Ornithine aminotransferase

 

Ornithine aminotransferase catalyses the conversion of L-ornithine and a 2-oxo acid to L-glutamate 5-semialdehyde and an L-amino acid. This enzyme is found in low-GC bacteria, where it is responsible for the fourth step in arginine biosynthesis, and in the mitochondrial matrix of eukaryotes, where it controls L-ornithine levels in tissues. In human hereditary ornithine aminotransferase deficiency, the elevated levels of intraocular concentrations of ornithine are responsible for gyrate atrophy, which affects the CNS and peripheral nervous system [PMID:12221166].

 

Reference Protein and Structure

Sequence
P04181 UniProt (2.6.1.13) IPR034758 (Sequence Homologues) (PDB Homologues)
Biological species
Homo sapiens (Human) Uniprot
PDB
2oat - ORNITHINE AMINOTRANSFERASE COMPLEXED WITH 5-FLUOROMETHYLORNITHINE (1.95 Å) PDBe PDBsum 2oat
Catalytic CATH Domains
3.40.640.10 CATHdb (see all for 2oat)
Cofactors
Pyridoxal 5'-phosphate(2-) (1)
Click To Show Structure

Enzyme Reaction (EC:2.6.1.13)

2-oxo monocarboxylic acid anion
CHEBI:35179ChEBI
+
L-ornithinium(1+)
CHEBI:46911ChEBI
→
L-glutamic 5-semialdehyde zwitterion
CHEBI:58066ChEBI
+
L-alpha-amino acid zwitterion
CHEBI:59869ChEBI
Alternative enzyme names: L-ornithine 5-aminotransferase, L-ornithine aminotransferase, L-ornithine:alpha-ketoglutarate delta-aminotransferase, OAT, Ornithine 5-aminotransferase, Ornithine delta-transaminase, Ornithine transaminase, Ornithine:alpha-oxoglutarate transaminase, Ornithine--2-oxoacid aminotransferase, Ornithine--alpha-ketoglutarate aminotransferase, Ornithine--keto acid aminotransferase, Ornithine--keto acid transaminase, Ornithine--ketoglutarate aminotransferase, Ornithine--oxo acid aminotransferase, Ornithine--oxo-acid transaminase, Ornithine ketoacid aminotransferase, GabT,

Enzyme Mechanism

Introduction

This PLP-dependent reaction proceeds via a ping-pong mechanism that requires two half-reactions to complete one cycle of transamination. In the first half-reaction the catalytic lysine is displaced from the PLP-cofactor by the ornithine substrate. This substrate is then deamminated to form the L-glutamate-gamma-semialdehyde. In the second half-reaction, the 2-oxoglutarate enters the active site and attacks the amminated PLP cofactor. The final glutamate product is then displaced from PLP to re-form the active site.

Catalytic Residues Roles

UniProt PDB* (2oat)
Asp263 Asp263A This residue helps stabilise the nitrogen atom of the PLP ring during catalysis, enabling the cofactor to act as an electron sink during the course of the reaction. electrostatic stabiliser
Phe177 Phe177A This residue is important for maintaining the correct orientation of the cofactor in the active site when it is no longer attached to the protein. steric role
Lys292 Lys292A This is the primary catalytic residue. It starts the reaction covalently attached to the PLP cofactor. It then acts as a general acid/base. In the final steps of the reaction it re-attaches to the PLP cofactor to regenerate the active site. covalent catalysis, 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. Storici P et al. (1999), J Mol Biol, 285, 297-309. Crystal structure of human ornithine aminotransferase complexed with the highly specific and potent inhibitor 5-fluoromethylornithine1. DOI:10.1006/jmbi.1998.2289. PMID:9878407.
  2. Lee H et al. (2015), Med Res Rev, 35, 286-305. Ornithine aminotransferase versus GABA aminotransferase: implications for the design of new anticancer drugs. DOI:10.1002/med.21328. PMID:25145640.
  3. Markova M et al. (2005), J Biol Chem, 280, 36409-36416. Determinants of substrate specificity in omega-aminotransferases. DOI:10.1074/jbc.M506977200. PMID:16096275.
  4. Peltola KE et al. (2002), Neurology, 59, 735-740. Peripheral nervous system in gyrate atrophy of the choroid and retina with hyperornithinemia. PMID:12221166.
  5. Shen BW et al. (1998), J Mol Biol, 277, 81-102. Crystal structure of human recombinant ornithine aminotransferase. DOI:10.1006/jmbi.1997.1583. PMID:9514741.
  6. Shah SA et al. (1997), Structure, 5, 1067-1075. Human ornithine aminotransferase complexed with L-canaline and gabaculine: structural basis for substrate recognition. PMID:9309222.

Step 1.

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Catalytic Residues Roles

Residue Roles
Asp263A electrostatic stabiliser
Phe177A steric role
Lys292A proton shuttle (general acid/base), covalent catalysis

Chemical Components

Step 1.

Contributors

Craig Porter, Gemma L. Holliday