KYNU

Summary

KYNU (kynureninase, HGNC:6469) is a protein-coding gene on chromosome 2q22.2, encoding Kynureninase (Q16719). Catalyzes the cleavage of L-kynurenine (L-Kyn) and L-3-hydroxykynurenine (L-3OHKyn) into anthranilic acid (AA) and 3-hydroxyanthranilic acid (3-OHAA), respectively.

Kynureninase is a pyridoxal-5’-phosphate (pyridoxal-P) dependent enzyme that catalyzes the cleavage of L-kynurenine and L-3-hydroxykynurenine into anthranilic and 3-hydroxyanthranilic acids, respectively. Kynureninase is involved in the biosynthesis of NAD cofactors from tryptophan through the kynurenine pathway. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 8942 — RefSeq curated summary.

At a glance

• Gene–disease (curated): vertebral, cardiac, renal, and limb defects syndrome 2 (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 13
• Clinical variants (ClinVar): 140 total — 13 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 43
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_003937

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6469
Approved symbol	KYNU
Name	kynureninase
Location	2q22.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000115919
Ensembl biotype	protein_coding
OMIM	605197
Entrez	8942

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 21 protein_coding, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000264170, ENST00000375773, ENST00000409512, ENST00000410015, ENST00000424385, ENST00000460143, ENST00000612147, ENST00000613664, ENST00000621320, ENST00000852076, ENST00000852077, ENST00000852078, ENST00000852079, ENST00000852080, ENST00000852081, ENST00000852082, ENST00000852083, ENST00000852084, ENST00000852085, ENST00000852086, ENST00000852087, ENST00000852088, ENST00000970110

RefSeq mRNA: 3 — MANE Select: NM_003937 NM_001032998, NM_001199241, NM_003937

CCDS: CCDS2183, CCDS33299

Canonical transcript exons

ENST00000264170 — 14 exons

Exon	Start	End
ENSE00000777481	143040428	143040658
ENSE00000964247	142918609	142918729
ENSE00000964251	142957641	142957715
ENSE00000964252	142960624	142960770
ENSE00000964253	142985084	142985182
ENSE00000964254	142985948	142986021
ENSE00000964255	143029627	143029679
ENSE00000964256	143033236	143033321
ENSE00001158917	143042047	143055833
ENSE00001273432	142885349	142885536
ENSE00001587322	142877664	142877736
ENSE00003598110	142954810	142954871
ENSE00003633112	142956203	142956274
ENSE00003655018	142927659	142927741

Expression profiles

Bgee: expression breadth ubiquitous, 236 present calls, max score 98.70.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 31.8868 / max 1679.6219, expressed in 992 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
22782	18.7815	859
22781	13.1053	795

Top tissues by expression

279 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
endometrium epithelium	UBERON:0004811	98.70	gold quality
palpebral conjunctiva	UBERON:0001812	97.36	gold quality
sperm	CL:0000019	96.30	gold quality
epithelium of nasopharynx	UBERON:0001951	95.66	gold quality
nasopharynx	UBERON:0001728	95.65	gold quality
monocyte	CL:0000576	95.57	gold quality
mononuclear cell	CL:0000842	95.33	gold quality
leukocyte	CL:0000738	94.98	gold quality
male germ cell	CL:0000015	94.75	gold quality
liver	UBERON:0002107	93.08	gold quality
nasal cavity epithelium	UBERON:0005384	93.06	gold quality
right lobe of liver	UBERON:0001114	91.11	gold quality
nephron tubule	UBERON:0001231	90.88	gold quality
mucosa of urinary bladder	UBERON:0001259	90.29	gold quality
granulocyte	CL:0000094	89.54	gold quality
pancreatic ductal cell	CL:0002079	88.26	silver quality
esophagus squamous epithelium	UBERON:0006920	87.83	gold quality
gingival epithelium	UBERON:0001949	87.82	gold quality
gingiva	UBERON:0001828	87.67	gold quality
epithelial cell of pancreas	CL:0000083	87.54	gold quality
squamous epithelium	UBERON:0006914	87.22	gold quality
blood	UBERON:0000178	87.15	gold quality
nasal cavity mucosa	UBERON:0001826	87.11	gold quality
buccal mucosa cell	CL:0002336	87.03	silver quality
placenta	UBERON:0001987	86.33	gold quality
vermiform appendix	UBERON:0001154	86.28	gold quality
epithelium of esophagus	UBERON:0001976	86.05	gold quality
cervix squamous epithelium	UBERON:0006922	85.87	gold quality
kidney epithelium	UBERON:0004819	85.75	gold quality
diaphragm	UBERON:0001103	84.94	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-MTAB-6075	yes	6388.25
E-GEOD-86618	yes	1280.87
E-MTAB-9801	yes	661.99
E-MTAB-8142	yes	91.87
E-MTAB-5061	no	3.66
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

