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Catalytic Site Atlas

CSA LITERATURE entry for 1qz9

E.C. namekynureninase
SpeciesPseudomonas fluorescens (Bacteria)
E.C. Number (IntEnz) 3.7.1.3
CSA Homologues of 1qz9There are 161 Homologs
CSA Entries With UniProtID P83788
CSA Entries With EC Number 3.7.1.3
PDBe Entry 1qz9
PDBSum Entry 1qz9
MACiE Entry 1qz9

Literature Report

IntroductionKynureninase is a pyridoxal-5'-phosphate (PLP)-dependent enzyme sourced from Pseudomonas fluorescens that catalyses the hydrolytic cleavage of L-kynurenine to anthranilic acid and L-alanine. This reaction is a key step in the catabolism of L-tryptophan. In fungi and vertebrates, kynurenine is first hydroxylated to 3-hydroxykynurenine - the preferred substrate of kynureninase in those organisms, resulting in 3-hydroxyanthranilate and L-alanine. Kynureninase also plays a role in the biosynthesis of NAD-(P)+. The product of kynureninase is subsequently converted by 3-hydroxyanthranilate-3,4-dioxygenase to quinolinic acid - a precursor of NAD-(P)+. Quinolinic acid is a neurotoxin due to it's agonist effects on N-methyl-D-aspartate receptor. Excessive levels of quinolinic acid have been implicated in a wide range of neurological disorders such as epilepsy, stroke and AIDS related dementia. Therefore, inhibitors of kynureninase are of interest as potential drugs for the treatment of these CNS disorders.
Mechansim1. Lys 227 binds PLP to Kynureninase. Electrophilicity of PLP is enhanced through close contact with Asp 201 which aids protonation of the pyridine ring. Phe 129 is Pi-stacked on top of the pyridine ring of PLP, stabilising the cofactor. 2. L-kynurenine displaces the Lys 227, binding to PLP, forming kynurenine external aldimine. 3. Lys 227 deprotonates the alpha-carbon of the kynurenine external aldimine. 4. Lys 227 protonates the C-4' of the quinonoid intermediate. 5. Lys 227 deprotonates a water molecule, which performs nucleophilic attack upon the gamma-carbonyl of the ketimine intermediate. This forms the gem-diolate intermediate. 6. The gem-diolate intermediate collapses, cleaving bond between the beta-carbon and gamma-carbon. 7. Lys 227 protonates the beta-carbon of the enamine intermediate. 8. Lys 227 deprotonates C-4' of the pyruvate ketimine intermediate. 9. Lys 227 protonates the alanine quinonoid intermediate, giving alanine external aldimine. 10. Lys 227 displaces L-alanine, releasing it.
Reaction

Catalytic Sites for 1qz9

Annotated By Reference To The Literature - Site 3 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
AspA201201macie:sideChainAsp 201 aids protonation of the pyridine ring, enhancing the electrophilicity of PLP.
PheA129129macie:sideChainPhe 129 is Pi-stacked on top of the pyridine ring of PLP, stabilising the cofactor.
LysA227227macie:sideChain1. Lys 227 binds PLP to Kynureninase. 2. Lys 227 deprotonates the alpha-carbon of the kynurenine external aldimine. 3. Lys 227 protonates the C-4' of the quinonoid intermediate. 4. Lys 227 deprotonates a water molecule, which performs nucleophilic attack upon the gamma-carbonyl of the ketimine intermediate. 5. Lys 227 protonates the beta-carbon of the enamine intermediate. 6. Lys 227 deprotonates C-4' of the pyruvate ketimine intermediate. 7. Lys 227 protonates the alanine quinonoid intermediate, giving alanine external aldimine. 8. Lys 227 displaces L-alanine, releasing it.

Literature References

Notes:
Momany C
Three-dimensional structure of kynureninase from Pseudomonas fluorescens.
Biochemistry 2004 43 1193-1203
PubMed: 14756555
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