Kynureninase

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kynureninase
Kynureninase2HZP.jpg
Crystal structure of Homo sapiens kynureninase. [1]
Identifiers
EC no. 3.7.1.3
CAS no. 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 / QuickGO
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PMC articles
PubMed articles
NCBI proteins
KYNU
PDB 3e9k EBI.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases KYNU , KYNUU, kynureninase, VCRL2
External IDs OMIM: 605197 MGI: 1918039 HomoloGene: 2925 GeneCards: KYNU
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001032998
NM_001199241
NM_003937

NM_027552
NM_001289593
NM_001289594
NM_001398676

RefSeq (protein)

NP_001028170
NP_001186170
NP_003928

NP_001276522
NP_001276523
NP_081828
NP_001385605

Location (UCSC) Chr 2: 142.88 – 143.06 Mb Chr 2: 43.45 – 43.57 Mb
PubMed search [4] [5]
Wikidata
View/Edit Human View/Edit Mouse

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 3-hydroxykynurenine (to produce 3-hydroxyanthranilate) and some other (3-arylcarbonyl)-alanines. Humans express one kynureninase enzyme that is encoded by the KYNU gene located on chromosome 2. [6] [7]

Contents

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:

L-kynurenine + H2O ↔ anthranilate + L-alanine

Structure

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] [8] 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

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

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References

  1. 1 2 3 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. 1 2 3 GRCh38: Ensembl release 89: ENSG00000115919 - Ensembl, May 2017
  3. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000026866 - Ensembl, May 2017
  4. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  6. 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.
  7. 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. S2CID   36265922.
  8. 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