Alcohol dehydrogenase (class II)

 

This entry represents the rodent class-II subfamily of the zinc-containing alcohol dehydrogenase family (ADH2). Most of the proteins in this subfamily are from mammals. They are involved in the reduction of benzoquinones [PMID:10514444].

Rodent ADH2s are inefficient in alcohol oxidation with roughly three orders of magnitude lower activity than the "classical" ADHs. They show a preference for aromatic alcohols (such as benzyl alcohols).

 

Reference Protein and Structure

Sequence
Q9QYY9 UniProt (1.1.1.105) IPR028632 (Sequence Homologues) (PDB Homologues)
Biological species
Mus musculus (house mouse) Uniprot
PDB
1e3i - Mouse class II alcohol dehydrogenase complex with NADH and inhibitor (2.08 Å) PDBe PDBsum 1e3i
Catalytic CATH Domains
3.90.180.10 CATHdb (see all for 1e3i)
Cofactors
Zinc(2+) (2)
Click To Show Structure

Enzyme Reaction (EC:1.1.1.1)

primary alcohol
CHEBI:15734ChEBI
+
NAD(1-)
CHEBI:57540ChEBI
→
hydron
CHEBI:15378ChEBI
+
aldehyde
CHEBI:17478ChEBI
+
NADH(2-)
CHEBI:57945ChEBI
Alternative enzyme names: ADH, NAD-dependent alcohol dehydrogenase, NAD-specific aromatic alcohol dehydrogenase, NADH-alcohol dehydrogenase, NADH-aldehyde dehydrogenase, Alcohol dehydrogenase (NAD), Aldehyde reductase, Aliphatic alcohol dehydrogenase, Ethanol dehydrogenase, Primary alcohol dehydrogenase, Yeast alcohol dehydrogenase,

Enzyme Mechanism

Introduction

Mouse ADH2 follows an ordered bi-bi mechanism, and hydride transfer is rate-limiting for oxidation of benzyl alcohols. The general mechanism is thought to proceed in the same manner as for other zinc-dependent ADHs: the substrate binds to a zinc ion at the active site, which allows deprotonation of the OH group by Thr48 or Ser182 and probably active site water in a proton relay system, because the zinc ion stabilises the oxyanion thus reducing the pKa of the OH to around 8.4. This allows hydride transfer from C2 to the NAD+ with the oxygen lone pair overlapping with the sigma* orbital of C2 to create the double bond that characterises the product.

Catalytic Residues Roles

UniProt PDB* (1e3i)
Thr49 Thr48A Exact role unclear, thought to act as a general acid/base. proton shuttle (general acid/base)
Pro48 Pro47A Causes a strained binding of the coenzyme, which prevents a sufficiently close approach of the coenzyme to the substrate for efficient hydrogen transfer. steric role
Ser183 Ser182A Thought to acts as a general acid/base. proton shuttle (general acid/base)
Cys47, His68, Cys179 Cys46A, His67A, Cys178A Forms part of the zinc binding site. metal ligand
*PDB label guide - RESx(y)B(C) - RES: Residue Name; x: Residue ID in PDB file; y: Residue ID in PDB sequence if different from PDB file; B: PDB Chain; C: Biological Assembly Chain if different from PDB. If label is "Not Found" it means this residue is not found in the reference PDB.

Chemical Components

References

  1. Strömberg P et al. (2004), Biochemistry, 43, 1323-1328. Enzymatic Mechanism of Low-Activity Mouse Alcohol Dehydrogenase 2†. DOI:10.1021/bi0354482. PMID:14756569.
  2. Svensson S et al. (2000), J Mol Biol, 302, 441-453. Crystal structures of mouse class II alcohol dehydrogenase reveal determinants of substrate specificity and catalytic efficiency. DOI:10.1006/jmbi.2000.4039. PMID:10970744.
  3. Svensson S et al. (1999), J Biol Chem, 274, 29712-29719. A novel subtype of class II alcohol dehydrogenase in rodents. Unique Pro(47) and Ser(182) modulates hydride transfer in the mouse enzyme. PMID:10514444.

Step 1.

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Catalytic Residues Roles

Residue Roles
Cys46A metal ligand
His67A metal ligand
Cys178A metal ligand
Pro47A steric role
Thr48A proton shuttle (general acid/base)
Ser182A proton shuttle (general acid/base)

Chemical Components

Step 1.

Contributors

Gemma L. Holliday