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Kynureninase - Wikipedia

From Wikipedia, the free encyclopedia

kynureninase

Crystal structure of Homo sapiens kynureninase.^[1]

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Databases

PDB structures

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NCBI	proteins

KYNU

Available structures

PDB

Ortholog search: PDBe RCSB

List of PDB id codes
2HZP, 3E9K

Identifiers

Aliases

KYNU, KYNUU, kynureninase, VCRL2

External IDs

OMIM: 605197; MGI: 1918039; HomoloGene: 2925; GeneCards: KYNU; OMA:KYNU - orthologs

Gene location (Human)

Chr.	Chromosome 2 (human)^[2]

Band	2q22.2	Start	142,877,657 bp^[2]
Band	2q22.2	End	143,055,833 bp^[2]

Gene location (Mouse)

Chr.	Chromosome 2 (mouse)^[3]

Band	2\|2 B	Start	43,445,341 bp^[3]
Band	2\|2 B	End	43,572,727 bp^[3]

RNA expression pattern

Bgee

Human

Mouse (ortholog)

Top expressed in

palpebral conjunctiva

sperm

epithelium of nasopharynx

monocyte

liver

nasal epithelium

right lobe of liver

kidney tubule

mucosa of urinary bladder

granulocyte

Top expressed in

left lobe of liver

yolk sac

embryo

epithelium of lens

spleen

embryo

zygote

right kidney

blood

mesenteric lymph nodes

More reference expression data

BioGPS

n/a

Gene ontology
Molecular function	protein homodimerization activity kynureninase activity catalytic activity pyridoxal phosphate binding hydrolase activity 3-hydroxykynureninase activity
Cellular component	cytosol mitochondrion cytoplasm nucleoplasm
Biological process	pyridine nucleotide biosynthetic process response to vitamin B6 response to interferon-gamma tryptophan catabolic process to acetyl-CoA L-kynurenine catabolic process tryptophan catabolic process tryptophan catabolic process to kynurenine quinolinate biosynthetic process anthranilate metabolic process NAD biosynthetic process 'de novo' NAD biosynthetic process from tryptophan ageing
Sources:Amigo / QuickGO

Orthologs

Species

Human

Mouse

Entrez


8942


70789

Ensembl


ENSG00000115919


ENSMUSG00000026866

UniProt


Q16719


Q9CXF0

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]

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 C_β-C_γ 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 (C_γ) of the tautomerized 3hKyn-PLP Schiff base. This is followed by C_β-C_γ 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**.
  KYNU

  PLP

  substrate names

  inorganic molecules

  3hAn's moiety

  Ala's moiety

References

^ ^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.
^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000115919 – Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000026866 – Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ 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.
^ 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.
^ 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.

External links

PDBe-KB provides an overview of all the structure information available in the PDB for Human Kynureninase

v t e PDB gallery
3e9k: Crystal structure of Homo sapiens kynureninase-3-hydroxyhippuric acid inhibitor complex 2hzp: Crystal Structure of Homo Sapiens Kynureninase

Mitochondrial proteins

Outer membrane

fatty acid degradation	Carnitine palmitoyltransferase I Long-chain-fatty-acid—CoA ligase
tryptophan metabolism	Kynureninase
monoamine neurotransmitter metabolism	Monoamine oxidase

Intermembrane space

Inner membrane

oxidative phosphorylation	Coenzyme Q – cytochrome c reductase Cytochrome c NADH dehydrogenase Succinate dehydrogenase
pyrimidine metabolism	Dihydroorotate dehydrogenase
mitochondrial shuttle	Malate-aspartate shuttle Glycerol phosphate shuttle
steroidogenesis	Cholesterol side-chain cleavage enzyme Steroid 11-beta-hydroxylase Aldosterone synthase
other	Glutamate aspartate transporter Glycerol-3-phosphate dehydrogenase ATP synthase Carnitine palmitoyltransferase II Uncoupling protein

Matrix

citric acid cycle	Citrate synthase Aconitase Isocitrate dehydrogenase Oxoglutarate dehydrogenase complex Succinyl coenzyme A synthetase Fumarase Malate dehydrogenase
anaplerotic reactions	Aspartate transaminase Glutamate dehydrogenase Pyruvate dehydrogenase complex
urea cycle	Carbamoyl phosphate synthetase I Ornithine transcarbamylase N-Acetylglutamate synthase
alcohol metabolism	ALDH2
PMPCB

