CTSZ

Summary

CTSZ (cathepsin Z, HGNC:2547) is a protein-coding gene on chromosome 20q13.32, encoding Cathepsin Z (Q9UBR2). Exhibits carboxy-monopeptidase as well as carboxy-dipeptidase activity.

The protein encoded by this gene is a lysosomal cysteine proteinase and member of the peptidase C1 family. It exhibits both carboxy-monopeptidase and carboxy-dipeptidase activities. The encoded protein has also been known as cathepsin X and cathepsin P. This gene is expressed ubiquitously in cancer cell lines and primary tumors and, like other members of this family, may be involved in tumorigenesis.

Source: NCBI Gene 1522 — RefSeq curated summary.

At a glance

• GWAS associations: 13
• Clinical variants (ClinVar): 60 total
• Druggable target: yes
• MANE Select transcript: NM_001336

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2547
Approved symbol	CTSZ
Name	cathepsin Z
Location	20q13.32
Locus type	gene with protein product
Status	Approved
Aliases	CTSX
Ensembl gene	ENSG00000101160
Ensembl biotype	protein_coding
OMIM	603169
Entrez	1522

Gene structure

Transcript identifiers

Ensembl transcripts: 33 — 14 protein_coding, 8 nonsense_mediated_decay, 7 retained_intron, 2 protein_coding_CDS_not_defined, 2 non_stop_decay

ENST00000217131, ENST00000472025, ENST00000488395, ENST00000503833, ENST00000679391, ENST00000679948, ENST00000679991, ENST00000680156, ENST00000680206, ENST00000680263, ENST00000680283, ENST00000680300, ENST00000680386, ENST00000680456, ENST00000680565, ENST00000680628, ENST00000680738, ENST00000680753, ENST00000680879, ENST00000680880, ENST00000680995, ENST00000681011, ENST00000681029, ENST00000681175, ENST00000681360, ENST00000681366, ENST00000681416, ENST00000681427, ENST00000681457, ENST00000681664, ENST00000681797, ENST00000681877, ENST00000889164

RefSeq mRNA: 1 — MANE Select: NM_001336 NM_001336

CCDS: CCDS13474

Canonical transcript exons

ENST00000217131 — 6 exons

Exon	Start	End
ENSE00000663003	58996639	58996801
ENSE00000845864	58995185	58995759
ENSE00001454208	59006986	59007254
ENSE00003546057	59001465	59001644
ENSE00003611751	58997603	58997753
ENSE00003673296	59006322	59006485

Expression profiles

Bgee: expression breadth ubiquitous, 254 present calls, max score 99.45.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 99.0506 / max 2883.0184, expressed in 1654 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
188201	80.6786	1614
188202	16.5105	1621
188203	0.8852	243
188200	0.7581	255
188198	0.1318	63
188199	0.0863	30

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	99.45	gold quality
granulocyte	CL:0000094	99.27	gold quality
mucosa of transverse colon	UBERON:0004991	99.21	gold quality
right coronary artery	UBERON:0001625	99.02	gold quality
ascending aorta	UBERON:0001496	98.95	gold quality
thoracic aorta	UBERON:0001515	98.95	gold quality
descending thoracic aorta	UBERON:0002345	98.91	gold quality
leukocyte	CL:0000738	98.90	gold quality
mononuclear cell	CL:0000842	98.87	gold quality
rectum	UBERON:0001052	98.84	gold quality
upper lobe of left lung	UBERON:0008952	98.73	gold quality
small intestine Peyer’s patch	UBERON:0003454	98.69	gold quality
right lobe of liver	UBERON:0001114	98.64	gold quality
right lung	UBERON:0002167	98.58	gold quality
left coronary artery	UBERON:0001626	98.53	gold quality
transverse colon	UBERON:0001157	98.51	gold quality
gall bladder	UBERON:0002110	98.38	gold quality
apex of heart	UBERON:0002098	98.35	gold quality
stromal cell of endometrium	CL:0002255	98.29	gold quality
omental fat pad	UBERON:0010414	98.05	gold quality
muscle layer of sigmoid colon	UBERON:0035805	98.05	gold quality
minor salivary gland	UBERON:0001830	98.01	gold quality
peritoneum	UBERON:0002358	98.00	gold quality
right atrium auricular region	UBERON:0006631	97.96	gold quality
aorta	UBERON:0000947	97.95	gold quality
right lobe of thyroid gland	UBERON:0001119	97.92	gold quality
left lobe of thyroid gland	UBERON:0001120	97.89	gold quality
lower esophagus muscularis layer	UBERON:0035833	97.88	gold quality
right adrenal gland cortex	UBERON:0035827	97.86	gold quality
lower esophagus	UBERON:0013473	97.85	gold quality