17 targeting KYNU, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4503	99.85	71.45	1869
HSA-MIR-3913-3P	99.74	66.53	938
HSA-MIR-510-3P	99.54	70.06	2965
HSA-MIR-302B-5P	99.50	69.49	1857
HSA-MIR-302D-5P	99.50	69.34	1863
HSA-MIR-203A-3P	99.49	70.56	2806
HSA-MIR-324-3P	99.26	66.31	1034
HSA-MIR-181A-2-3P	98.91	67.60	1168
HSA-MIR-4662A-5P	98.48	67.18	1007
HSA-MIR-2117	98.48	67.97	1307
HSA-MIR-6509-3P	98.32	67.33	1343
HSA-MIR-595	98.25	67.44	699
HSA-MIR-10397-5P	97.31	69.06	710
HSA-MIR-3654	96.43	66.55	646
HSA-MIR-6879-3P	93.93	64.00	759
HSA-MIR-6826-5P	93.80	67.42	514
HSA-MIR-4638-5P	92.31	65.23	86

Literature-anchored findings (GeneRIF, showing 7)

• The Lys412Glu polymorphism of the KYNU gene in a hypertensive candidate chromosomal region is associated with essential hypertension in Han Chinese. (PMID:16080802)
• A rare variant at the KYNU gene is associated with essential hypertension in the Han Chinese population. (PMID:22012986)
• Our results suggest that tryptophan metabolism might dichotomously modulate immune responses, with KYNU as a switch between immunosuppressive versus inflammatory outcomes. (PMID:26725996)
• A novel role of kynureninase in the growth control of breast cancer cells and its relationships with breast cancer. (PMID:31332944)
• TDO2 knockdown inhibits colorectal cancer progression via TDO2-KYNU-AhR pathway. (PMID:34051337)
• The TZM-bl Reporter Cell Line Expresses Kynureninase That Can Neutralize 2F5-like Antibodies in the HIV-1 Neutralization Assay. (PMID:35054825)
• Re-sequencing of candidate genes FOXF1, HSPA6, HAAO, and KYNU in 522 individuals with VATER/VACTERL, VACTER/VACTERL-like association, and isolated anorectal malformation. (PMID:35362267)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	kynu	ENSDARG00000099546
mus_musculus	Kynu	ENSMUSG00000026866
rattus_norvegicus	Kynu	ENSRNOG00000029993
caenorhabditis_elegans		WBGENE00015802

Protein

Protein identifiers

Kynureninase — Q16719 (reviewed: Q16719)

Alternative names: L-kynurenine hydrolase

All UniProt accessions (6): A0A087WYM2, A0A087WYQ7, A0A087X297, B8ZZA3, Q16719, F8WEP1

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the cleavage of L-kynurenine (L-Kyn) and L-3-hydroxykynurenine (L-3OHKyn) into anthranilic acid (AA) and 3-hydroxyanthranilic acid (3-OHAA), respectively. Has a preference for the L-3-hydroxy form. Also has cysteine-conjugate-beta-lyase activity.

Subunit / interactions. Homodimer.

Subcellular location. Cytoplasm. Cytosol.

Tissue specificity. Expressed in all tissues tested (heart, brain placenta, lung, liver, skeletal muscle, kidney and pancreas). Highest levels found in placenta, liver and lung. Expressed in all brain regions.