Other/to be sorted

Mitochondrial DNA

Complex I	MT-ND1 MT-ND2 MT-ND3 MT-ND4 MT-ND4L MT-ND5 MT-ND6
Complex III	MT-CYB
Complex IV	MT-CO1 MT-CO2 MT-CO3
ATP synthase	MT-ATP6 MT-ATP8
tRNA	MT-TA MT-TC MT-TD MT-TE MT-TF MT-TG MT-TH MT-TI MT-TK MT-TL1 MT-TL2 MT-TM MT-TN MT-TP MT-TQ MT-TR MT-TS1 MT-TS2 MT-TT MT-TV MT-TW MT-TY

see also mitochondrial diseases

Metabolism: Protein metabolism, synthesis and catabolism enzymes

Essential amino acids are in Capitals

K→acetyl-CoA

LYSINE→	Saccharopine dehydrogenase Glutaryl-CoA dehydrogenase
LEUCINE→	3-Hydroxybutyryl-CoA dehydrogenase Branched-chain amino acid aminotransferase Branched-chain alpha-keto acid dehydrogenase complex Enoyl-CoA hydratase HMG-CoA lyase HMG-CoA reductase Isovaleryl coenzyme A dehydrogenase α-Ketoisocaproate dioxygenase Leucine 2,3-aminomutase Methylcrotonyl-CoA carboxylase Methylglutaconyl-CoA hydratase (See Template:Leucine metabolism in humans – this diagram does not include the pathway for β-leucine synthesis via leucine 2,3-aminomutase)
TRYPTOPHAN→	Indoleamine 2,3-dioxygenase/Tryptophan 2,3-dioxygenase Arylformamidase Kynureninase 3-hydroxyanthranilate oxidase Aminocarboxymuconate-semialdehyde decarboxylase Aminomuconate-semialdehyde dehydrogenase
PHENYLALANINE→tyrosine→	(see below)

G→pyruvate
→citrate

glycine→serine→	Serine hydroxymethyltransferase Serine dehydratase glycine→creatine: Guanidinoacetate N-methyltransferase Creatine kinase
alanine→	Alanine transaminase
cysteine→	D-cysteine desulfhydrase
threonine→	L-threonine dehydrogenase

G→glutamate→
α-ketoglutarate

HISTIDINE→	Histidine ammonia-lyase Urocanate hydratase Formiminotransferase cyclodeaminase
proline→	Proline oxidase Pyrroline-5-carboxylate reductase 1-Pyrroline-5-carboxylate dehydrogenase/ALDH4A1 PYCR1
arginine→	Ornithine aminotransferase Ornithine decarboxylase Agmatinase
→alpha-ketoglutarate→TCA	Glutamate dehydrogenase
Other	cysteine+glutamate→glutathione: Gamma-glutamylcysteine synthetase Glutathione synthetase Gamma-glutamyl transpeptidase glutamate→glutamine: Glutamine synthetase Glutaminase

G→propionyl-CoA→
succinyl-CoA

VALINE→	Branched-chain amino acid aminotransferase Branched-chain alpha-keto acid dehydrogenase complex Enoyl-CoA hydratase 3-hydroxyisobutyryl-CoA hydrolase 3-hydroxyisobutyrate dehydrogenase Methylmalonate semialdehyde dehydrogenase
ISOLEUCINE→	Branched-chain amino acid aminotransferase Branched-chain alpha-keto acid dehydrogenase complex 3-hydroxy-2-methylbutyryl-CoA dehydrogenase
METHIONINE→	generation of homocysteine: Methionine adenosyltransferase Adenosylhomocysteinase regeneration of methionine: Methionine synthase/Homocysteine methyltransferase Betaine-homocysteine methyltransferase conversion to cysteine: Cystathionine beta synthase Cystathionine gamma-lyase
THREONINE→	Threonine aldolase
→succinyl-CoA→TCA	Propionyl-CoA carboxylase Methylmalonyl CoA epimerase Methylmalonyl-CoA mutase

G→fumarate

PHENYLALANINE→tyrosine→	Phenylalanine hydroxylase Tyrosine aminotransferase 4-Hydroxyphenylpyruvate dioxygenase Homogentisate 1,2-dioxygenase Fumarylacetoacetate hydrolase tyrosine→melanin: Tyrosinase

G→oxaloacetate

asparagine→aspartate→	Asparaginase/Asparagine synthetase Aspartate transaminase

v t e Enzymes
Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Diffusion-limited enzyme Cofactor Enzyme catalysis
Regulation	Allosteric regulation Cooperativity Enzyme inhibitor Enzyme activator
Classification	EC number Enzyme superfamily Enzyme family List of enzymes
Kinetics	Enzyme kinetics Eadie–Hofstee diagram Hanes–Woolf plot Lineweaver–Burk plot Michaelis–Menten kinetics
Types	EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list) EC7 Translocases (list)

Categories:

Structure

Function

References

Further reading

External links