Kynureninase

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kynureninase
Kynureninase2HZP.jpg
Crystal structure of Homo sapiens kynureninase.[1]
Identifiers
EC number 3.7.1.3
CAS number 9024-78-6
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO
Kynureninase
PDB 3e9k EBI.png
PDB rendering based on 3e9k.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbol KYNU
External IDs OMIM605197 MGI1918039 HomoloGene2925 ChEMBL: 5100 GeneCards: KYNU Gene
EC number 3.7.1.3
Orthologs
Species Human Mouse
Entrez 8942 70789
Ensembl ENSG00000115919 ENSMUSG00000026866
UniProt Q16719 Q9CXF0
RefSeq (mRNA) NM_001032998 NM_027552
RefSeq (protein) NP_001028170 NP_081828
Location (UCSC) Chr 2:
143.64 – 143.8 Mb
Chr 2:
43.56 – 43.68 Mb
PubMed search [1] [2]

Kynureninase or L-Kynurenine hydrolase (KYNU) (EC 3.7.1.3) is a PLP dependent enzyme that catalyses the cleavage of kynurenine (Kyn) into anthranilic acid (Ant). It can also act on 3hKyn (to produce 3hAnt) and some other (3-arylcarbonyl)-alanines. Humans express one kynureninase enzyme that is encoded by the KYNU gene located on chromosome 2.[2][3]

KYNU is part of the pathway for the catabolism of Trp and the biosynthesis of NAD cofactors from tryptophan (Trp).

Kynureninase catalyzes the following reaction:

Structure[edit]

Kynureninase belongs to the class V group of aspartate aminotransferase superfamily of structurally homologous pyridoxal 5'-phosphate (PLP) dependent enzymes. To date, two structures of human kynureninase have determined by X-ray diffraction with resolutions of 2.0 and 1.7 Å.[1][4] Forty percent of the amino acids are arranged in an alpha helical and twelve percent are arranged in beta sheets. Docking of the kynurenine substrate into the active site suggests that Asn-333 and His-102 are involved in substrate binding.[1]

Function[edit]

In KYNU reaction, PLP facilitates Cβ-Cγ bond cleavage. The reaction follows the same steps as the transamination reaction but does not hydrolyze the tautomerized Schiff base. The proposed reaction mechanism involves an attack of an enzyme nucleophile on the carbonyl carbon (Cγ) of the tautomerized 3hKyn-PLP Schiff base. This is followed by Cβ-Cγ bond cleavage to generate an acyl-enzyme intermediate together with a tautomerized Ala-PLP adduct. Hydrolysis of the acyl-enzyme then yields 3hAnt.

The KYNU's reaction mechanism.
The color scheme is as follows: KYNU, PLP, substrate names, inorganic molecules, 3hAn's moiety, Ala's moiety

References[edit]

  1. ^ a b c PDB 2HZP; Lima S, Khristoforov R, Momany C, Phillips RS (March 2007). "Crystal structure of Homo sapiens kynureninase". Biochemistry 46 (10): 2735–44. doi:10.1021/bi0616697. PMC 2531291. PMID 17300176. 
  2. ^ Alberati-Giani D, Buchli R, Malherbe P, Broger C, Lang G, Köhler C, Lahm HW, Cesura AM (July 1996). "Isolation and expression of a cDNA clone encoding human kynureninase". Eur. J. Biochem. 239 (2): 460–8. doi:10.1111/j.1432-1033.1996.0460u.x. PMID 8706755. 
  3. ^ Toma S, Nakamura M, Toné S, Okuno E, Kido R, Breton J, Avanzi N, Cozzi L, Speciale C, Mostardini M, Gatti S, Benatti L (May 1997). "Cloning and recombinant expression of rat and human kynureninase". FEBS Lett. 408 (1): 5–10. doi:10.1016/S0014-5793(97)00374-8. PMID 9180257. 
  4. ^ PDB 3E9K; Lima S, Kumar S, Gawandi V, Momany C, Phillips RS (January 2009). "Crystal structure of the Homo sapiens kynureninase-3-hydroxyhippuric acid inhibitor complex: insights into the molecular basis of kynureninase substrate specificity". J. Med. Chem. 52 (2): 389–96. doi:10.1021/jm8010806. PMID 19143568. 


Further reading[edit]