Single-cell (SCXA)

Detected in 19 experiment(s), a significant marker in 18.

Experiment	Marker?	Max mean expression
E-MTAB-6653	yes	1539.28
E-HCAD-15	yes	933.76
E-GEOD-139324	yes	782.10
E-HCAD-1	yes	90.25
E-MTAB-8142	yes	82.59
E-MTAB-6701	yes	78.37
E-CURD-122	yes	72.67
E-GEOD-135922	yes	52.92
E-MTAB-8410	yes	47.26
E-HCAD-6	yes	44.49
E-MTAB-10553	yes	33.54
E-MTAB-10287	yes	29.61
E-MTAB-9221	yes	29.00
E-CURD-88	yes	22.50
E-CURD-112	yes	21.03

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

19 targeting CTSZ, 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-3185	99.99	68.12	1959
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-7152-5P	99.60	69.33	2094
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-3609	99.52	69.89	2587
HSA-MIR-548AH-5P	99.52	69.73	2626
HSA-MIR-4316	99.37	65.75	1360
HSA-MIR-4667-3P	99.26	65.45	1608
HSA-MIR-664A-3P	99.22	71.08	2696
HSA-MIR-9986	98.91	69.28	1024
HSA-MIR-6852-3P	98.54	67.60	1468
HSA-MIR-4289	98.26	66.90	810
HSA-MIR-93-3P	98.15	66.65	1309
HSA-MIR-4469	97.93	65.81	1319
HSA-MIR-3664-3P	97.85	67.62	1452
HSA-MIR-6501-5P	97.41	68.24	712
HSA-MIR-6815-5P	96.05	65.55	662
HSA-MIR-6865-5P	96.05	65.58	675
HSA-MIR-10401-3P	91.66	66.01	97

Literature-anchored findings (GeneRIF, showing 26)

