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Information on EC 3.7.1.3 - kynureninase and Organism(s) Homo sapiens and UniProt Accession Q16719
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3.7.1.3 kynureninaseIUBMB Comments
A pyridoxal-phosphate protein. Also acts on 3'-hydroxy-L-kynurenine and some other (3-arylcarbonyl)-alanines.
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Word Map
- 3.7.1.3
-
3-hydroxyanthranilic
- medicine
-
quinolinic
- 3-hydroxykynurenine
-
kynurenic
-
anthranilic
- indoleamine
-
3-monooxygenase
- l-tryptophan
-
ido
-
3,4-dioxygenase
-
xanthurenic
- aminocarboxymuconate-semialdehyde
-
3-hydroxylase
-
quin
-
excitotoxins
-
quinonoid
-
pyrrolase
- marginalis
- indoleamine-2,3-dioxygenase
- synthesis
-
b6-deficient
- drug development
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
Synonyms
kynureninase, kynase, pfkynase, l-kynurenine hydrolase, hskynase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
L-kynurenine hydrolase
L-kynurenine hydrolase
-
-
-
-
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
L-kynurenine + H2O = anthranilate + L-alanine
catalytic reaction mechanism via several intermediates, e.g. external aldimine, quinonoid, ketimine, Gem-diolate, and enamine
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
hydrolysis of C-C bond
hydrolysis of C-C bond
-
-
-
-
SYSTEMATIC NAME
IUBMB Comments
L-kynurenine hydrolase
A pyridoxal-phosphate protein. Also acts on 3'-hydroxy-L-kynurenine and some other (3-arylcarbonyl)-alanines.
CAS REGISTRY NUMBER
COMMENTARY
9024-78-6
-
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
3,5-dibromo-L-kynurenine + H2O
3,5-dibromoanthranilate + DL-kynurenine
-
-
-
?
5-bromo-3-chloro-DL-kynurenine + H2O
5-bromo-3-chloroanthranilate + DL-alanine
-
-
-
?
3-hydroxy-L-kynurenine + H2O
3-hydroxyanthranilate + L-alanine
-
-
-
?
3-hydroxy-L-kynurenine + H2O
3-hydroxyanthranilate + L-alanine
preferred substrate
-
-
?
3-hydroxy-L-kynurenine + H2O
3-hydroxyanthranilate + L-alanine
-
-
-
-
?
3-hydroxy-L-kynurenine + H2O
3-hydroxyanthranilate + L-alanine
-
biosynthesis of NAD+
-
-
?
3-hydroxy-L-kynurenine + H2O
3-hydroxyanthranilate + L-alanine
-
L-tryptophan metabolism, biosynthesis of nicotinamide nucleotides
-
-
?
3-hydroxy-L-kynurenine + H2O
3-hydroxyanthranilate + L-alanine
-
the hydroxyl group at the 3-position thus appears to be an important recognition element
-
-
?
additional information
?
-
for the human enzyme, 3- and 5-substituted kynurenines have kcat and kcat/Km values higher than L-kynurenine, but less than that of the physiological substrate, 3-hydroxykynurenine. 3,5-Dibromo- and 5-bromo-3-chlorokynurenine have kcat and kcat/Km values close to that of 3-hydroxykynurenine with human kynureninase. The effects of the 3-halo substituents on the reactivity with human kynureninase may be due to electronic effects and/or halogen bonding. 5-Bromo and 5-chloro-L-kynurenine are good substrates the human enzyme, indicating that the enzyme has space for substituents in the active site near C-5. The increased activity of the 5-halokynurenines may be due to van der Waals contacts or hydrophobic effects. The mammalian kynureninase cleaves 3-hydroxy-L-kynurenine more rapidly than L-kynurenine, substrate synthesis and specificity, overview
-
-
?
additional information
?
