TYW5

Summary

TYW5 (tRNA-yW synthesizing protein 5, HGNC:26754) is a protein-coding gene on chromosome 2q33.1, encoding tRNA wybutosine-synthesizing protein 5 (A2RUC4). tRNA hydroxylase that acts as a component of the wybutosine biosynthesis pathway.

Enables several functions, including iron ion binding activity; protein homodimerization activity; and tRNA(Phe) (7-(3-amino-3-carboxypropyl)wyosine37-C2)-hydroxylase activity. Involved in wybutosine biosynthetic process. Predicted to be located in cytoplasm.

Source: NCBI Gene 129450 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 37 total
• MANE Select transcript: NM_001039693

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26754
Approved symbol	TYW5
Name	tRNA-yW synthesizing protein 5
Location	2q33.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ37953
Ensembl gene	ENSG00000162971
Ensembl biotype	protein_coding
OMIM	619882
Entrez	129450

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 10 protein_coding, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000354611, ENST00000441832, ENST00000452512, ENST00000483328, ENST00000493181, ENST00000874895, ENST00000874896, ENST00000933513, ENST00000933514, ENST00000933515, ENST00000933516, ENST00000933517, ENST00000933518, ENST00000933519

RefSeq mRNA: 1 — MANE Select: NM_001039693 NM_001039693

CCDS: CCDS42795

Canonical transcript exons

ENST00000354611 — 8 exons

Exon	Start	End
ENSE00001429490	199948318	199948472
ENSE00003468422	199940089	199940133
ENSE00003491525	199938933	199939070
ENSE00003511888	199935931	199936047
ENSE00003619478	199928913	199933323
ENSE00003682388	199943765	199943834
ENSE00003683852	199936405	199936492
ENSE00003842566	199955393	199955491

Expression profiles

Bgee: expression breadth ubiquitous, 210 present calls, max score 88.48.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.3399 / max 100.4753, expressed in 1741 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
33159	7.3399	1741

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
epithelial cell of pancreas	CL:0000083	88.48	silver quality
ileal mucosa	UBERON:0000331	82.53	gold quality
oviduct epithelium	UBERON:0004804	81.50	gold quality
tendon of biceps brachii	UBERON:0008188	81.28	silver quality
adrenal tissue	UBERON:0018303	81.27	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.56	gold quality
tibialis anterior	UBERON:0001385	80.02	silver quality
buccal mucosa cell	CL:0002336	79.86	silver quality
medial globus pallidus	UBERON:0002477	79.19	gold quality
bone marrow	UBERON:0002371	78.82	gold quality
tendon	UBERON:0000043	78.80	gold quality
endothelial cell	CL:0000115	78.76	silver quality
right adrenal gland cortex	UBERON:0035827	78.73	gold quality
left adrenal gland	UBERON:0001234	78.54	gold quality
right adrenal gland	UBERON:0001233	78.51	gold quality
cartilage tissue	UBERON:0002418	78.19	gold quality
bone marrow cell	CL:0002092	78.04	gold quality
esophagus squamous epithelium	UBERON:0006920	78.04	gold quality
left adrenal gland cortex	UBERON:0035825	78.04	gold quality
adrenal gland	UBERON:0002369	77.62	gold quality
body of pancreas	UBERON:0001150	77.36	gold quality
ventricular zone	UBERON:0003053	77.32	gold quality
islet of Langerhans	UBERON:0000006	77.01	gold quality
calcaneal tendon	UBERON:0003701	76.87	gold quality
stromal cell of endometrium	CL:0002255	76.77	gold quality
pancreas	UBERON:0001264	76.77	gold quality
adrenal cortex	UBERON:0001235	76.65	gold quality
pancreatic ductal cell	CL:0002079	76.52	silver quality
monocyte	CL:0000576	76.43	gold quality
leukocyte	CL:0000738	76.33	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	5.67

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

136 targeting TYW5, 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-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-380-3P	99.89	70.18	1978
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-4503	99.85	71.45	1869

Literature-anchored findings (GeneRIF, showing 2)

• Regulatory variants at 2q33.1 confer schizophrenia risk by modulating distal gene TYW5 expression. (PMID:34581804)
• Comprehensive and integrative analyses identify TYW5 as a schizophrenia risk gene. (PMID:35527273)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	tyw5	ENSDARG00000069672
mus_musculus	Tyw5	ENSMUSG00000048495
rattus_norvegicus	Tyw5	ENSRNOG00000010100

Paralogs (4): KDM8 (ENSG00000155666), HIF1AN (ENSG00000166135), HSPBAP1 (ENSG00000169087), JMJD7 (ENSG00000243789)

