyme-binding region of ALDH2 binds NAD+ in a manner not seen in other
NAD+-binding enzymes. The positions of the residues near the nicotinamide ring
of NAD+ suggest a chemical mechanism whereby Glu268 functions as a general base
through a bound water molecule. The sidechain amide nitrogen of Asn169 and the
peptide nitrogen of Cys302 are in position to stabilize the oxyanion present in
the tetrahedral transition state prior to hydride transfer. The functional
importance of residue Glu487 now appears to be due to indirect interactions of
this residue with the substrate-binding site via Arg264 and Arg475.
|
|
|
|
|
|
Figure 5.
Figure 5. Interactions between the enzyme and the bound
cofactor from a single subunit in ALDH2. The bound NAD^+
molecule is shown using a ball-and-stick representation and
colored according to atom type. Dashed lines indicate potential
hydrogen-bonding interactions <3.3 Å, except for the interaction
between the peptide nitrogen of Trp168 and the nicotinamide
phosphate which is 3.6 Å (see text). (Figure was produced using
the program MOLSCRIPT [52].)
|
|
|
|
|
|
The above figure is
reprinted
by permission from Cell Press:
Structure
(1997,
5,
701-711)
copyright 1997.
|
|
|
|
|
|
|