Disease relevance. Hydroxykynureninuria (HYXKY) [MIM:236800] An inborn error of amino acid metabolism characterized by massive urinary excretion of large amounts of kynurenine, 3-hydroxykynurenine and xanthurenic acid. Affected individuals manifest renal tubular dysfunction, metabolic acidosis, psychomotor retardation, non-progressive encephalopathy, and muscular hypertonia. The disease is caused by variants affecting the gene represented in this entry. Vertebral, cardiac, renal, and limb defects syndrome 2 (VCRL2) [MIM:617661] An autosomal recessive congenital malformation syndrome characterized by vertebral segmentation abnormalities, congenital cardiac defects, renal defects, and distal mild limb defects. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by o-methoxybenzoylalanine (OMBA).

Induction. Increased levels in several cerebral and systemic inflammatory conditions.

Pathway. Amino-acid degradation; L-kynurenine degradation; L-alanine and anthranilate from L-kynurenine: step 1/1. Cofactor biosynthesis; NAD(+) biosynthesis; quinolinate from L-kynurenine: step 2/3.

Similarity. Belongs to the kynureninase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q16719-1	1	yes
Q16719-2	2

RefSeq proteins (3): NP_001028170, NP_001186170, NP_003928* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR010111	Kynureninase	Family
IPR015421	PyrdxlP-dep_Trfase_major	Homologous_superfamily
IPR015422	PyrdxlP-dep_Trfase_small	Homologous_superfamily
IPR015424	PyrdxlP-dep_Trfase	Homologous_superfamily

Pfam: PF22580

Enzyme classification (BRENDA):

• EC 3.7.1.3 — kynureninase (BRENDA: 27 organisms, 56 substrates, 134 inhibitors, 65 Km, 50 kcat entries)

Substrate kinetics (BRENDA)

31 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
L-KYNURENINE	0.0035–1	23
3-HYDROXY-L-KYNURENINE	0.003–3	11
L-3-HYDROXYKYNURENINE	0.013–0.54	9
KYNURENINE	0.006–0.08	4
O-BENZOYL-L-SERINE	0.071–2.4	3
BETA-BENZOYL-L-ALANINE	0.008–0.009	2
3-BROMO-L-KYNURENINE	2	1
3-HYDROXY-DL-KYNURENINE	0.0283	1
4-FLUORO-L-KYNURENINE	0.067	1
5-BROMO-L-KYNURENINE	0.011	1
5-FLUORO-L-KYNURENINE	0.048	1
BETA-BENZOYL-L-KYNURENINE	0.16	1
GAMMA-(O-AMINOPHENYL)-L-HOMOSERINE	0.067	1
L-ALANINE	11	1
L-ORNITHINE	40	1

Catalyzed reactions (Rhea), 2 shown:

• L-kynurenine + H2O = anthranilate + L-alanine + H(+) (RHEA:16813)
• 3-hydroxy-L-kynurenine + H2O = 3-hydroxyanthranilate + L-alanine + H(+) (RHEA:25143)

UniProt features (68 total): helix 28, strand 15, binding site 9, turn 7, sequence variant 4, modified residue 2, splice variant 2, chain 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
3E9K	X-RAY DIFFRACTION	1.7
2HZP	X-RAY DIFFRACTION	2
7S3V	X-RAY DIFFRACTION	3.25

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q16719-F1	95.55	0.93

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (9): 137; 138; 165–168; 221; 250; 253; 275; 305; 333

Post-translational modifications (2): 1, 276

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-71240	Tryptophan catabolism
R-HSA-1430728	Metabolism
R-HSA-71291	Metabolism of amino acids and derivatives

MSigDB gene sets: 468 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_DN, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, MULLIGHAN_NPM1_SIGNATURE_3_UP, MCLACHLAN_DENTAL_CARIES_UP, GOBP_RESPONSE_TO_PEPTIDE, ENK_UV_RESPONSE_KERATINOCYTE_UP, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, REACTOME_TRYPTOPHAN_CATABOLISM, MODULE_45, MODULE_418, GOZGIT_ESR1_TARGETS_DN, SMID_BREAST_CANCER_RELAPSE_IN_LIVER_UP, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, MODULE_16