-
-
for the human enzyme, 3- and 5-substituted kynurenines have kcat and kcat/Km values higher than L-kynurenine, but less than that of the physiological substrate, 3-hydroxykynurenine. 3,5-Dibromo- and 5-bromo-3-chlorokynurenine have kcat and kcat/Km values close to that of 3-hydroxykynurenine with human kynureninase. The effects of the 3-halo substituents on the reactivity with human kynureninase may be due to electronic effects and/or halogen bonding. 5-Bromo and 5-chloro-L-kynurenine are good substrates the human enzyme, indicating that the enzyme has space for substituents in the active site near C-5. The increased activity of the 5-halokynurenines may be due to van der Waals contacts or hydrophobic effects. The mammalian kynureninase cleaves 3-hydroxy-L-kynurenine more rapidly than L-kynurenine, substrate synthesis and specificity, overview
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
3-hydroxy-L-kynurenine + H2O
3-hydroxyanthranilate + L-alanine
-
-
-
?
3-hydroxy-L-kynurenine + H2O
3-hydroxyanthranilate + L-alanine
-
biosynthesis of NAD+
-
-
?
3-hydroxy-L-kynurenine + H2O
3-hydroxyanthranilate + L-alanine
-
L-tryptophan metabolism, biosynthesis of nicotinamide nucleotides
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
2-amino-4-[3'-hydroxyphenyl]-4-hydroxybutanoic acid
most potent inhibitor
2-amino-(4-oxo-4-naphthyl)-butyric acid
-
competitive inhibition, reversible inhibition by dilution
amino-(1-oxo-1,2,3,4-tetrahydro-2-naphthalenyl)-acetic acid
-
competitive inhibition, reversible inhibition by dilution
amino-(1-oxo-2,3-dihydro-1H-inden-2-yl)-acetic acid
-
competitive inhibition, reversible inhibition by dilution
amino-(4-oxo-3,4-dihydro-2H-chromen-3-yl)-acetic acid
-
competitive inhibition, reversible inhibition by dilution
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0283
3-hydroxy-L-kynurenine
wild type enzyme, in 30 mM potassium phosphate, pH 8.0, and 0.04 mM pyridoxal 5'-phosphate, at 37°C
0.2
3-hydroxy-L-kynurenine
Km above 0.2 mM, mutant enzyme N333T, in 30 mM potassium phosphate, pH 8.0, and 0.04 mM pyridoxal 5'-phosphate, at 37°C
0.51
3-hydroxy-L-kynurenine
Km above 0.51 mM, mutant enzyme S332G/N333T, in 30 mM potassium phosphate, pH 8.0, and 0.04 mM pyridoxal 5'-phosphate, at 37°C
0.327
L-kynurenine
mutant enzyme H102W/N333T, in 30 mM potassium phosphate, pH 8.0, and 0.04 mM pyridoxal 5'-phosphate, at 37°C
0.495
L-kynurenine
wild type enzyme, in 30 mM potassium phosphate, pH 8.0, and 0.04 mM pyridoxal 5'-phosphate, at 37°C
0.499
L-kynurenine
mutant enzyme N333T, in 30 mM potassium phosphate, pH 8.0, and 0.04 mM pyridoxal 5'-phosphate, at 37°C
0.51
L-kynurenine
Km above 0.51 mM, mutant enzyme H102W/S332G/N333T, in 30 mM potassium phosphate, pH 8.0, and 0.04 mM pyridoxal 5'-phosphate, at 37°C
0.54
L-kynurenine
mutant enzyme S332G/N333T, in 30 mM potassium phosphate, pH 8.0, and 0.04 mM pyridoxal 5'-phosphate, at 37°C
additional information
additional information
kinetic analysis of kynurenine analogues, overview
-
additional information
additional information
-
kinetic analysis of kynurenine analogues, overview
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0039
3-hydroxy-L-kynurenine
kcat less than 0.0039 1/s, mutant enzyme N333T, in 30 mM potassium phosphate, pH 8.0, and 0.04 mM pyridoxal 5'-phosphate, at 37°C
0.0109
3-hydroxy-L-kynurenine
kcat less than 0.0109 1/s, mutant enzyme S332G/N333T, in 30 mM potassium phosphate, pH 8.0, and 0.04 mM pyridoxal 5'-phosphate, at 37°C
3.5
3-hydroxy-L-kynurenine
wild type enzyme, in 30 mM potassium phosphate, pH 8.0, and 0.04 mM pyridoxal 5'-phosphate, at 37°C