• These results show that cathepsin P, in contrast to other mammalian cathepsins, has a restricted catalytic specificity. (PMID:15680921)
• the extracellular function of cathepsin X may include binding to integrins thereby modulating the attachment of migrating cells to ECM components [Cathepsin X] (PMID:17065156)
• unlikely that CTSZ gene plays a major role in tuberculosis susceptibility in African populations (PMID:18420963)
• Cysteine proteases bleomycin hydrolase and cathepsin Z mediate N-terminal proteolysis and toxicity of mutant huntingtin. (PMID:21310951)
• associated with tuberculosis in a Ugandan household contact study (PMID:21354459)
• Polymorphisms in MC3R promoter and CTSZ 3’UTR are associated with tuberculosis susceptibility. (PMID:21368909)
• We show that sequential cleavage of C-terminal amino acids from the beta(2) cytoplasmic tail of LFA-1, by CatX, enhances binding of the adaptor protein talin to LFA-1 and triggers formation of the latter’s high-affinity form (PMID:21454358)
• cathepsin X deficiency leads to accelerated cellular senescence and consequently to diminished cellular proliferation and migration/invasion implying a potential role of cathepsin X in bypassing cellular senescence. (PMID:21616554)
• cathepsin Z contributes to tumor metastasis by inducing epithelial-mesenchymal transition in hepatocellular carcinoma (PMID:21966391)
• Cathepsins L and Z are critical in degrading polyglutamine-containing proteins within lysosomes. (PMID:22451661)
• Suggest CTSZ rs34069356 polymorphism is not associated with pulmonary tuberculosis in a sample Iranian population. (PMID:23827504)
• The significant association of cathepsin X with survival in a group of patients who received no chemotherapy and the absence of this association in the group who received chemotherapy, suggest the possible predictive value for response to chemotherapy. (PMID:24725597)
• Down-regulation of RPLP0 resulted in G1 arrest of gastric cancer cells, whereas knockdown of Cathepsin X led to G1 arrest and apoptosis (PMID:25433997)
• Cathepsin X (CTSX) is involved in early tumorigenesis and in the stabilization of tumor cell formation in colorectal cancer. (PMID:25442015)
• we evaluated the involvement of cathepsin B and X in the TGF-b1 signaling pathway, one of the key signaling mechanisms triggering epithelial-mesenchymal transition in cancer. In MCF-7 cells the expression of cathepsin B was shown to depend on their activation with TGF-b1 while, for cathepsin X, a TGF-b1 independent mechanism of induction during EMT is indicated. (PMID:28495172)
• CTSZ polymorphisms are associated with jaundice-stage progression in primary biliary cholangitis. (PMID:29795304)
• Deguelin inhibits the activation of CtsZ downstream FAK/Src/Paxillin signaling. (PMID:30018008)
• expression of cathepsin B and X was detected in stromal cells and cancer cells throughout the glioblastoma (GBM) sections, whereas cathepsin K expression was more restricted to arteriole-rich regions in the GBM sections. Metabolic mapping showed that cathepsin B, but not cathepsin K is active in GSC niches. (PMID:30046941)
• results indicate that altered expression and localization of cathepsin Z in hepatocytes are characteristic features of primary biliary cholangitis (PBC) and other cholestatic liver diseases, and are implicated in the progression of PBC. (PMID:30087368)
• our present study revealed that KMT2A epigenetically promotes cancer progression by targeting CTSZ, which has specific functions in cancer invasion and metastasis. (PMID:31090199)
• Decreased levels of cathepsin Z mRNA expressed by immune blood cells: diagnostic and prognostic implications in prostate cancer. (PMID:34378678)
• Upregulation of Cathepsin X in Glioblastoma: Interplay with gamma-Enolase and the Effects of Selective Cathepsin X Inhibitors. (PMID:35163706)
• Granulomatous rosacea in Chinese patients: Clinical-histopathological analysis and pathogenesis exploration. (PMID:37020415)
• Defective cathepsin Z affects EGFR expression and causes autosomal dominant palmoplantar keratoderma. (PMID:37210216)
• Blood DNA methylation profiling identifies cathepsin Z dysregulation in pulmonary arterial hypertension. (PMID:38184627)
• PDCD4 interacting with PIK3CB and CTSZ promotes the apoptosis of multiple myeloma cells. (PMID:39190024)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ctsz	ENSDARG00000043081
mus_musculus	Ctsz	ENSMUSG00000016256
rattus_norvegicus	Ctsz	ENSRNOG00000050697
caenorhabditis_elegans		WBGENE00000789

Paralogs (12): CTSH (ENSG00000103811), CTSC (ENSG00000109861), CTSL (ENSG00000135047), CTSV (ENSG00000136943), TINAG (ENSG00000137251), TINAGL1 (ENSG00000142910), CTSK (ENSG00000143387), CTSS (ENSG00000163131), CTSB (ENSG00000164733), CTSW (ENSG00000172543), CTSF (ENSG00000174080), CTSO (ENSG00000256043)

Protein

Protein identifiers

Cathepsin Z — Q9UBR2 (reviewed: Q9UBR2)

Alternative names: Cathepsin P, Cathepsin X

All UniProt accessions (22): Q9UBR2, A0A7P0T8I6, A0A7P0T8X2, A0A7P0T900, A0A7P0T926, A0A7P0T989, A0A7P0T9G9, A0A7P0T9U1, A0A7P0T9U4, A0A7P0T9X4, A0A7P0TA25, A0A7P0TAD4, A0A7P0TAT6, A0A7P0TB41, A0A7P0TBB5, A0A7P0TBM7, A0A7P0Z469, A0A7P0Z4A7, A0A7P0Z4L1, A0A7P0Z4L7, A0A7P0Z4Q4, A0A7P0Z4R9

UniProt curated annotations — full annotation on UniProt →

Function. Exhibits carboxy-monopeptidase as well as carboxy-dipeptidase activity. Capable of producing kinin potentiating peptides.