GO Biological Process (12): L-tryptophan catabolic process (GO:0006569), NAD+ biosynthetic process (GO:0009435), obsolete L-tryptophan catabolic process to L-kynurenine (GO:0019441), quinolinate biosynthetic process (GO:0019805), response to type II interferon (GO:0034341), ‘de novo’ NAD+ biosynthetic process from L-tryptophan (GO:0034354), response to vitamin B6 (GO:0034516), obsolete anthranilate metabolic process (GO:0043420), obsolete L-kynurenine catabolic process (GO:0097053), nucleoside phosphate metabolic process (GO:0006753), pyridine nucleotide biosynthetic process (GO:0019363), purine-containing compound metabolic process (GO:0072521)

GO Molecular Function (5): pyridoxal phosphate binding (GO:0030170), kynureninase activity (GO:0030429), protein homodimerization activity (GO:0042803), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (4): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrion (GO:0005739), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Metabolism of amino acids and derivatives	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
pyridine-containing compound biosynthetic process	2
cytoplasm	2
aromatic amino acid catabolic process	1
indole-containing compound catabolic process	1
L-amino acid catabolic process	1
proteinogenic amino acid catabolic process	1
purine nucleotide biosynthetic process	1
nicotinamide nucleotide biosynthetic process	1
NAD+ metabolic process	1
dicarboxylic acid biosynthetic process	1
quinolinate metabolic process	1
response to cytokine	1
innate immune response	1
aromatic amino acid metabolic process	1
NAD+ biosynthetic process	1
indole-containing compound metabolic process	1
L-amino acid metabolic process	1
proteinogenic amino acid metabolic process	1
response to vitamin	1
response to nitrogen compound	1
response to oxygen-containing compound	1
organophosphate metabolic process	1
nucleobase-containing small molecule metabolic process	1
nucleotide biosynthetic process	1
metabolic process	1
anion binding	1
vitamin B6 binding	1
hydrolase activity, acting on carbon-carbon bonds, in ketonic substances	1
identical protein binding	1
protein dimerization activity	1
binding	1
catalytic activity	1
nuclear lumen	1
intracellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1592 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KYNU	KMO	O15229	919
KYNU	HAAO	P46952	912
KYNU	TDO2	P48775	874
KYNU	QPRT	Q15274	847
KYNU	IDO1	P14902	810
KYNU	AADAT	Q8N5Z0	796
KYNU	ACMSD	Q8TDX5	795
KYNU	IDO2	Q6ZQW0	793
KYNU	AFMID	Q63HM1	788
KYNU	KYAT1	Q16773	774
KYNU	KYAT3	Q6YP21	709
KYNU	SF3B3	Q15393	620
KYNU	A0A494C066	A0A494C066	617
KYNU	NADSYN1	Q6IA69	558
KYNU	GPR35	Q9HC97	534

IntAct

12 interactions, top by confidence:

A	B	Type	Score
ECE1	KYNU	psi-mi:“MI:0915”(physical association)	0.370
RET	ZBTB48	psi-mi:“MI:0914”(association)	0.350
	SHTN1	psi-mi:“MI:0914”(association)	0.350
rep	CA12	psi-mi:“MI:0914”(association)	0.350
	CLIC1	psi-mi:“MI:0914”(association)	0.350
KYNU	ACTA2	psi-mi:“MI:0914”(association)	0.350
AGPAT1	A2ML1	psi-mi:“MI:0914”(association)	0.350
GATA2	EFCAB5	psi-mi:“MI:0914”(association)	0.350
KYNU	nhaA	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (79): KYNU (Affinity Capture-RNA), ADK (Co-fractionation), ASS1 (Co-fractionation), CFL1 (Co-fractionation), DSTN (Co-fractionation), ETFA (Co-fractionation), FUBP1 (Co-fractionation), GLRX (Co-fractionation), KYNU (Co-fractionation), KYNU (Co-fractionation), MEMO1 (Co-fractionation), PPIA (Co-fractionation), PSAT1 (Co-fractionation), SPR (Co-fractionation), KYNU (Affinity Capture-MS)

ESM2 similar proteins: A0A2H5AIY0, A0AA51Z3J4, A0M4Y1, A1C688, A1CHT0, A1CWY1, A1DGW4, A2QJI5, A2R7T0, A5DM91, A5FMM4, A6H1P7, A6RSP5, A7ESB8, A7SCH8, A7TR79, A8XKT0, A9V3C0, B0XS72, B0Y6H2, B1KJM4, O96567, P05031, P17770, P20228, P54769, P54770, P70712, P93083, Q05979, Q0CPB0, Q0CZX6, Q0UZK0, Q0ZQX0, Q16719, Q16S21, Q18026, Q1DZA6, Q2U038, Q2UJE8

