Homoserine dehydrogenase

 

Homoserine dehydrogenase belongs to the oxioreductase class of enzymes, although the residues implicated in catalysis are quite different from other enzymes within the class. It is involved in the NAD(P)H dependent reduction of L-aspartate semi-aldehyde to L homoserine, a pathway not found within the animal kingdom. The enzyme has therefore been targeted for the development of antimycotic drugs.

 

Reference Protein and Structure

Sequence
P31116 UniProt (1.1.1.3) IPR022697 (Sequence Homologues) (PDB Homologues)
Biological species
Saccharomyces cerevisiae S288c (Baker's yeast) Uniprot
PDB
1ebf - HOMOSERINE DEHYDROGENASE FROM S. CEREVISIAE COMPLEX WITH NAD+ (2.3 Å) PDBe PDBsum 1ebf
Catalytic CATH Domains
3.30.360.10 CATHdb (see all for 1ebf)
Cofactors
Nadph(4-) (1)
Click To Show Structure

Enzyme Reaction (EC:1.1.1.3)

L-homoserine zwitterion
CHEBI:57476ChEBI
+
NAD(1-)
CHEBI:57540ChEBI
→
L-aspartic acid 4-semialdehyde betaine
CHEBI:537519ChEBI
+
hydron
CHEBI:15378ChEBI
+
NADH(2-)
CHEBI:57945ChEBI
Alternative enzyme names: HSD, HSDH,

Enzyme Mechanism

Introduction

The NAD(P)H dependent reduction of L aspartate semi-aldehyde proceeds via hydride transfer. The hydride donating NAD(P)H cofactor is bound in the Rossmann fold, where enzyme-cofactor hydrogen bond interactions exist between cofactor phosphate moieties and sugar hydroxyl groups and the enzyme amide back bone groups. The amino substrate is thought to bind predominantly in the aldehyde rather than the hydrate form through hydrogen bond interactions with Asp 214, Glu 208, and a water molecule (460). The catalytic Lys 223 donates a proton to the developing alkoxide tetrahedral intermediate during hydride transfer. Asp 219 is key in positioning the catalytic residue, while the N terminal helix alpha J is important in stabilising the developing negative charge on the substrate carbonyl.

Catalytic Residues Roles

UniProt PDB* (1ebf)
Asp219 Asp219(218)A The residue is involved in orientating the catalytic Lys 223 towards the substrate by hydrogen bonding. electrostatic stabiliser
Lys223 Lys223(222)A The residue acts as the proton donor towards the developing anion on the substrate during hydride transfer from the NAD(P)H cofactor. Its position within the active site is dictated by hydrogen bonding to Asp 219. proton shuttle (general acid/base)
*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. DeLaBarre B et al. (2000), Nat Struct Biol, 7, 238-244. Crystal structures of homoserine dehydrogenase suggest a novel catalytic mechanism for oxidoreductases. DOI:10.1038/73359. PMID:10700284.
  2. Ejim L et al. (2004), Bioorg Med Chem, 12, 3825-3830. New phenolic inhibitors of yeast homoserine dehydrogenase. DOI:10.1016/j.bmc.2004.05.009. PMID:15210149.
  3. Jacques SL et al. (2003), Chem Biol, 10, 989-995. Enzyme-assisted suicide: molecular basis for the antifungal activity of 5-hydroxy-4-oxonorvaline by potent inhibition of homoserine dehydrogenase. PMID:14583265.
  4. Jacques SL et al. (2001), Biochim Biophys Acta, 1544, 42-54. Homoserine dehydrogenase from Saccharomyces cerevisiae: kinetic mechanism and stereochemistry of hydride transfer. PMID:11341915.

Step 1.

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Catalytic Residues Roles

Residue Roles
Lys223(222)A proton shuttle (general acid/base)
Asp219(218)A electrostatic stabiliser

Chemical Components

Step 1.

Contributors

James W. Murray, Craig Porter, Gemma L. Holliday