CTSH

Summary

CTSH (cathepsin H, HGNC:2535) is a protein-coding gene on chromosome 15q25.1, encoding Pro-cathepsin H (P09668). Important for the overall degradation of proteins in lysosomes.

The protein encoded by this gene is a lysosomal cysteine proteinase important in the overall degradation of lysosomal proteins. It is composed of a dimer of disulfide-linked heavy and light chains, both produced from a single protein precursor. The encoded protein, which belongs to the peptidase C1 protein family, can act both as an aminopeptidase and as an endopeptidase. Increased expression of this gene has been correlated with malignant progression of prostate tumors. Alternate splicing of this gene results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 1512 — RefSeq curated summary.

At a glance

• GWAS associations: 15
• Clinical variants (ClinVar): 77 total
• GTEx eGene: eQTL in 46 tissues, sQTL in 41 (q < 0.05)
• Phenotypes (HPO): 30
• ChEMBL bioactivity: 1 clinical-phase molecule tested; no curated mechanism-of-action drug
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.27 (unconstrained)
• MANE Select transcript: NM_004390
• Notable: 77 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2535
Approved symbol	CTSH
Name	cathepsin H
Location	15q25.1
Locus type	gene with protein product
Status	Approved
Aliases	ACC-4, ACC-5, ACC4, ACC5
Ensembl gene	ENSG00000103811
Ensembl biotype	protein_coding
OMIM	116820
Entrez	1512

Gene structure

Transcript identifiers

Ensembl transcripts: 105 — 53 nonsense_mediated_decay, 28 retained_intron, 21 protein_coding, 2 protein_coding_CDS_not_defined, 1 non_stop_decay

MANE Select: ENST00000220166

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 4, TSL 2: 1, TSL 3: 5, TSL 4: 4, TSL 5: 4

ENST00000220166, ENST00000525807, ENST00000527138, ENST00000527715, ENST00000528191, ENST00000528436, ENST00000528741, ENST00000529263, ENST00000529612, ENST00000529861, ENST00000530010, ENST00000530929, ENST00000533777, ENST00000534038, ENST00000534237, ENST00000534268, ENST00000534533, ENST00000615999, ENST00000649928, ENST00000676486, ENST00000676510, ENST00000676588, ENST00000676596, ENST00000676639, ENST00000676668, ENST00000676671, ENST00000676738, ENST00000676763, ENST00000676808, ENST00000676850, ENST00000676865, ENST00000676880, ENST00000677011, ENST00000677049, ENST00000677102, ENST00000677207, ENST00000677238, ENST00000677254, ENST00000677316, ENST00000677320, ENST00000677367, ENST00000677448, ENST00000677534, ENST00000677789, ENST00000677810, ENST00000677874, ENST00000677921, ENST00000677936, ENST00000678031, ENST00000678033, ENST00000678114, ENST00000678281, ENST00000678283, ENST00000678397, ENST00000678415, ENST00000678487, ENST00000678644, ENST00000678727, ENST00000678799, ENST00000678817, ENST00000678841, ENST00000678886, ENST00000678940, ENST00000679017, ENST00000679047, ENST00000679125, ENST00000679172, ENST00000679211, ENST00000679334, ENST00000906226, ENST00000906227, ENST00000906228, ENST00000906229, ENST00000969896, ENST00000969897, ENST00000980396, ENST00000980397, ENST00000980398, ENST00000980400, ENST00000980401, ENST00000980402, ENST00000980403, ENST00001032359, ENST00001032360, ENST00001032361, ENST00001032363, ENST00001032364, ENST00001032365, ENST00001032366, ENST00001032367, ENST00001032369, ENST00001032370, ENST00001032371, ENST00001032373, ENST00001032374, ENST00001032375, ENST00001032376, ENST00001032377, ENST00001121542, ENST00001121543, ENST00001127403, ENST00001127404, ENST00001127405, ENST00001127406, ENST00001136626

RefSeq mRNA: 3 — MANE Select: NM_004390 NM_001319137, NM_001411095, NM_004390

CCDS: CCDS10308, CCDS92047

Canonical transcript exons

ENST00000220166 — 12 exons

Exon	Start	End
ENSE00001866662	78921058	78922205
ENSE00003471593	78922993	78923118
ENSE00003492490	78925334	78925440
ENSE00003537664	78927713	78927781
ENSE00003567421	78934978	78935082
ENSE00003638633	78931451	78931506
ENSE00003649291	78939140	78939171
ENSE00003673862	78935680	78935750
ENSE00003683025	78937318	78937423
ENSE00003690225	78932372	78932458
ENSE00003787933	78929412	78929493
ENSE00003904144	78944891	78945046

Expression profiles

Bgee: expression breadth ubiquitous, 290 present calls, max score 99.83.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 81.4082 / max 1418.7102, expressed in 1601 samples.