Diamond homologs: A0M4Y1, A0REX2, A1C688, A1CHT0, A1CWY1, A1DGW4, A2QJI5, A2R7T0, A3LQD7, A4IT57, A4UBV5, A4XAL2, A5DM91, A5DTF4, A5FMM4, A6H1P7, A6RSP5, A7ESB8, A7GPY3, A7SCH8, A7TR79, A8XKT0, A9V3C0, A9VHP9, B0RUZ9, B0XS72, B0Y6H2, B1KJM4, B1YHD6, B2FL97, B2SIT8, P0CO52, P0CO53, P70712, Q05979, Q0CPB0, Q0CZX6, Q0UIN2, Q0UZK0, Q16719

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

140 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	13
Likely pathogenic	6
Uncertain significance	78
Likely benign	10
Benign	7

Top pathogenic / likely-pathogenic (19)

Variant ID	HGVS	Classification
160355	NM_003937.3(KYNU):c.592A>G (p.Thr198Ala)	Pathogenic
1695427	NM_003937.3(KYNU):c.374-433_435+369del	Pathogenic
2198678	NM_003937.3(KYNU):c.967del (p.Ile323fs)	Pathogenic
403691	Single allele	Pathogenic
403729	NM_003937.3(KYNU):c.170-1G>T	Pathogenic
403730	NM_003937.3(KYNU):c.468T>A (p.Tyr156Ter)	Pathogenic
403731	NM_003937.3(KYNU):c.1045_1051del (p.Phe349fs)	Pathogenic
4279215	GRCh37/hg19 2q22.2(chr2:143273366-143719356)x1	Pathogenic
4538498	NM_003937.3(KYNU):c.1301G>A (p.Arg434Gln)	Pathogenic
978267	NC_000002.12:g.142877008_142961693del	Pathogenic
978269	NM_003937.3(KYNU):c.989G>A (p.Arg330Gln)	Pathogenic
988089	NM_003937.3(KYNU):c.788A>G (p.His263Arg)	Pathogenic
988093	NM_003937.3(KYNU):c.489del (p.Ala164fs)	Pathogenic
1333644	NM_003937.3(KYNU):c.902+1G>A	Likely pathogenic
2178788	NM_003937.3(KYNU):c.903-2A>C	Likely pathogenic
2584440	NM_003937.3(KYNU):c.510T>A (p.Tyr170Ter)	Likely pathogenic
2584441	NM_003937.3(KYNU):c.825C>A (p.Tyr275Ter)	Likely pathogenic
2632261	NM_003937.3(KYNU):c.373_373+3del	Likely pathogenic
3357978	NM_003937.3(KYNU):c.737dup (p.Tyr246Ter)	Likely pathogenic

SpliceAI

3326 predictions. Top by Δscore:

Variant	Effect	Δscore
2:142881429:GT:G	donor_gain	1.0000
2:142885347:A:AG	acceptor_gain	1.0000
2:142885348:G:GG	acceptor_gain	1.0000
2:142885348:GTTTT:G	acceptor_gain	1.0000
2:142885473:GAAGA:G	donor_gain	1.0000
2:142885477:A:G	donor_gain	1.0000
2:142885537:G:C	donor_loss	1.0000
2:142885538:T:G	donor_loss	1.0000
2:142918607:A:AG	acceptor_gain	1.0000
2:142918607:AGTT:A	acceptor_gain	1.0000
2:142918608:G:GG	acceptor_gain	1.0000
2:142918608:GTT:G	acceptor_gain	1.0000
2:142918608:GTTG:G	acceptor_gain	1.0000
2:142918714:A:G	donor_gain	1.0000
2:142918725:AAAAT:A	donor_gain	1.0000
2:142918726:AAAT:A	donor_gain	1.0000
2:142918727:AAT:A	donor_gain	1.0000
2:142918727:AATG:A	donor_loss	1.0000
2:142918728:AT:A	donor_gain	1.0000
2:142918728:ATG:A	donor_loss	1.0000
2:142918729:TGT:T	donor_loss	1.0000
2:142918730:G:GG	donor_gain	1.0000
2:142918731:TAA:T	donor_loss	1.0000
2:142918732:AAGTA:A	donor_loss	1.0000
2:142924771:T:G	donor_gain	1.0000
2:142927651:A:AG	acceptor_gain	1.0000
2:142927652:A:G	acceptor_gain	1.0000
2:142927653:TTTCA:T	acceptor_loss	1.0000
2:142927656:CA:C	acceptor_loss	1.0000
2:142927657:A:AC	acceptor_loss	1.0000