Subcellular location. Lysosome.

Tissue specificity. Widely expressed.

Activity regulation. The disulfide bridge formed between Cys-33 in the propeptide and the active site residue Cys-92 may prevent activation of the zymogen through formation of a reversible covalent bond with the active site residue.

Similarity. Belongs to the peptidase C1 family.

RefSeq proteins (1): NP_001327* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000668	Peptidase_C1A_C	Domain
IPR013128	Peptidase_C1A	Family
IPR025661	Pept_asp_AS	Active_site
IPR033157	CTSZ	Family
IPR038765	Papain-like_cys_pep_sf	Homologous_superfamily

Pfam: PF00112

Enzyme classification (BRENDA):

• EC 3.4.18.1 — cathepsin X (BRENDA: 10 organisms, 136 substrates, 40 inhibitors, 13 Km, 12 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
(2,4-DINITROPHENYL)-GFFGW	0.0018	1
(2,4-DINITROPHENYL)-GFFRW	0.0036	1
(2,4-DINITROPHENYL)-GFFW	0.001	1
(2,4-DINITROPHENYL)-GFRFW	0.0024	1
(2,4-DINITROPHENYL)-GFRW	0.0042	1
(2,4-DINITROPHENYL)-GRFFW	0.0046	1
CBZ-FR-7-AMIDO-4-METHYLCOUMARIN	0.063	1
CBZ-RR-7-AMIDO-4-METHYLCOUMARIN	0.13	1
GLUCAGON	0.5	1
HIPPURYL-L-ARG	0.69	1
ORTHO-AMINOBENZOYL-ARG-ARG-(2,3-DIAMINOPROPIONYL	0.0083	1
ORTHO-AMINOBENZOYL-LYS-ARG-(2,3-DIAMINOPROPIONYL	0.0105	1
ORTHO-AMINOBENZOYL-PHE-ARG-(2,3-DIAMINOPROPIONYL	0.0037	1
2-AMINOBENZOYL-ARG-ARG-(2,3-DIAMINOPROPIONYL)-(2	—	0
2-AMINOBENZOYL-LEU-ARG-(2,3-DIAMINOPROPIONYL)-(2	—	0

UniProt features (45 total): strand 14, helix 10, disulfide bond 6, sequence variant 3, active site 3, sequence conflict 2, turn 2, glycosylation site 2, signal peptide 1, propeptide 1, chain 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
1DEU	X-RAY DIFFRACTION	1.7
1EF7	X-RAY DIFFRACTION	2.67

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UBR2-F1	92.35	0.86

Functional residue map

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

Catalytic / active sites (3): 92; 241; 261

Disulfide bonds (6): 126–164, 154–170, 173–179, 214–296, 33–92, 89–132

Glycosylation sites (2): 184, 224

Function

Pathways and Gene Ontology

Reactome pathways

16 pathways

ID	Pathway
R-HSA-2022377	Metabolism of Angiotensinogen to Angiotensins
R-HSA-204005	COPII-mediated vesicle transport
R-HSA-432720	Lysosome Vesicle Biogenesis
R-HSA-5694530	Cargo concentration in the ER
R-HSA-6798695	Neutrophil degranulation
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-199977	ER to Golgi Anterograde Transport
R-HSA-199991	Membrane Trafficking
R-HSA-199992	trans-Golgi Network Vesicle Budding
R-HSA-2980736	Peptide hormone metabolism
R-HSA-392499	Metabolism of proteins
R-HSA-446203	Asparagine N-linked glycosylation
R-HSA-5653656	Vesicle-mediated transport
R-HSA-597592	Post-translational protein modification
R-HSA-948021	Transport to the Golgi and subsequent modification

MSigDB gene sets: 256 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_PROTEOLYSIS, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_SYSTEMIC_ARTERIAL_BLOOD_PRESSURE_BY_CIRCULATORY_RENIN_ANGIOTENSIN, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_CIRCULATORY_SYSTEM_PROCESS, MODULE_255, GOCC_SECRETORY_GRANULE, GOBP_EPITHELIAL_TUBE_BRANCHING_INVOLVED_IN_LUNG_MORPHOGENESIS, STEARMAN_LUNG_CANCER_EARLY_VS_LATE_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_REGULATION_OF_SYSTEMIC_ARTERIAL_BLOOD_PRESSURE, GOBP_LUNG_MORPHOGENESIS, MODULE_317

GO Biological Process (5): angiotensin maturation (GO:0002003), proteolysis (GO:0006508), negative regulation of plasminogen activation (GO:0010757), obsolete proteolysis involved in protein catabolic process (GO:0051603), epithelial tube branching involved in lung morphogenesis (GO:0060441)

GO Molecular Function (7): carboxypeptidase activity (GO:0004180), cysteine-type endopeptidase activity (GO:0004197), cysteine-type peptidase activity (GO:0008234), cysteine-type carboxypeptidase activity (GO:0016807), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787)

GO Cellular Component (16): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), lysosome (GO:0005764), endoplasmic reticulum (GO:0005783), endoplasmic reticulum lumen (GO:0005788), plasma membrane (GO:0005886), cell cortex (GO:0005938), cell surface (GO:0009986), COPII-coated ER to Golgi transport vesicle (GO:0030134), growth cone (GO:0030426), extracellular matrix (GO:0031012), cytoplasmic vesicle (GO:0031410), endoplasmic reticulum-Golgi intermediate compartment membrane (GO:0033116), specific granule lumen (GO:0035580), extracellular exosome (GO:0070062), ficolin-1-rich granule lumen (GO:1904813)

Reactome top-level categories

Rollup of top-11 pathways:

Category	Pathways
ER to Golgi Anterograde Transport	2
Membrane Trafficking	2
Metabolism of proteins	2
Peptide hormone metabolism	1
trans-Golgi Network Vesicle Budding	1
Innate Immune System	1
Immune System	1
Transport to the Golgi and subsequent modification	1
Vesicle-mediated transport	1
Post-translational protein modification	1
Asparagine N-linked glycosylation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	3
cellular anatomical structure	2
intracellular organelle lumen	2
cell periphery	2
regulation of angiotensin levels in blood	1
peptide hormone processing	1
protein metabolic process	1
regulation of plasminogen activation	1
negative regulation of protein processing	1
plasminogen activation	1
branching morphogenesis of an epithelial tube	1
lung morphogenesis	1
exopeptidase activity	1
endopeptidase activity	1
cysteine-type peptidase activity	1
peptidase activity	1
carboxypeptidase activity	1
cysteine-type exopeptidase activity	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
lytic vacuole	1
endomembrane system	1
intracellular membrane-bounded organelle	1
endoplasmic reticulum	1
membrane	1
coated vesicle	1
site of polarized growth	1
distal axon	1
external encapsulating structure	1
intracellular vesicle	1
endoplasmic reticulum-Golgi intermediate compartment	1
bounding membrane of organelle	1
secretory granule lumen	1
specific granule	1
extracellular vesicle	1
ficolin-1-rich granule	1

Protein interactions and networks

STRING

2403 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CTSZ	MC3R	P41968	850
CTSZ	ATP5F1E	P56381	822
CTSZ	TUBB1	Q9H4B7	742
CTSZ	CTSD	P07339	701
CTSZ	LMAN1	P49257	653
CTSZ	LGMN	Q99538	627
CTSZ	TUBB	P05218	597
CTSZ	GNAS	Q5JWF2	590
CTSZ	CTSF	Q9UBX1	581
CTSZ	CTSG	P08311	574
CTSZ	LAMP2	P13473	547
CTSZ	CTSA	P10619	535
CTSZ	NELFCD	Q8IXH7	521
CTSZ	MMP8	P22894	520
CTSZ	CTSE	P14091	510

IntAct

82 interactions, top by confidence:

A	B	Type	Score
KRTAP5-9	CTSZ	psi-mi:“MI:0915”(physical association)	0.830
CTSZ	KRTAP5-9	psi-mi:“MI:0915”(physical association)	0.830
MID2	CTSZ	psi-mi:“MI:0915”(physical association)	0.720
CTSZ	MID2	psi-mi:“MI:0915”(physical association)	0.720
NOTCH2NLA	CTSZ	psi-mi:“MI:0915”(physical association)	0.670
CTSZ	NOTCH2NLA	psi-mi:“MI:0915”(physical association)	0.670
PLSCR1	CTSZ	psi-mi:“MI:0915”(physical association)	0.560
CTSZ	MTUS2	psi-mi:“MI:0915”(physical association)	0.560
KRT40	CTSZ	psi-mi:“MI:0915”(physical association)	0.560
MTUS2	CTSZ	psi-mi:“MI:0915”(physical association)	0.560
CTSZ	KRT40	psi-mi:“MI:0915”(physical association)	0.560
CTSZ	PLSCR1	psi-mi:“MI:0915”(physical association)	0.560
FHL5	CTSZ	psi-mi:“MI:0915”(physical association)	0.560
TNS2	CTSZ	psi-mi:“MI:0915”(physical association)	0.560
KRT35	CTSZ	psi-mi:“MI:0915”(physical association)	0.560
BACH2	CTSZ	psi-mi:“MI:0915”(physical association)	0.560
KRTAP2-4	CTSZ	psi-mi:“MI:0915”(physical association)	0.560
KRTAP10-10	CTSZ	psi-mi:“MI:0915”(physical association)	0.560
KRTAP6-3	CTSZ	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (63): KRTAP5-9 (Two-hybrid), PLSCR1 (Two-hybrid), MID2 (Two-hybrid), MTUS2 (Two-hybrid), KRT40 (Two-hybrid), NOTCH2NL (Two-hybrid), KRTAP5-9 (Two-hybrid), CTSZ (Affinity Capture-MS), CTSZ (Affinity Capture-MS), CTSZ (Affinity Capture-MS), CTSZ (Affinity Capture-MS), CTSZ (Affinity Capture-MS), CTSZ (Affinity Capture-MS), CTSZ (Affinity Capture-MS), CTSZ (Affinity Capture-MS)

ESM2 similar proteins: A0A072UTP9, A1E295, G5EGP8, O45734, O65039, O70370, P00787, P04988, P05689, P07688, P07711, P07858, P10605, P19092, P25326, P25773, P25774, P25792, P25793, P25802, P25804, P25807, P43157, P43233, P43296, P43507, P43508, P43509, P43510, P83205, P90850, Q02765, Q26534, Q3SZI1, Q4R5M2, Q5E998, Q5R6D1, Q63088, Q6PN98, Q8HY81

Diamond homologs: A0A068CNX1, A0A072UTP9, A0A0F7G352, A0A1S4F2V5, A1E295, A5HII1, B2LSD2, F4HVZ1, O45734, O70370, O97578, P00784, P00786, P00787, P05167, P05993, P07688, P07711, P07858, P0DO76, P10056, P10605, P12412, P13277, P14658, P15242, P19092, P25249, P25250, P25251, P25326, P25774, P25778, P25782, P25784, P25792, P25793, P25802, P25803, P25807

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 39 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Keratinization	8	26.2×	1e-08

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	44
Likely benign	4
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

3737 predictions. Top by Δscore:

Variant	Effect	Δscore
20:58986081:A:AG	acceptor_gain	1.0000
20:58986082:T:G	acceptor_gain	1.0000
20:58986085:A:AG	acceptor_gain	1.0000
20:58986087:CAACA:C	acceptor_loss	1.0000
20:58986088:AACAG:A	acceptor_loss	1.0000
20:58986089:ACAGC:A	acceptor_loss	1.0000
20:58986091:A:AG	acceptor_gain	1.0000
20:58986091:AG:A	acceptor_loss	1.0000
20:58986092:G:GT	acceptor_gain	1.0000
20:58986204:AAGAG:A	donor_gain	1.0000
20:58986205:AGAG:A	donor_gain	1.0000
20:58986206:GAG:G	donor_gain	1.0000
20:58986206:GAGG:G	donor_gain	1.0000
20:58986209:GTAT:G	donor_gain	1.0000
20:58987705:CAG:C	acceptor_loss	1.0000
20:58987706:A:AG	acceptor_gain	1.0000
20:58987706:A:G	acceptor_loss	1.0000
20:58987706:AG:A	acceptor_gain	1.0000
20:58987707:G:GG	acceptor_gain	1.0000
20:58987707:GG:G	acceptor_gain	1.0000
20:58987707:GGT:G	acceptor_gain	1.0000
20:58987707:GGTGT:G	acceptor_gain	1.0000
20:58987814:A:T	donor_gain	1.0000
20:58987814:AGAGG:A	donor_loss	1.0000
20:58987815:GAG:G	donor_gain	1.0000
20:58987816:AGGT:A	donor_loss	1.0000
20:58987817:GGT:G	donor_loss	1.0000
20:58987818:G:GG	donor_gain	1.0000
20:58987818:GTG:G	donor_loss	1.0000
20:58987819:T:G	donor_loss	1.0000

AlphaMissense

1981 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:59001641:C:G	R104P	0.998
20:59006350:C:A	W93C	0.998
20:59006350:C:G	W93C	0.998
20:58996661:C:G	R260P	0.997
20:59001557:C:G	C132S	0.997
20:59001558:A:T	C132S	0.997
20:59001589:C:A	Q121H	0.997
20:59001589:C:G	Q121H	0.997
20:59006363:C:G	C89S	0.997
20:59006363:C:T	C89Y	0.997
20:59006364:A:T	C89S	0.997
20:58996798:A:C	C214W	0.996
20:59001491:C:T	C154Y	0.996
20:59001557:C:T	C132Y	0.996
20:59001575:C:G	C126S	0.996
20:59001576:A:T	C126S	0.996
20:59001596:G:A	S119F	0.996
20:59006362:G:C	C89W	0.996
20:58996671:A:G	W257R	0.995
20:58996671:A:T	W257R	0.995
20:58996799:C:T	C214Y	0.995
20:58997732:C:G	C170S	0.995
20:58997733:A:T	C170S	0.995
20:59001521:G:T	A144D	0.995
20:59006325:C:G	A102P	0.995
20:59006338:G:C	S97R	0.995
20:59006338:G:T	S97R	0.995
20:59006340:T:G	S97R	0.995
20:59006354:C:T	C92Y	0.995
20:59006363:C:A	C89F	0.995

dbSNP variants (sampled 300 via entrez): RS1000409839 (20:59008246 G>A), RS1000441604 (20:58997479 G>C), RS1000506139 (20:59001329 C>G,T), RS1000510762 (20:58997326 C>T), RS1000664531 (20:59006499 A>T), RS1000862327 (20:59008566 C>A,G), RS1001148655 (20:59006944 G>A), RS1001172751 (20:59003782 G>T), RS1001267725 (20:59003509 C>T), RS1001339264 (20:59008704 G>A,C,T), RS1001809992 (20:59008908 T>C), RS1002383272 (20:58998642 G>C), RS1002411176 (20:59007681 G>T), RS1002513162 (20:58995833 C>T), RS1002849468 (20:59004894 C>T)

Disease associations

OMIM: gene MIM:603169 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST001335_4	Mean platelet volume	1.000000e-09
GCST001725_67	Inflammatory bowel disease	1.000000e-12
GCST002184_7	Mean platelet volume	7.000000e-06
GCST004599_215	Mean platelet volume	4.000000e-34
GCST004616_156	Platelet distribution width	1.000000e-63
GCST004616_157	Platelet distribution width	2.000000e-24
GCST006585_1670	Blood protein levels	8.000000e-60
GCST012489_61	Heel bone mineral density x serum urate levels interaction	3.000000e-12
GCST90002383_306	Hematocrit	4.000000e-10
GCST90002388_585	Lymphocyte count	5.000000e-09
GCST90002395_606	Mean platelet volume	3.000000e-16
GCST90002401_327	Platelet distribution width	2.000000e-10
GCST90002402_597	Platelet count	2.000000e-12

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0007984	platelet component distribution width
EFO:0004531	urate measurement
EFO:0009270	heel bone mineral density
EFO:0004348	hematocrit
EFO:0004587	lymphocyte count
EFO:0004309	platelet count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4160 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — C1: Papain

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
odanacatib	Inhibition	8.0	pIC50

ChEMBL bioactivities

9 potent at pChembl≥5 of 14 total, top 9 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.50	IC50	316.2	nM	CHEMBL567134
6.03	IC50	933.2	nM	CHEMBL567341
5.50	IC50	3162	nM	CHEMBL568171
5.19	IC50	6457	nM	CHEMBL567785
5.15	IC50	7130	nM	CHEMBL4754916
5.06	Kd	8669	nM	CHEMBL5653589
5.06	ED50	8669	nM	CHEMBL5653589
5.02	IC50	9540	nM	CHEMBL4743093
5.00	IC50	1e+04	nM	GRASSYSTATIN A

PubChem BioAssay actives

8 with measured affinity, of 64 total; 8 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
9-(3,5-difluorophenyl)-6-(ethylamino)purine-2-carbonitrile	444711: Inhibition of human Cathepsin X/Z	ic50	0.3162	uM
6-(3,5-difluoroanilino)-9-ethylpurine-2-carbonitrile	444711: Inhibition of human Cathepsin X/Z	ic50	0.9333	uM
4-(cyclopentylamino)-6-(3,5-difluoroanilino)-1,3,5-triazine-2-carbonitrile	444711: Inhibition of human Cathepsin X/Z	ic50	3.1623	uM
4-(3-chloroanilino)-6-(cyclopentylamino)-1,3,5-triazine-2-carbonitrile	444711: Inhibition of human Cathepsin X/Z	ic50	6.4565	uM
2-[2-[2-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-oxoethyl]sulfanylimidazol-1-yl]acetonitrile	1691510: Inhibition of human cathepsin X expressed in Pichia pastoris assessed as residual activity using Abz-FEK(Dnp)-OH as substrate incubated for 30 to 45 mins by fluorescence assay	ic50	7.1300	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148178: Binding affinity to human CTSZ incubated for 45 mins by Kinobead based pull down assay	kd	8.6689	uM
1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(1-methylimidazol-2-yl)sulfanylethanone	1691510: Inhibition of human cathepsin X expressed in Pichia pastoris assessed as residual activity using Abz-FEK(Dnp)-OH as substrate incubated for 30 to 45 mins by fluorescence assay	ic50	9.5400	uM
methyl (2S)-1-[(2R)-2-[[(2S)-2-[[(2S,3R)-2-[[(3S,4S)-4-[[(2S)-4-amino-2-[[(2S)-2-[[(2R)-2-[(2S)-2-[(2S)-2-(dimethylamino)-3-methylbutanoyl]oxy-3-methylbutanoyl]oxy-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoyl]amino]-3-hydroxy-6-methylheptanoyl]amino]-3-hydroxybutanoyl]amino]propanoyl]-methylamino]-3-phenylpropanoyl]pyrrolidine-2-carboxylate	448880: Inhibition of cathepsin Z after 10 to 15 mins by fluorescence assay	ic50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, increases expression, increases methylation, affects expression	4
trichostatin A	affects cotreatment, increases expression	3
sodium arsenite	increases expression, decreases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	2
Decitabine	affects cotreatment, affects expression	2
Smoke	decreases expression	2
28-O-acetylbetulin-3-ylglucopyranoside	affects localization	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
kojic acid	increases expression	1
sodium bichromate	decreases expression	1
ICG 001	increases expression	1
bisphenol B	increases expression	1
dorsomorphin	increases expression, affects cotreatment	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	increases expression	1
bisphenol AF	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Sunitinib	decreases expression	1
Vorinostat	affects cotreatment, affects expression	1
Benzo(a)pyrene	increases methylation	1
Benzoates	increases expression	1
Chelating Agents	affects binding, decreases expression	1
Copper	affects binding, decreases expression	1
Diazinon	increases methylation	1
Doxorubicin	increases expression	1
Estradiol	increases expression, affects cotreatment	1
Formaldehyde	increases expression	1
Hydrogen Peroxide	affects expression	1
Ivermectin	increases expression	1
Nickel	increases expression	1

ChEMBL screening assays

16 unique, capped per target: 16 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1039251	Binding	Inhibition of cathepsin Z after 10 to 15 mins by fluorescence assay	Grassystatins A-C from marine cyanobacteria, potent cathepsin E inhibitors that reduce antigen presentation. — J Med Chem

Clinical trials (associated diseases)

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