Protein

Protein identifiers

tRNA wybutosine-synthesizing protein 5 — A2RUC4 (reviewed: A2RUC4)

Alternative names: tRNA(Phe) (7-(3-amino-3-carboxypropyl)wyosine(37)-C(2))-hydroxylase

All UniProt accessions (2): A2RUC4, A8KAJ9

UniProt curated annotations — full annotation on UniProt →

Function. tRNA hydroxylase that acts as a component of the wybutosine biosynthesis pathway. Wybutosine is a hyper modified guanosine with a tricyclic base found at the 3’-position adjacent to the anticodon of eukaryotic phenylalanine tRNA. Catalyzes the hydroxylation of 7-(a-amino-a-carboxypropyl)wyosine (yW-72) into undermodified hydroxywybutosine (OHyW*). OHyW* being further transformed into hydroxywybutosine (OHyW) by LCMT2/TYW4. OHyW is a derivative of wybutosine found in higher eukaryotes.

Subunit / interactions. Homodimer.

Cofactor. Binds 1 Fe(2+) ion per subunit.

Pathway. tRNA modification; wybutosine-tRNA(Phe) biosynthesis.

Similarity. Belongs to the TYW5 family.

Isoforms (2)

UniProt ID	Names	Canonical?
A2RUC4-1	1	yes
A2RUC4-2	2

RefSeq proteins (1): NP_001034782* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003347	JmjC_dom	Domain
IPR041667	Cupin_8	Domain

Pfam: PF13621

Enzyme classification (BRENDA):

• EC 1.14.11.42 — tRNAPhe (7-(3-amino-3-carboxypropyl)wyosine37-C2)-hydroxylase (BRENDA: 1 organisms, 3 substrates, 0 inhibitors, 0 Km, 0 kcat entries)

Catalyzed reactions (Rhea), 1 shown:

• 7-[(3S)-3-amino-3-carboxypropyl]wyosine(37) in tRNA(Phe) + 2-oxoglutarate + O2 = 7-(2-hydroxy-3-amino-3-carboxypropyl)wyosine(37) in tRNA(Phe) + succinate + CO2 (RHEA:37899)

UniProt features (44 total): strand 16, helix 13, binding site 6, turn 3, mutagenesis site 2, chain 1, domain 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
3AL5	X-RAY DIFFRACTION	2.5
3AL6	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-A2RUC4-F1	95.90	0.97

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 (6): 106; 160; 162; 166; 175; 235

Mutagenesis-validated functional residues (2):

Position	Phenotype
108	abolishes enzyme activity and ability to bind trna.
149	abolishes enzyme activity and ability to bind trna.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6782861	Synthesis of wybutosine at G37 of tRNA(Phe)

MSigDB gene sets: 107 (showing top): SHEPARD_BMYB_MORPHOLINO_UP, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, GOBP_TRNA_METABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_RNA_MODIFICATION, WANG_LMO4_TARGETS_DN, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS, GOBP_GLYCOSYL_COMPOUND_BIOSYNTHETIC_PROCESS, GOBP_TRNA_PROCESSING, REACTOME_METABOLISM_OF_RNA, GOBP_TRNA_MODIFICATION, GINESTIER_BREAST_CANCER_ZNF217_AMPLIFIED_DN, MASSARWEH_TAMOXIFEN_RESISTANCE_UP, GOMF_PROTEIN_DIMERIZATION_ACTIVITY, GOMF_PROTEIN_HOMODIMERIZATION_ACTIVITY

GO Biological Process (2): wybutosine biosynthetic process (GO:0031591), tRNA processing (GO:0008033)

GO Molecular Function (8): tRNA binding (GO:0000049), iron ion binding (GO:0005506), protein homodimerization activity (GO:0042803), tRNA(Phe) (7-(3-amino-3-carboxypropyl)wyosine37-C2)-hydroxylase activity (GO:0102524), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), metal ion binding (GO:0046872), dioxygenase activity (GO:0051213)

GO Cellular Component (1): cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
tRNA modification in the nucleus and cytosol	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
tRNA modification	1
glycosyl compound biosynthetic process	1
RNA processing	1
tRNA metabolic process	1
RNA binding	1
transition metal ion binding	1
identical protein binding	1
protein dimerization activity	1
2-oxoglutarate-dependent dioxygenase activity	1
catalytic activity, acting on a tRNA	1
binding	1
catalytic activity	1
cation binding	1
oxidoreductase activity	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