0.007
L-kynurenine
mutant enzyme H102W/N333T, in 30 mM potassium phosphate, pH 8.0, and 0.04 mM pyridoxal 5'-phosphate, at 37°C
0.017
L-kynurenine
mutant enzyme S332G/N333T, in 30 mM potassium phosphate, pH 8.0, and 0.04 mM pyridoxal 5'-phosphate, at 37°C
0.018
L-kynurenine
Km above 0.51 mM, mutant enzyme H102W/S332G/N333T, in 30 mM potassium phosphate, pH 8.0, and 0.04 mM pyridoxal 5'-phosphate, at 37°C
0.026
L-kynurenine
mutant enzyme N333T, in 30 mM potassium phosphate, pH 8.0, and 0.04 mM pyridoxal 5'-phosphate, at 37°C
0.23
L-kynurenine
wild type enzyme, in 30 mM potassium phosphate, pH 8.0, and 0.04 mM pyridoxal 5'-phosphate, at 37°C
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.227
amino-(1-oxo-1,2,3,4-tetrahydro-2-naphthalenyl)-acetic acid
-
at 37ºC, pH 7.5
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
-
the catalytic activity of kynureninase is very low in most tissue with exception of liver and kidney
-
the catalytic activity of kynureninase is very low in most tissue with exception of liver and kidney
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
metabolism
physiological function
kynureninase may function as a tumour suppressor in breast cancer
additional information
metabolism
the enzyme is a key enzyme in the kynurenine pathway of tryptophan catabolism in both bacteria and animals, and catalyzes the unique beta,gamma-cleavage of aryl substituted gamma-keto-alpha-amino acids
metabolism
the role of the enzyme (KYNU) in cancer cell proliferation, tumour growth and development is evaluated by MTT assay, soft agar colony formation assay and xenograft mouse models. Among 137 primary breast cancer tissues, 46.7% (64/137) have high KYNU expression while 53.3% have low KYNU expression. The expression of KYNU is positively correlated with the expressions of biomarkers ER, PR and E-cad, while negatively associated with tumour grade, tumour stage and the expressions of biomarker HER2 and Ki-67. Overexpression of KYNU significantly inhibits cell proliferation in cell culture, colony formation in soft agar and xenograft BC development in NOD/SCID mice. Kynureninase suppresses breast cancer cell proliferation, tumour growth and development
additional information
modeling of 3,5-dibromo-L-kynurenine in the active site of the human enzyme
additional information
-
modeling of 3,5-dibromo-L-kynurenine in the active site of the human enzyme
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). KYNU_HUMAN
465
0
52352
Swiss-Prot
other Location (Reliability: 1)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
52400
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
crystals of recombinant kynureninase that diffracted to 2.0 A are obtained, and the atomic structure of the PLP-bound holoenzyme is determined by molecular replacement using the Pseudomonas fluorescens structure as the phasing model
the wild type enzyme is cocrystallized with 3-hydroxyhippuric acid, using the modified microbatch under oil technique at 25?C, with 0.05 M MgCl2, 0.1 M Tris (pH 8.0), and 25% (w/v) PEG 3000
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
H102W/N333T
the mutant shows complete reversal of substrate specificity between 3-hydroxy-L-kynurenine and L-kynurenine
H102W/S332G/N333T
the mutant shows complete reversal of substrate specificity between 3-hydroxy-L-kynurenine and L-kynurenine
N333T
the mutant reveals a 9fold decrease in kcat for L-kynurenine, but no change in Km, the mutant has weaker 3-hydroxy-L-kyrenine binding (6fold higher Km) and kcat at least 1100times slower than wild type Kynase
S332G/N333T the