AlphaMissense

3050 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:142956260:T:C	F165L	0.997
2:142956262:C:A	F165L	0.997
2:142956262:C:G	F165L	0.997
2:142985168:T:A	W272R	0.995
2:142985168:T:C	W272R	0.995
2:142985173:T:G	C273W	0.995
2:142918719:T:A	W94R	0.994
2:142918719:T:C	W94R	0.994
2:142927693:T:A	W109R	0.993
2:142927693:T:C	W109R	0.993
2:142985181:A:T	K276M	0.993
2:143029637:T:A	W305R	0.993
2:143029637:T:C	W305R	0.993
2:142985181:A:C	K276T	0.991
2:142956261:T:G	F165C	0.990
2:142985125:T:A	N257K	0.990
2:142985125:T:G	N257K	0.990
2:142985163:C:A	A270D	0.990
2:142985182:G:C	K276N	0.990
2:142985182:G:T	K276N	0.990
2:143033313:A:C	S345R	0.990
2:143033315:T:A	S345R	0.990
2:143033315:T:G	S345R	0.990
2:142985171:T:C	C273R	0.989
2:142985984:T:C	F289L	0.989
2:142985986:C:A	F289L	0.989
2:142985986:C:G	F289L	0.989
2:143042075:G:C	R434P	0.989
2:143042104:T:C	F444L	0.989
2:143042106:C:A	F444L	0.989

dbSNP variants (sampled 300 via entrez): RS1000021755 (2:142957225 C>T), RS1000022988 (2:143002796 G>A), RS1000027073 (2:143047362 A>T), RS1000035084 (2:142924165 C>T), RS1000117256 (2:142886386 A>G), RS1000125035 (2:142960196 T>C), RS1000133672 (2:142917287 G>A), RS1000135224 (2:143005701 G>A,C), RS1000169477 (2:143041164 T>C), RS1000172101 (2:142910640 C>T), RS1000183861 (2:143054836 A>C), RS1000192527 (2:142953105 C>T), RS1000200232 (2:142999204 G>A), RS1000210940 (2:142988514 G>A), RS1000227129 (2:143039078 T>A)

Disease associations

OMIM: gene MIM:605197 | disease phenotypes: MIM:236800, MIM:617661, MIM:302380, MIM:616145

GenCC curated gene-disease

Disease	Classification	Inheritance
encephalopathy due to hydroxykynureninuria	Strong	Autosomal recessive
vertebral, cardiac, renal, and limb defects syndrome 2	Strong	Autosomal recessive
congenital vertebral-cardiac-renal anomalies syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
vertebral, cardiac, renal, and limb defects syndrome 2	Definitive	AR

Mondo (5): encephalopathy due to hydroxykynureninuria (MONDO:0009372), vertebral, cardiac, renal, and limb defects syndrome 2 (MONDO:0060555), intellectual disability (MONDO:0001071), Catel-Manzke syndrome (MONDO:0014507), congenital vertebral-cardiac-renal anomalies syndrome (MONDO:0020831)

Orphanet (3): Hydroxykynureninuria (Orphanet:79155), Catel-Manzke syndrome (Orphanet:1388), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

43 total (30 of 43 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000089	Renal hypoplasia
HP:0000122	Unilateral renal agenesis
HP:0000252	Microcephaly
HP:0000369	Low-set ears
HP:0000733	Motor stereotypy
HP:0000750	Delayed speech and language development
HP:0000774	Narrow chest
HP:0000878	11 pairs of ribs
HP:0000952	Jaundice
HP:0000958	Dry skin
HP:0001249	Intellectual disability
HP:0001259	Coma
HP:0001263	Global developmental delay
HP:0001276	Hypertonia
HP:0001298	Encephalopathy
HP:0001545	Anteriorly placed anus
HP:0001643	Patent ductus arteriosus
HP:0001649	Tachycardia
HP:0001883	Talipes
HP:0001942	Metabolic acidosis
HP:0001947	Renal tubular acidosis
HP:0002007	Frontal bossing
HP:0002013	Vomiting
HP:0002315	Headache
HP:0002448	Progressive encephalopathy
HP:0002615	Hypotension
HP:0002937	Hemivertebrae
HP:0003422	Vertebral segmentation defect
HP:0003577	Congenital onset