668 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TYW5	TYW1	Q9NV66	759
TYW5	RIOX2	Q8IUF8	743
TYW5	TYW3	Q6IPR3	743
TYW5	RIOX1	Q9H6W3	702
TYW5	JMJD4	Q9H9V9	697
TYW5	JMJD8	Q96S16	667
TYW5	JMJD6	Q6NYC1	640
TYW5	TRMT5	Q32P41	628
TYW5	LCMT2	O60294	619
TYW5	FTCDNL1	E5RQL4	610
TYW5	TYW2	Q53H54	600
TYW5	C2orf69	Q8N8R5	582
TYW5	ALKBH8	Q96BT7	560
TYW5	ALKBH1	Q13686	559
TYW5	OGFOD1	Q8N543	518

IntAct

20 interactions, top by confidence:

A	B	Type	Score
USE1	NBAS	psi-mi:“MI:0914”(association)	0.640
TYW5	POTEF	psi-mi:“MI:0915”(physical association)	0.590
SUN1	TYW5	psi-mi:“MI:0914”(association)	0.530
NSA2	TYW5	psi-mi:“MI:0914”(association)	0.530
SPATA46	TYW5	psi-mi:“MI:0914”(association)	0.530
METTL6	TYW5	psi-mi:“MI:0914”(association)	0.530
HLA-DPA1	TYW5	psi-mi:“MI:0914”(association)	0.530
ANKRD36	TYW5	psi-mi:“MI:0915”(physical association)	0.400
HLA-DPA1	GXYLT2	psi-mi:“MI:0914”(association)	0.350
USE1	NBAS	psi-mi:“MI:0914”(association)	0.350
STX7	TYW5	psi-mi:“MI:0914”(association)	0.350
FAM153B	TYW5	psi-mi:“MI:0914”(association)	0.350
SAP30BP	TYW5	psi-mi:“MI:0914”(association)	0.350

BioGRID (32): TYW5 (Affinity Capture-MS), TYW5 (Affinity Capture-MS), TYW5 (Affinity Capture-MS), TYW5 (Affinity Capture-MS), TYW5 (Affinity Capture-MS), TYW5 (Affinity Capture-MS), TYW5 (Affinity Capture-MS), TYW5 (Affinity Capture-MS), TYW5 (Affinity Capture-MS), POTEF (Affinity Capture-MS), TYW5 (Affinity Capture-MS), TYW5 (Affinity Capture-MS), TYW5 (Affinity Capture-MS), TYW5 (Affinity Capture-MS), TYW5 (Affinity Capture-MS)

ESM2 similar proteins: A2AV36, A2RSX7, A2RUC4, A4IHY0, A6QQV6, A8E534, B2GUS6, B5XF11, E1C7T6, E9PYK3, F1RET2, P0C870, P0C872, P47823, P59723, P83006, Q08BV2, Q08BY5, Q0VCA8, Q0WVR4, Q3UDE2, Q3V3E1, Q58CU3, Q5BKC6, Q5EA24, Q5R673, Q5U4E8, Q5ZHV5, Q5ZIB9, Q66KI9, Q67XX3, Q67ZB6, Q6AXL5, Q6PCI6, Q7T0X7, Q7TMC8, Q8BFT6, Q8BGG7, Q8BK58, Q8BLR9

Diamond homologs: A2RSX7, A2RUC4, B3MSI4, E1C7T6, F4K2M8, Q08BV2, Q2U6D4, Q4IER0, Q4WVD1, Q54FG7, Q5BH52, Q67ZB6, Q6AXL5, Q6C3P4, Q9P3K9, A8E534, B5XF11, Q54LV7, Q58CU3, Q96EW2, B2GUS6, Q1JP61, Q497B8, Q55DF5, Q5BKC6, Q8N371, Q8RWR1, Q9CXT6, Q9NWT6, Q9W0M3, Q3TA59, Q5UQY3, Q8BK58, P59723, Q0WVR4, Q8BLR9, O94606, Q6AY40, Q08282, Q5A931

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	32
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1658 predictions. Top by Δscore:

Variant	Effect	Δscore
2:199933319:TAAAG:T	acceptor_gain	1.0000
2:199933321:AAG:A	acceptor_gain	1.0000
2:199933323:GC:G	acceptor_loss	1.0000
2:199933324:C:CA	acceptor_loss	1.0000
2:199933324:C:CC	acceptor_gain	1.0000
2:199935924:ATCTT:A	donor_loss	1.0000
2:199935925:TCTTA:T	donor_loss	1.0000
2:199935926:CTTA:C	donor_loss	1.0000
2:199935927:TTA:T	donor_loss	1.0000
2:199935928:TACCA:T	donor_loss	1.0000
2:199935929:A:AC	donor_gain	1.0000
2:199935929:ACCA:A	donor_loss	1.0000
2:199935930:C:CA	donor_loss	1.0000
2:199935930:C:CC	donor_gain	1.0000
2:199936048:CT:C	acceptor_loss	1.0000
2:199936049:T:C	acceptor_loss	1.0000
2:199938934:T:TA	donor_gain	1.0000
2:199938997:T:TA	donor_gain	1.0000
2:199939069:TC:T	acceptor_gain	1.0000
2:199939070:CC:C	acceptor_gain	1.0000
2:199939081:A:T	acceptor_gain	1.0000
2:199940145:C:CT	acceptor_gain	1.0000
2:199940146:A:T	acceptor_gain	1.0000
2:199948335:A:AC	donor_gain	1.0000
2:199948336:C:CC	donor_gain	1.0000
2:199933320:AAAG:A	acceptor_gain	0.9900
2:199933322:AG:A	acceptor_gain	0.9900
2:199933333:G:GC	acceptor_gain	0.9900
2:199933335:T:C	acceptor_gain	0.9900
2:199933335:T:TC	acceptor_gain	0.9900

AlphaMissense

2065 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:199933312:G:C	H235D	0.999
2:199938934:T:A	D162V	0.999
2:199938947:A:G	W158R	0.999
2:199938947:A:T	W158R	0.999
2:199948421:A:G	W44R	0.999
2:199948421:A:T	W44R	0.999
2:199933268:A:C	F249L	0.998
2:199933268:A:T	F249L	0.998
2:199933270:A:G	F249L	0.998
2:199933274:A:C	N247K	0.998
2:199933274:A:T	N247K	0.998
2:199933318:A:G	W233R	0.998
2:199933318:A:T	W233R	0.998
2:199938933:A:C	D162E	0.998
2:199938933:A:T	D162E	0.998
2:199938934:T:C	D162G	0.998
2:199938934:T:G	D162A	0.998
2:199938935:C:G	D162H	0.998
2:199936481:A:C	N166K	0.997
2:199936481:A:T	N166K	0.997
2:199936485:T:A	D165V	0.997
2:199938939:A:C	H160Q	0.997
2:199938939:A:T	H160Q	0.997
2:199938941:G:C	H160D	0.997
2:199948326:A:C	F75L	0.997
2:199948326:A:T	F75L	0.997
2:199948328:A:G	F75L	0.997
2:199948341:G:C	F70L	0.997
2:199948341:G:T	F70L	0.997
2:199948343:A:G	F70L	0.997

dbSNP variants (sampled 300 via entrez): RS1000082555 (2:199932759 C>A), RS1000215915 (2:199947063 C>A,T), RS1000237398 (2:199954769 G>A,C), RS1000334702 (2:199948415 C>T), RS1000346380 (2:199948955 A>C), RS1000400058 (2:199953802 T>C), RS1000437411 (2:199955066 G>T), RS1000442986 (2:199940555 G>A), RS1000553327 (2:199945322 C>T), RS1000653835 (2:199952595 T>C), RS1000771000 (2:199954091 C>T), RS1000794311 (2:199942522 A>C), RS1000951785 (2:199950440 C>T), RS1001059872 (2:199935208 C>G), RS1001137173 (2:199952333 T>C)

Disease associations

OMIM: gene MIM:619882 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST002149_16	Schizophrenia	1.000000e-08
GCST002806_2	Type 2 diabetes	9.000000e-07
GCST004031_2	QT interval (sulfonylurea treatment interaction)	3.000000e-07
GCST004521_125	Autism spectrum disorder or schizophrenia	3.000000e-12
GCST004946_83	Schizophrenia	2.000000e-16
GCST006803_6	Schizophrenia	4.000000e-17
GCST007561_69	Sleep duration	2.000000e-08
GCST009600_102	Anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, or Tourette syndrome (pleiotropy)	1.000000e-12

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004682	QT interval
EFO:0007922	response to sulfonylurea

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, increases expression	5
sodium arsenite	increases expression, decreases expression, affects cotreatment, increases abundance	3
Arsenic	affects methylation, affects cotreatment, increases abundance, increases expression	2
triphenyl phosphate	affects expression	1
salinomycin	decreases expression	1
butyraldehyde	decreases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
di-n-butylphosphoric acid	affects expression	1
cylindrospermopsin	increases expression	1
perfluoro-n-nonanoic acid	increases expression	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	affects cotreatment, decreases expression	1
Sunitinib	increases expression	1
Benzo(a)pyrene	decreases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Ivermectin	decreases expression	1
Manganese	affects cotreatment, increases abundance, increases expression	1
Methyl Methanesulfonate	increases expression	1
Testosterone	decreases expression	1
Tretinoin	increases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, decreases expression	1
Cyclosporine	increases expression	1
Lactic Acid	decreases expression	1

Clinical trials (associated diseases)

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