mutant shows a very slight preference for L-kynurenine over 3-hydroxy-L-kynurenine
T198A
-
screening of cDNA from KYNU revealed homozygosity for a c.593A>G substitution in exon 7 in the proband, leading to a threonine-to-alanine shift, T198A, in kynureninase
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-80ºC, without pyridoxal 5'-phosphate, more than 12 months, no loss of activity
-
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
by strong cationic column, strong anion exchange column and hydroxyapatite column
-
recombinant enzyme, ammonium sulfate precipitation, DEAE-Sepharose CL-6B affinity column, hydroxyapatite column, strong anion-exchange column at pH 8.6, strong cation-exchange column at pH 6.0 strong anion-exchange column at pH 6.0, 60fold
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expression of the recombinant enzyme in Escherichia coli strain BL21(DE3)
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
drug development
the enzyme is a target for the design of potent and/or selective inhibitors of human kynureninase
medicine
synthesis
-
of inhibitors of kynureninase could prove to be useful in the development of the successful treatment regimen for neurological disorders such as septicemia, AIDS related dementia, Lyme disease, Huntington's and Alzheimer's disease
medicine
-
xanthurenic aciduria is linked to a mutation in the gene encoding kynureninase
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Soda, K.; Tanizawa, K.
Kynureninases: Enzymological properties and regulation mechanism
Adv. Enzymol. Relat. Areas Mol. Biol.
49
1-40
1979
amphibia, Aspergillus niger, aves, Bos taurus, Canis lupus familiaris, Cavia porcellus, Chondrichthyes, Homo sapiens, Mus musculus, Neurospora crassa, Penicillium roqueforti, Pseudomonas fluorescens, Pseudomonas marginalis, Rattus norvegicus, Rhizopus stolonifer, Saccharomyces cerevisiae, Testudines, Xanthomonas arboricola pv. pruni
Okuno, E.; Kido, R.
Kynureninase and kynurenine 3-hydroxylase in mammalian tissues
Adv. Exp. Med. Biol.
294
167-176
1991
Homo sapiens, Rattus norvegicus, Suncus murinus
Fitzgerald, D.H.; Muirhead, K.M.; Botting, N.P.
A comparative study on the inhibition of human and bacterial kynureninase by novel bicyclic kynurenine analogues
Bioorg. Med. Chem.
9
983-989
2001
Homo sapiens, Pseudomonas fluorescens
Walsh, H.A.; O'Shea, K.C.; Botting, N.P.
Comparative inhibition by substrate analogues 3-methoxy- and 3-hydroxydesaminokynurenine and an improved 3 step purification of recombinant human kynureninase
BMC Biochem.
4
13
2003
Homo sapiens, Pseudomonas fluorescens, Rattus norvegicus
Walsh, H.A.; Botting, N.P.
Purification and biochemical characterization of some of the properties of recombinant human kynureninase
Eur. J. Biochem.
269
2069-2074
2002
Homo sapiens
Lima, S.; Khristoforov, R.; Momany, C.; Phillips, R.S.
Crystal structure of Homo sapiens kynureninase
Biochemistry
46
2735-2744
2007
Homo sapiens (Q16719), Homo sapiens
Christensen, M.; Duno, M.; Lund, A.M.; Skovby, F.; Christensen, E.
Xanthurenic aciduria due to a mutation in KYNU encoding kynureninase
J. Inherit. Metab. Dis.
30
248-255
2007
Homo sapiens
Lima, S.; Kumar, S.; Gawandi, V.; Momany, C.; Phillips, R.S.
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
389-396
2009
Homo sapiens (Q16719), Homo sapiens
Maitrani, C.; Phillips, R.S.
Substituents effects on activity of kynureninase from Homo sapiens and Pseudomonas fluorescens
Bioorg. Med. Chem.
21
4670-4677
2013
Homo sapiens (Q16719), Homo sapiens, Pseudomonas fluorescens (P83788), Pseudomonas fluorescens
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