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST002671_3	Toenail selenium levels	4.000000e-06
GCST003139_14	Glomerular filtration rate in chronic kidney disease	7.000000e-06
GCST005038_48	Allergic disease (asthma, hay fever or eczema)	2.000000e-09
GCST005751_10	Empathy quotient	1.000000e-07
GCST005751_7	Empathy quotient	2.000000e-07
GCST006585_1902	Blood protein levels	7.000000e-83
GCST007060_1	Response to SSRI (symptom remission)	5.000000e-06
GCST008478_5	Neurological blood protein biomarker levels	7.000000e-17
GCST010042_114	Asthma	2.000000e-08
GCST012013_20	Cataracts	4.000000e-08
GCST012462_2	Asthma and eczema	5.000000e-06
GCST90002402_250	Platelet count	1.000000e-11
GCST90014268_9	Cataracts	6.000000e-14

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0009183	empathy measurement
EFO:0005658	response to selective serotonin reuptake inhibitor
EFO:0004309	platelet count

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C535347	Catel Manzke syndrome (supp.)
C536081	Hydroxykynureninuria (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5100 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 13,947 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL498416	L-KYNURENINE	1	13,947

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs352887	KYNU		0.00	0

ChEMBL bioactivities

8 potent at pChembl≥5 of 10 total, top 6 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.16	Ki	70	nM	CHEMBL280572
7.16	Ki	70	nM	CHEMBL88626
7.00	Ki	100	nM	CHEMBL120534
5.37	Ki	4280	nM	L-KYNURENINE
5.06	Ki	8800	nM	CHEMBL89851
5.00	Ki	1e+04	nM	CHEMBL120534

PubChem BioAssay actives

5 with measured affinity, of 37 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-amino-3-(2-aminophenyl)sulfonylpropanoic acid	94528: Compound was tested for the binding affinity against bacterial kynureninase	ki	0.0700	uM
2-amino-4-hydroxy-4-(3-hydroxyphenyl)butanoic acid	1996026: Binding affinity to human recombinant Kynureninase assessed as inhibition constant	ki	0.1000	uM

CTD chemical–gene interactions

103 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, decreases methylation, affects cotreatment, increases expression	6
sodium arsenite	increases expression	4
Acetaminophen	affects cotreatment, decreases expression	4
Estradiol	affects cotreatment, decreases expression	4
Cyclosporine	affects cotreatment, increases expression	4
bisphenol A	affects expression, decreases expression, increases expression	3
Silicon Dioxide	affects secretion, increases expression	3
Asbestos, Crocidolite	affects expression, increases expression	3
Arsenic Trioxide	increases expression	2
Air Pollutants	increases abundance, increases expression, decreases expression	2
Nickel	increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Smoke	increases abundance, increases expression, decreases expression	2
Tobacco Smoke Pollution	increases expression, affects expression	2
Tretinoin	increases expression	2
Particulate Matter	increases abundance, increases expression	2
aristolochic acid I	decreases expression	1
TAK-243	increases sumoylation	1
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
glycidyl methacrylate	decreases expression	1
sulforaphane	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
cobaltous chloride	decreases expression	1
nickel chloride	increases expression	1
perfluorooctanoic acid	decreases expression	1
zinc chromate	increases abundance, increases expression	1
cupric chloride	increases expression	1
nickel sulfate	increases expression	1

ChEMBL screening assays

21 unique, capped per target: 21 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1009938	Binding	Activity of human wild type kynureninase	Crystal structure of the Homo sapiens kynureninase-3-hydroxyhippuric acid inhibitor complex: insights into the molecular basis of kynureninase substrate specificity. — J Med Chem

Clinical trials (associated diseases)

197 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders