Kynureninase

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

RefSeq (protein)


NP_001028170.1 NP_001186170.1 NP_003928.1


NP_001276522.1 NP_001276523.1 NP_081828.1

Location (UCSC)

Chr 2: 142.88 – 143.06 Mb

Chr 2: 43.56 – 43.68 Mb

PubMed search

^[2]

^[3]

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 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.^[4]^[5]

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]^[6] 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.

References

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.
↑ "Human PubMed Reference:".
↑ "Mouse PubMed Reference:".
↑ 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.
↑ 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.

Lima S, Khristoforov R, Momany C, Phillips RS (2007). "Crystal structure of Homo sapiens kynureninase". Biochemistry. 46: 2735–2744. doi:10.1021/bi0616697. PMC 2531291. PMID 17300176. |access-date= requires |url= (help)
Heyes MP, Chen CY, Major EO, Saito K (1997). "Different kynurenine pathway enzymes limit quinolinic acid formation by various human cell types.". Biochem. J. 326 (2): 351–6. PMC 1218677. PMID 9291104.
Rose JE, Behm FM, Drgon T, et al. "Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.". Mol. Med. 16 (7-8): 247–53. doi:10.2119/molmed.2009.00159. PMC 2896464. PMID 20379614.
Zhang Y, Zhang KX, He X, et al. (2005). "[A polymorphism of kynureninase gene in a hypertensive candidate chromosomal region is associated with essential hypertension]". Zhonghua Xin Xue Guan Bing Za Zhi. 33 (7): 588–91. PMID 16080802.
Inada J, Okuno E, Kimura M, Kido R (1984). "Intracellular localization and characterization of 3-hydroxykynureninase in human liver.". Int. J. Biochem. 16 (6): 623–8. doi:10.1016/0020-711x(84)90031-4. PMID 6468727.
Ubbink JB, Vermaak WJ, Bissbort SH (1991). "High-performance liquid chromatographic assay of human lymphocyte kynureninase activity levels.". J. Chromatogr. 566 (2): 369–75. doi:10.1016/0378-4347(91)80253-9. PMID 1939450.
Maruyama K, Sugano S (1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides.". Gene. 138 (1-2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
Magni G, Amici A, Emanuelli M, et al. (2004). "Enzymology of NAD+ homeostasis in man.". Cell. Mol. Life Sci. 61 (1): 19–34. doi:10.1007/s00018-003-3161-1. PMID 14704851.
Strausberg RL, Feingold EA, Grouse LH, et al. (2002). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
Christensen M, Duno M, Lund AM, et al. (2007). "Xanthurenic aciduria due to a mutation in KYNU encoding kynureninase.". J. Inherit. Metab. Dis. 30 (2): 248–55. doi:10.1007/s10545-007-0396-2. PMID 17334708.
Walsh HA, Botting NP (2002). "Purification and biochemical characterization of some of the properties of recombinant human kynureninase.". Eur. J. Biochem. 269 (8): 2069–74. doi:10.1046/j.1432-1033.2002.02854.x. PMID 11985583.
Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, et al. (1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library.". Gene. 200 (1-2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.

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

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

steroidogenesis	Cholesterol side-chain cleavage enzyme Steroid 11-beta-hydroxylase Aldosterone synthase Frataxin

Mitochondrial membrane transport protein Mitochondrial permeability transition pore Mitochondrial carrier

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→	Branched chain aminotransferase Branched-chain alpha-keto acid dehydrogenase complex Isovaleryl coenzyme A dehydrogenase Methylcrotonyl-CoA carboxylase Methylglutaconyl-CoA hydratase 3-hydroxy-3-methylglutaryl-CoA lyase

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 aminotransferase Branched-chain alpha-keto acid dehydrogenase complex Enoyl-CoA hydratase 3-hydroxyisobutyryl-CoA hydrolase 3-hydroxyisobutyrate dehydrogenase Methylmalonate semialdehyde dehydrogenase

ISOLEUCINE→	Branched chain 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

Hydrolases: carbon-carbon (EC 3.7)

3.7.1	Fumarylacetoacetate hydrolase Kynureninase

Enzymes

Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Catalytically perfect enzyme Coenzyme Cofactor Enzyme catalysis Enzyme kinetics Lineweaver–Burk plot Michaelis–Menten kinetics

Regulation	Allosteric regulation Cooperativity Enzyme inhibitor

Classification	EC number Enzyme superfamily Enzyme family List of enzymes

Types	EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list)

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Kynureninase

Structure

Function

References

Further reading