Highest expression (Bgee): cranial nerve II, nephron tubule, lower lobe of lung, bronchial epithelial cell, adult mammalian kidney.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CTSH is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 46 tissues and its splicing (sQTL) in 41 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 87 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Adipose Subcutaneous	eqtl	6.6e-58	+0.90	15:78937302:A:G
Cells Cultured fibroblasts	eqtl	7.8e-50	+0.57	15:78953549:G:A
Whole Blood	eqtl	1.1e-47	-0.60	15:78942615:G:A
Artery Tibial	eqtl	5.9e-46	-0.56	15:78944951:C:T
Thyroid	eqtl	1.6e-45	-0.90	15:78944951:C:T
Nerve Tibial	eqtl	1.1e-41	+0.74	15:78937302:A:G
Breast Mammary Tissue	eqtl	6.2e-40	+0.87	15:78936890:A:G
Esophagus Muscularis	eqtl	6.4e-40	+0.89	15:78938395:G:T
Cells EBV-transformed lymphocytes	eqtl	1.4e-38	+0.69	15:78939274:A:G
Adipose Visceral Omentum	eqtl	2.1e-38	-0.98	15:78944951:C:T
Artery Aorta	eqtl	5.8e-36	-0.82	15:78944951:C:T
Heart Atrial Appendage	eqtl	6.1e-36	-1.10	15:78944951:C:T
Muscle Skeletal	eqtl	5.1e-32	-0.75	15:78942128:T:C
Lung	eqtl	7.1e-30	-0.38	15:78942128:T:C
Skin Sun Exposed Lower leg	eqtl	5.4e-29	+0.54	15:78938704:G:T
Cells EBV-transformed lymphocytes	sqtl	7.3e-29	-0.92	15:78953549:G:A
Skin Sun Exposed Lower leg	sqtl	1.4e-28	+0.88	15:78935915:A:G
Adipose Subcutaneous	sqtl	7.2e-27	-0.86	15:78937617:TGGCCAGAATG:T
Pancreas	eqtl	5.6e-26	-0.80	15:78944951:C:T
Stomach	eqtl	6.4e-26	-0.52	15:78944951:C:T

FANTOM5 promoters

5 alternative TSS:

Promoter ID	TPM avg	Samples expressed
151138	77.9099	1581
151139	2.2465	1012
151136	0.7303	189
151137	0.3743	208
151135	0.1472	83

Top tissues by expression

showing 100 of 296 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
cranial nerve II	UBERON:0000941	99.83	gold quality
nephron tubule	UBERON:0001231	99.45	gold quality
lower lobe of lung	UBERON:0008949	99.32	gold quality
bronchial epithelial cell	CL:0002328	99.19	gold quality
adult mammalian kidney	UBERON:0000082	99.15	gold quality
renal medulla	UBERON:0000362	99.05	gold quality
visceral pleura	UBERON:0002401	99.05	gold quality
epithelium of bronchus	UBERON:0002031	99.03	gold quality
monocyte	CL:0000576	98.95	gold quality
bronchus	UBERON:0002185	98.94	gold quality
mononuclear cell	CL:0000842	98.88	gold quality
lymph node	UBERON:0000029	98.84	gold quality
leukocyte	CL:0000738	98.83	gold quality
upper lobe of lung	UBERON:0008948	98.77	gold quality
adult organism	UBERON:0007023	98.72	gold quality
upper lobe of left lung	UBERON:0008952	98.72	gold quality
gall bladder	UBERON:0002110	98.71	gold quality
parotid gland	UBERON:0001831	98.51	gold quality
lung	UBERON:0002048	98.50	gold quality
kidney epithelium	UBERON:0004819	98.46	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	98.45	gold quality
nasal cavity epithelium	UBERON:0005384	98.41	gold quality
upper leg skin	UBERON:0004262	98.39	gold quality
vermiform appendix	UBERON:0001154	98.29	gold quality
endocervix	UBERON:0000458	98.21	gold quality
right lung	UBERON:0002167	98.07	gold quality
granulocyte	CL:0000094	97.98	gold quality
metanephros cortex	UBERON:0010533	97.94	gold quality
kidney	UBERON:0002113	97.89	gold quality
caecum	UBERON:0001153	97.69	gold quality
nasal cavity mucosa	UBERON:0001826	97.69	gold quality
pancreatic ductal cell	CL:0002079	97.68	gold quality
mucosa of urinary bladder	UBERON:0001259	97.56	gold quality
renal glomerulus	UBERON:0000074	97.54	gold quality
duodenum	UBERON:0002114	97.52	gold quality
pylorus	UBERON:0001166	97.35	gold quality
upper arm skin	UBERON:0004263	97.22	gold quality
metanephric glomerulus	UBERON:0004736	97.12	gold quality
jejunal mucosa	UBERON:0000399	97.05	gold quality
ileal mucosa	UBERON:0000331	97.03	gold quality
ectocervix	UBERON:0012249	97.01	gold quality
spleen	UBERON:0002106	96.96	gold quality
prostate gland	UBERON:0002367	96.96	gold quality
cortex of kidney	UBERON:0001225	96.87	gold quality
body of stomach	UBERON:0001161	96.77	gold quality
seminal vesicle	UBERON:0000998	96.76	gold quality
small intestine Peyer’s patch	UBERON:0003454	96.75	gold quality
pleura	UBERON:0000977	96.62	gold quality
vena cava	UBERON:0004087	96.61	gold quality
urinary bladder	UBERON:0001255	96.60	gold quality
tonsil	UBERON:0002372	96.43	gold quality
blood	UBERON:0000178	96.39	gold quality
small intestine	UBERON:0002108	96.38	gold quality
skin of leg	UBERON:0001511	96.36	gold quality
pigmented layer of retina	UBERON:0001782	96.27	gold quality
retina	UBERON:0000966	96.24	gold quality
uterine cervix	UBERON:0000002	96.23	gold quality
right uterine tube	UBERON:0001302	96.19	gold quality
right ovary	UBERON:0002118	96.19	gold quality
right lobe of liver	UBERON:0001114	96.15	gold quality
stomach	UBERON:0000945	96.14	gold quality
left ovary	UBERON:0002119	96.07	gold quality
epithelial cell of pancreas	CL:0000083	96.06	gold quality
saliva-secreting gland	UBERON:0001044	96.05	gold quality
peritoneum	UBERON:0002358	96.03	gold quality
omental fat pad	UBERON:0010414	96.03	gold quality
cervix squamous epithelium	UBERON:0006922	96.02	gold quality
urethra	UBERON:0000057	95.96	gold quality
mammalian vulva	UBERON:0000997	95.87	gold quality
vagina	UBERON:0000996	95.86	gold quality
periodontal ligament	UBERON:0008266	95.81	gold quality
zone of skin	UBERON:0000014	95.78	gold quality
trachea	UBERON:0003126	95.77	gold quality
adipose tissue of abdominal region	UBERON:0007808	95.69	gold quality
superficial temporal artery	UBERON:0001614	95.66	gold quality
right adrenal gland cortex	UBERON:0035827	95.61	gold quality
minor salivary gland	UBERON:0001830	95.59	gold quality
decidua	UBERON:0002450	95.58	gold quality
skin of hip	UBERON:0001554	95.52	gold quality
body of pancreas	UBERON:0001150	95.51	gold quality
skin of abdomen	UBERON:0001416	95.49	gold quality
penis	UBERON:0000989	95.48	gold quality
epithelium of nasopharynx	UBERON:0001951	95.38	gold quality
cervix epithelium	UBERON:0004801	95.38	gold quality
nasopharynx	UBERON:0001728	95.36	gold quality
parietal pleura	UBERON:0002400	95.24	gold quality
cardia of stomach	UBERON:0001162	95.23	gold quality
body of uterus	UBERON:0009853	95.23	gold quality
left adrenal gland	UBERON:0001234	95.19	gold quality
mammary duct	UBERON:0001765	95.15	gold quality
apex of heart	UBERON:0002098	95.09	gold quality
left adrenal gland cortex	UBERON:0035825	95.09	gold quality
metanephros	UBERON:0000081	95.02	gold quality
pancreas	UBERON:0001264	95.02	gold quality
adrenal cortex	UBERON:0001235	95.00	gold quality
right adrenal gland	UBERON:0001233	94.96	gold quality
epithelium of mammary gland	UBERON:0003244	94.90	gold quality
bone marrow cell	CL:0002092	94.85	gold quality
fundus of stomach	UBERON:0001160	94.82	gold quality
liver	UBERON:0002107	94.82	gold quality

Single-cell (SCXA)

Detected in 27 experiment(s), a significant marker in 24.

Experiment	Marker?	Max mean expression
E-HCAD-38	yes	889.35
E-MTAB-9801	yes	544.22
E-HCAD-1	yes	109.27
E-HCAD-4	yes	72.47
E-MTAB-8142	yes	41.16
E-MTAB-10553	yes	32.48
E-MTAB-5061	yes	28.38
E-GEOD-134144	yes	27.56
E-CURD-112	yes	27.45
E-HCAD-10	yes	26.78
E-CURD-122	yes	26.73
E-MTAB-9221	yes	26.26
E-GEOD-130148	yes	25.62
E-MTAB-6701	yes	24.17
E-GEOD-81547	yes	22.22

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 78 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Lung	tissue	329.6	high
Kidney	tissue	222.3	high
Urinary bladder	tissue	189.2	high
Lymph node	tissue	179.6	high
Tonsil	tissue	122.9	high
Cervix	tissue	106.3	high
Gallbladder	tissue	98.0	high
Appendix	tissue	95.0	high
Stomach 1	tissue	88.6	high
Liver	tissue	83.6	medium
Duodenum	tissue	73.2	high
Parathyroid gland	tissue	72.9	not detected
Pancreas	tissue	71.1	medium
Seminal vesicle	tissue	66.7	low
Salivary gland	tissue	59.4	medium
Prostate	tissue	56.0	medium
Fallopian tube	tissue	54.3	medium
Small intestine	tissue	53.5	high
Ovary	tissue	52.3	medium
Spleen	tissue	48.9	low
Thymus	tissue	48.4
Heart muscle	tissue	48.1	not detected
Skin 1	tissue	45.8	low
Breast	tissue	45.7	low
Endometrium 1	tissue	43.9	medium
Smooth muscle	tissue	40.2	not detected
Esophagus	tissue	35.7	not detected
Tongue	tissue	35.2
Bone marrow	tissue	34.9	low
Adrenal gland	tissue	34.4	medium
Adipose tissue	tissue	32.1	not detected
Colon	tissue	30.5	medium
Vagina	tissue	30.0	not detected
Thyroid gland	tissue	26.0	not detected
Rectum	tissue	25.7	low
Epididymis	tissue	25.3	low
Placenta	tissue	24.2	not detected
Spinal cord	tissue	21.0
Caudate putamen	tissue	18.6
Frontal cortex	tissue	18.1
Skeletal muscle	tissue	15.3	not detected
Pituitary gland	tissue	12.9
Testis	tissue	9.5	low
Choroid plexus	tissue	9.4
Superior colliculi	tissue	9.1
Medulla oblongata	tissue	7.6
Olfactory bulb	tissue	7.5
Substantia nigra	tissue	7.3
Postcentral gyrus	tissue	6.6
Hippocampus	tissue	5.6	not detected
Thalamus	tissue	5.1
Pons	tissue	4.9
Midbrain	tissue	4.7
Retina	tissue	4.6
Cerebellum	tissue	4.6	not detected
Periaqueductal gray	tissue	4.6
Hypothalamus	tissue	4.5
Cerebral cortex	tissue	4.4	not detected
Temporal cortex	tissue	4.4
Septum	tissue	4.2

Brain sub-regions (HPA Brain Atlas): detected in 191; highest nTPM — Dorsal spinal cord (21.0), Blood vessel (18.3), Anterior thalamic nucleus, ventral (13.2), Supraoptic nucleus (12.9), Ventral spinal cord (12.0).

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets:

Target	Regulation
MMP2	Activation
MMP3	Activation

Upstream regulators (CollecTRI, top): GATA2

miRNA regulators (miRDB)

Targeting CTSH by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

17 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-4685-5P	99.25	65.99	1563
HSA-MIR-6837-5P	99.25	65.47	1632
HSA-MIR-129-1-3P	98.86	68.41	779
HSA-MIR-129-2-3P	98.86	68.41	779
HSA-MIR-4436B-3P	98.25	65.26	1494
HSA-MIR-6735-5P	98.24	65.36	1488
HSA-MIR-7843-5P	98.12	65.26	1421
HSA-MIR-4638-3P	97.90	65.75	905
HSA-MIR-4632-5P	97.82	65.38	1470
HSA-MIR-6879-5P	97.77	65.52	1521
HSA-MIR-3616-3P	96.96	65.45	983
HSA-MIR-4491	96.53	66.20	935
HSA-MIR-4657	96.53	66.57	895
HSA-MIR-8081	96.42	67.75	738
HSA-MIR-627-5P	95.51	66.80	509

Functional genomics

gnomAD constraint: pLI 5.96e-15, LOEUF 1.27, missense Z 0.111 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000220166 — one region, missense o/e 0.96.

Literature-anchored findings (GeneRIF, showing 25)

• involvement in processing of hydrophobic surfactant-associated protein C in type II pneumocytes (PMID:12034564)
• production of cathepsins B and H by tumor cells along with concomitant decrease of their inhibitor, cystatin C, in the CSF might contribute in the process of metastasis and spread of the cancer cells in the leptomeningeal tissues (PMID:12589965)
• Cathepsin H could contribute to the transformation of LDL to an atherogenic moiety; the process might involve a self-sustaining amplifying circle. (PMID:12615673)
• kinetic data on substrates hydrolysis and enzyme inhibition show the role of the mini-chain as a framework for transition state stabilization of free alpha-amino groups of substrates and as a structural barrier for endopeptidase-like substrate cleavage. (PMID:14515996)
• AKR1B1 and CTSH may be good markers for prediction of sensitivity to certain drugs (PMID:14662023)
• cathepsin H is involved in maturation of the biologically active surfactant associated protein B (PMID:14766755)
• cathepsin H has a role in progression of colorectal cancer that is distinct from that of cathepsins B and L (PMID:15646835)
• A general defect in napsin A or cathepsin H expression or activity was not the specific cause for abnormal surfactant accumulation in juvenile pulmonary alveolar proteinosis (PMID:18216060)
• cathepsin B, cathepsin H, cathepsin X and cystatin C may have roles in inflammatory breast cancer (PMID:18949742)
• In contrast to cathepsin S, cathepsin H values did not correlate with markers of inflammation, indicating a specific role for cathepsin H in the pleural host response. (PMID:19404922)
• These data indicate that cathepsins B, L and S may act as cell-death mediators in in monocytic cells infected with ICP4 and Us3 deletion mutant herpes simplex virus type 1. (PMID:20881085)
• CTSH overexpression in a subset hepatoma may be thyroid hormone receptor dependent and suggests that this overexpression has an important role in hepatoma progression. (PMID:21217776)
• The processing of procathepsin H is an autocatalytic, multistep process proceeding from an inactive 41kDa pro-form, through a 30kDa intermediate form, to the 28kDa mature form. (PMID:22704610)
• Quantification of immunohistochemistry showed that there is no difference in the global expression of CTSD, CTSH and CTSK between asthmatics and non-asthmatics. (PMID:23483898)
• The data provide strong evidence that CTSH is an important regulator of beta-cell function during progression of T1D (PMID:24982147)
• mutation in LRPAP1 is associated with high myopia. Further studies are expected to evaluate the pathogenicity of the variants in CTSH, LEPREL1, ZNF644, SLC39A5, and SCO2. (PMID:25525168)
• In conclusion, CTSH/rs3825932 and ERBB3/rs2292239 SNPs were associated with reduced risk of progression to proliferative diabetic retinopathy and two-step progression of diabetic retinopathy on the ETDRS scale accordingly. (PMID:26245339)
• Especially, rs3825932 in CTSH has integrative functional evidence supporting the association with type 1 diabetes mellitus. (PMID:26429317)
• p41 fragment is also shown to reduce the secretion of interleukin-12 (IL-12/p70) during the subsequent maturation of treated dendritic cells. (PMID:26960148)
• the up-regulation of MMP genes is mediated through degradation of class IIa histone deacetylases (HDACs) by certain cysteine cathepsins (Cts). (PMID:28157489)
• Study presents the crystal structures of human procathepsin H at 2.00 A and 1.66 A resolution. These structures allow us to explore in detail the molecular basis for the inhibition of the mature domain by the prodomain. Comparison with cathepsin H structure reveals how mini-chain reorients upon activation. Results demonstrate that procathepsin H is not auto-activated but can be trans-activated by cathepsin L. (PMID:30044821)
• The Rac2 GTPase contributes to cathepsin H-mediated protection against cytokine-induced apoptosis in insulin-secreting cells. (PMID:32814070)
• Genetic and environmental factors regulate the type 1 diabetes gene CTSH via differential DNA methylation. (PMID:33992646)
• Functional genomics identify causal variant underlying the protective CTSH locus for Alzheimer’s disease. (PMID:36739351)
• Cathepsin H: Molecular characteristics and clues to function and mechanism. (PMID:37148981)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ctsh	ENSDARG00000041108
mus_musculus	Ctsh	ENSMUSG00000032359
rattus_norvegicus	Ctsh	ENSRNOG00000014064
caenorhabditis_elegans		WBGENE00008861

Paralogs (12): CTSZ (ENSG00000101160), CTSC (ENSG00000109861), CTSL (ENSG00000135047), CTSV (ENSG00000136943), TINAG (ENSG00000137251), TINAGL1 (ENSG00000142910), CTSK (ENSG00000143387), CTSS (ENSG00000163131), CTSB (ENSG00000164733), CTSW (ENSG00000172543), CTSF (ENSG00000174080), CTSO (ENSG00000256043)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:107285) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 9 distinct phenotype terms.

Mouse phenotype (MP)	Records
increased bone mineral density	1
abnormal eye morphology	1
abnormal respiratory system physiology	1
abnormal retina outer nuclear layer morphology	1
abnormal retina inner nuclear layer morphology	1
increased bone mineral content	1
decreased surfactant secretion	1
abnormal eye anterior chamber depth	1
decreased total retina thickness	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Macaca fascicularis	P61276	100.0%	Diamond
Macaca mulatta	P61277	100.0%	Diamond
Bos taurus	P25975	99.7%	Diamond
Rachiplusia ou MNPV (strain R1)	Q8B9D5	99.1%	Diamond
Hordeum vulgare	P25249	98.1%	Diamond
Vanilla planifolia	A0A0F7G352	98.0%	Diamond
Haemonchus contortus	P19092	98.0%	Diamond
Pongo abelii	Q5RB02	97.6%	Diamond
Canis lupus familiaris	Q3ZKN1	96.4%	Diamond
Sus scrofa	Q9GLE3	96.4%	Diamond
Chlorocebus aethiops	Q9GKL8	96.1%	Diamond
Oryctolagus cuniculus	P43236	95.8%	Diamond
Ovis aries	Q10991	94.1%	Diamond
Saimiri boliviensis boliviensis	Q8HY82	94.0%	Diamond
Plasmodium falciparum 3D7	Q8I6U4	93.4%	Diamond
Vasconcellea cundinamarcensis	P32956	93.0%	Diamond
Tabernaemontana divaricata	A8DS38	91.3%	Diamond
Oryza sativa Japonica Group	P25778	88.8%	Diamond
Zea mays	Q10717	88.8%	Diamond
Arabidopsis thaliana	Q94B08	87.7%	Diamond
Dermatophagoides farinae	P16311	86.0%	Diamond
Euroglyphus maynei	P25780	86.0%	Diamond
Dermatophagoides pteronyssinus	P08176	84.4%	Diamond
Giardia duodenalis	P92133	82.9%	Diamond
Jacaratia mexicana	P84346	81.9%	Diamond
Zingiber officinale	P82473	78.9%	Diamond
Carica papaya	P05994	78.4%	Diamond
Onchocerca volvulus	Q6PN98	77.1%	Diamond
Glechoma hederacea	A0A068CNX1	74.1%	Diamond
Solanum lycopersicum	Q40143	73.5%	Diamond
Medicago truncatula	A0A072UTP9	73.1%	Diamond
Dictyostelium discoideum	Q94503	73.1%	Diamond
Autographa californica nucleopolyhedrovirus	P25783	99.1%	Diamond
Bombyx mori nucleopolyhedrovirus	P41721	96.3%	Diamond
Choristoneura fumiferana DEF multiple nucleopolyhedrovirus	Q6VTL7	91.7%	Diamond
Antheraea pernyi nucleopolyhedrovirus	Q91CL9	91.7%	Diamond
Choristoneura fumiferana multiple nucleopolyhedrovirus	P41715	90.1%	Diamond
Hyphantria cunea nucleopolyhedrovirus	Q9WGE0	85.8%	Diamond
Mamestra configurata nucleopolyhedrovirus A	Q8QLK1	84.8%	Diamond
Spodoptera exigua nuclear polyhedrosis virus (strain US)	Q9J8B9	84.8%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
RASGRF1	protein-coding	5923
MIR184	ncRNA	406960
ANKRD34C-AS1	ncRNA	729911
MORF4L1	protein-coding	10933
TRK-CTT1-2	tRNA	100189013

Protein

Protein identifiers

Pro-cathepsin H — P09668 (reviewed: P09668)

All UniProt accessions (27): P09668, A0A087X0D5, A0A0B4J217, A0A3B3IRM7, A0A7I2V2E4, A0A7I2V2L7, A0A7I2V2T8, A0A7I2V314, A0A7I2V3E8, A0A7I2V3T9, A0A7I2V439, A0A7I2V4H2, A0A7I2V4N9, A0A7I2V4W0, A0A7I2V4X5, A0A7I2V532, A0A7I2V563, A0A7I2V673, A0A7I2YQ92, A0A7I2YQE6, A0A7I2YQH4, A0A7I2YQL1, A0A7I2YQL6, A0A7I2YQX6, E9PKT6, E9PN60, E9PN84

UniProt curated annotations — full annotation on UniProt →

Function. Important for the overall degradation of proteins in lysosomes.

Subunit / interactions. Composed of a mini chain and a large chain. The large chain may be split into heavy and light chain. All chains are held together by disulfide bonds.

Subcellular location. Lysosome.

Similarity. Belongs to the peptidase C1 family.

RefSeq proteins (3): NP_001306066, NP_001398024, NP_004381* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000169	Pept_cys_AS	Active_site
IPR000668	Peptidase_C1A_C	Domain
IPR013128	Peptidase_C1A	Family
IPR013201	Prot_inhib_I29	Domain
IPR025660	Pept_his_AS	Active_site
IPR025661	Pept_asp_AS	Active_site
IPR038765	Papain-like_cys_pep_sf	Homologous_superfamily
IPR039417	Peptidase_C1A_papain-like	Domain

Pfam: PF00112, PF08246

Enzyme classification (BRENDA)

• EC 3.4.22.16 — cathepsin H (BRENDA: 16 organisms, 94 substrates, 306 inhibitors, 41 Km, 22 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
ARG-4-METHYLCOUMARYL-7-AMIDE	0.097–72	3
BENZOYL-DL-ARG-2-NAPHTHYLAMIDE	0.039–4.32	3
ARG-2-NAPHTHYLAMIDE	0.097–0.169	2
BENZOYL-L-PHE-L-VAL-L-ARG-4-METHYLCOUMARYL-7-AMI	0.025–0.038	2
H-L-ARG-NH-4-METHYLCOUMARYL-7-AMIDE	0.05–3.6	2
L-LEU-BETA-NAPHTHYLAMIDE	0.203–0.22	2
ALA-4-METHYLCOUMARYL-7-AMIDE	210	1
ALPHA-N-BENZOYL-DL-ARG-BETA-NAPHTHYLAMIDE	0.367	1
BENZOYL-ARG-2-NAPHTHYLAMIDE	0.637	1
BENZOYL-ARG-4-METHYLCOUMARYL-7-AMIDE	0.321	1
BENZOYL-L-ARG-2-NAPHTHYLAMIDE	0.46	1
BENZOYL-L-PHE-L-ARG-7-AMIDO-4-METHYLCOUMARIN	0.082	1
BENZYLOXYCARBONYL-PRO-ALA-ALA-ALA-PRO	7.4	1
BENZYLOXYCARBONYL-PRO-ALA-ALA-ALA-PRO-NH2	3.5	1
CITRULLINE-4-METHYLCOUMARYL-7-AMIDE	0.076	1

UniProt features (51 total): helix 15, strand 12, sequence variant 5, disulfide bond 4, chain 3, active site 3, propeptide 2, glycosylation site 2, turn 2, signal peptide 1, peptide 1, sequence conflict 1

Structure

Experimental structures (PDB)

2 structures by resolution:

PDB	Title	Method	Resolution (Å)
6CZS	Crystal structure of human pro-cathepsin H C26S mutant	X-RAY DIFFRACTION	1.66
6CZK	Crystal structure of wild-type human pro-cathepsin H	X-RAY DIFFRACTION	2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P09668-F1	94.30	0.91

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Hydrolases, Peptidases, Cysteine-type peptidases, Metabolic proteins, Predicted intracellular proteins, Plasma proteins, Cancer-related genes, Candidate cancer biomarkers, Human disease related genes, Diabetes

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytoplasmic bodies; cytosol; vesicles

Antibody reliability (HPA): IH enhanced · IF supported

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)

Position	Role
141
281
301

Disulfide bonds (4)

Type	Positions
Disulfide bond	102–327, 138–181, 172–214, 272–322

Glycosylation sites (2)

Type	Positions
N-linked (glcnac…) asparagine	101, 230

Function

Pathways and Gene Ontology

Reactome pathways

4 curated (TAS) of 8; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

8 pathways:

ID	Pathway	Evidence
R-HSA-2132295	MHC class II antigen presentation	curated
R-HSA-6798695	Neutrophil degranulation	curated
R-HSA-9979719	Processing of antigen in germinal center B cells	curated
R-HSA-5683826	Surfactant metabolism	curated
R-HSA-1280218	Adaptive Immune System	—
R-HSA-168256	Immune System	—
R-HSA-168249	Innate Immune System	—
R-HSA-392499	Metabolism of proteins	—

MSigDB gene sets: 501 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_EPITHELIUM_DEVELOPMENT, KOBAYASHI_EGFR_SIGNALING_24HR_UP, REACTOME_INNATE_IMMUNE_SYSTEM, MCLACHLAN_DENTAL_CARIES_UP, GOBP_METANEPHROS_DEVELOPMENT, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, BASSO_B_LYMPHOCYTE_NETWORK, GOCC_SECRETORY_GRANULE, GOBP_EPITHELIAL_TUBE_BRANCHING_INVOLVED_IN_LUNG_MORPHOGENESIS, GOBP_REGULATION_OF_EPITHELIAL_CELL_MIGRATION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_LUNG_MORPHOGENESIS, IVANOVA_HEMATOPOIESIS_MATURE_CELL

GO Biological Process (25): metanephros development (GO:0001656), T cell mediated cytotoxicity (GO:0001913), adaptive immune response (GO:0002250), immune response-regulating signaling pathway (GO:0002764), proteolysis (GO:0006508), immune response (GO:0006955), spermatogenesis (GO:0007283), positive regulation of gene expression (GO:0010628), positive regulation of epithelial cell migration (GO:0010634), neuropeptide catabolic process (GO:0010813), bradykinin catabolic process (GO:0010815), antigen processing and presentation (GO:0019882), positive regulation of cell migration (GO:0030335), zymogen activation (GO:0031638), protein destabilization (GO:0031648), response to retinoic acid (GO:0032526), membrane protein proteolysis (GO:0033619), surfactant homeostasis (GO:0043129), dichotomous subdivision of terminal units involved in lung branching (GO:0060448), ERK1 and ERK2 cascade (GO:0070371), cellular response to thyroid hormone stimulus (GO:0097067), lysosomal protein catabolic process (GO:1905146), response to odorant (GO:1990834), positive regulation of apoptotic signaling pathway (GO:2001235), apoptotic process (GO:0006915)

GO Molecular Function (15): endopeptidase activity (GO:0004175), aminopeptidase activity (GO:0004177), cysteine-type endopeptidase activity (GO:0004197), serine-type endopeptidase activity (GO:0004252), peptidase activity (GO:0008233), cysteine-type peptidase activity (GO:0008234), cysteine-type endopeptidase activator activity involved in apoptotic process (GO:0008656), HLA-A specific activating MHC class I receptor activity (GO:0030108), kininogen binding (GO:0030984), identical protein binding (GO:0042802), protein-containing complex binding (GO:0044877), thyroid hormone binding (GO:0070324), protein binding (GO:0005515), peptidase activator activity involved in apoptotic process (GO:0016505), hydrolase activity (GO:0016787)

GO Cellular Component (13): outer dense fiber (GO:0001520), acrosomal vesicle (GO:0001669), extracellular region (GO:0005576), lysosome (GO:0005764), cytosol (GO:0005829), axoneme (GO:0005930), extracellular matrix (GO:0031012), secretory granule lumen (GO:0034774), extracellular exosome (GO:0070062), alveolar lamellar body (GO:0097208), multivesicular body lumen (GO:0097486), tertiary granule lumen (GO:1904724), ficolin-1-rich granule lumen (GO:1904813)

Reactome top-level categories

5 top-level categories:

Category	Pathways
Immune System	2
Adaptive Immune System	1
Metabolism of proteins	1
Innate Immune System	1
Affinity selection of immunoglobulins	1

GO top-level categories

showing 60 of 65 GO namespaces:

Category	Terms
cellular anatomical structure	3
immune system process	2
peptidase activity	2
endopeptidase activity	2
protein binding	2
binding	2
secretory granule	2
intracellular organelle lumen	2
kidney development	1
leukocyte mediated cytotoxicity	1
T cell mediated immunity	1
immune response	1
signal transduction	1
regulation of immune response	1
protein metabolic process	1
response to stimulus	1
developmental process involved in reproduction	1
male gamete generation	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
epithelial cell migration	1
regulation of epithelial cell migration	1
positive regulation of cell migration	1
peptide catabolic process	1
catabolic process	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
protein processing	1
regulation of protein stability	1
response to lipid	1
response to oxygen-containing compound	1
proteolysis	1
multicellular organismal-level chemical homeostasis	1
epithelial tube branching involved in lung morphogenesis	1
dichotomous subdivision of an epithelial terminal unit	1
MAPK cascade	1
exopeptidase activity	1
cysteine-type peptidase activity	1
serine-type peptidase activity	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activator activity involved in apoptotic process	1
cysteine-type endopeptidase regulator activity involved in apoptotic process	1
activating MHC class I receptor activity	1
hormone binding	1
apoptotic process	1
peptidase activator activity	1
catalytic activity	1
sperm flagellum	1
polymeric cytoskeletal fiber	1
lytic vacuole	1
cytoplasm	1
cytoskeleton	1
microtubule	1
ciliary plasm	1
external encapsulating structure	1
cytoplasmic vesicle lumen	1
extracellular vesicle	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 27 of 55 annotations. The rest are phylogenetic / computational / electronic (IEA).

27 experimentally-supported GO terms:

GO term	NS	Evidence
ERK1 and ERK2 cascade	BP	direct assay
adaptive immune response	BP	expression pattern
bradykinin catabolic process	BP	direct assay
cellular response to thyroid hormone stimulus	BP	expression pattern
immune response-regulating signaling pathway	BP	direct assay
lysosomal protein catabolic process	BP	direct assay
membrane protein proteolysis	BP	direct assay
neuropeptide catabolic process	BP	direct assay
positive regulation of cell migration	BP	direct assay
positive regulation of gene expression	BP	direct assay
protein destabilization	BP	mutant phenotype
proteolysis	BP	direct assay
surfactant homeostasis	BP	direct assay
zymogen activation	BP	direct assay
alveolar lamellar body	CC	direct assay
cytosol	CC	direct assay
extracellular exosome	CC	high-throughput assay
extracellular matrix	CC	high-throughput assay
lysosome	CC	direct assay
HLA-A specific activating MHC class I receptor activity	MF	direct assay
aminopeptidase activity	MF	direct assay
cysteine-type endopeptidase activator activity involved in apoptotic process	MF	direct assay
cysteine-type endopeptidase activity	MF	direct assay
cysteine-type peptidase activity	MF	direct assay
endopeptidase activity	MF	direct assay
peptidase activity	MF	direct assay
thyroid hormone binding	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,139 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CTSH	LGMN	Q99538	765
CTSH	CTSD	P07339	695
CTSH	C1QTNF6	Q9BXI9	624
CTSH	CLEC16A	Q2KHT3	609
CTSH	BACH2	Q9BYV9	603
CTSH	PTPN2	P17706	556
CTSH	SFTPB	P07988	553
CTSH	SH2B3	Q9UQQ2	543
CTSH	TAGAP	Q8N103	523
CTSH	NAA25	Q14CX7	505
CTSH	HMSD	A8MTL9	502
CTSH	CLN3	Q13286	488
CTSH	CTSB	P07858	485
CTSH	HLA-DQB1	P01917	484
CTSH	ZNF644	Q9H582	482

IntAct

Human interaction partners of CTSH in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

8 partners by confidence:

Partner	Interaction type	MIscore	Records
ATN1	physical association	0.560	3
DYNC1H1	physical association	0.560	3
KLK6	physical association	0.560	3
CTSL	association	0.530	1
CSTB	association	0.350	1
SF3A1	association	0.350	1
SLCO6A1	association	0.350	1
TCTN3	association	0.350	1

BioGRID (77 interactions; top human partners by supporting records): CTSL (Affinity Capture-MS; 3 records), MMRN1 (Affinity Capture-MS; 3 records), SLC25A41 (Affinity Capture-MS; 3 records), AIRE (Affinity Capture-MS; 2 records), CCDC103 (Affinity Capture-MS; 2 records), CST1 (Affinity Capture-MS; 2 records), CSTA (Co-crystal Structure; 2 records), CSTB (Reconstituted Complex; 2 records), POC5 (Affinity Capture-MS; 2 records), SLCO6A1 (Affinity Capture-MS; 2 records), TBC1D22B (Affinity Capture-MS; 2 records), TCTN3 (Affinity Capture-MS; 2 records), ZIC1 (Affinity Capture-MS; 2 records), APTX (Affinity Capture-MS), ATP6AP2 (Affinity Capture-MS)

SIGNOR signaling

showing 1 of 2 signaling interactions:

A	Effect	B	Mechanism
CTSH	“down-regulates quantity by destabilization”	BGLAP	cleavage

Disease & clinical

Genetic variants

Variant evidence for CTSH: 77 ClinVar records (0 pathogenic / likely pathogenic); 15 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	43
Likely benign	10
Benign	4

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 28 predictions of 1,139):

Position(s)	Effect	Δscore	Sites
15:78922991–78922992	donor_loss	1.0000	5
15:78923119–78923120	acceptor_loss	1.0000	5
15:78925333	donor_loss	1.0000	3
15:78925441–78925442	acceptor_loss	1.0000	4
15:78925451	acceptor_gain	1.0000
15:78925457	acceptor_gain	1.0000
15:78927782–78927783	acceptor_loss	1.0000	6
15:78927785	acceptor_gain	1.0000
15:78927791	acceptor_gain	1.0000
15:78927795	acceptor_gain	1.0000

AlphaMissense

925 missense substitutions predicted likely pathogenic (of 2,220 scored), across 213 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
H281	8	0.992	0.996
N301	8	0.990	0.998
F144	8	0.969	0.999
D171	8	0.969	0.990
D84	8	0.943	0.977
D121	8	0.943	0.981
F259	8	0.938	0.986
S140	8	0.907	0.997
N178	8	0.898	0.995
S187	8	0.873	0.987
N320	8	0.873	0.979
F313	8	0.870	0.981
W142	7	0.995	0.999
C172	7	0.995	0.997
C181	7	0.993	0.998
C272	7	0.993	0.997
C138	7	0.992	0.997
C322	7	0.992	0.998
C214	7	0.991	0.996
C102	7	0.989	0.994

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

3 prognostic cancer types:

Cancer	Prognostic	p-value
Bladder Urothelial Carcinoma (TCGA)	favorable	0.000293
Pancreatic Adenocarcinoma (TCGA)	unfavorable	0.000298
Lung Adenocarcinoma (TCGA)	favorable	0.000387

Disease associations

OMIM: gene MIM:116820 | disease phenotypes:

HPO phenotypes

30 phenotypes (HPO-id order):

HPO	Term
HP:0000017	Nocturia
HP:0000709	Psychosis
HP:0000711	Restlessness
HP:0000716	Depression
HP:0000738	Hallucinations
HP:0000739	Anxiety
HP:0000822	Hypertension
HP:0000826	Precocious puberty
HP:0000975	Hyperhidrosis
HP:0001262	Excessive daytime somnolence
HP:0001279	Syncope
HP:0001350	Slurred speech
HP:0001513	Obesity
HP:0002019	Constipation
HP:0002076	Migraine
HP:0002307	Drooling
HP:0002360	Sleep disturbance
HP:0002494	Abnormal rapid eye movement sleep
HP:0002519	Hypnagogic hallucination
HP:0002524	Cataplexy
HP:0006896	Hypnopompic hallucination
HP:0007018	Attention deficit hyperactivity disorder
HP:0007686	Abnormal pupillary function
HP:0010534	Transient global amnesia
HP:0010535	Sleep apnea
HP:0012452	Restless legs
HP:0025233	Sleep paralysis
HP:0025235	NREM parasomnia
HP:0030014	Female sexual dysfunction
HP:0040307	Male sexual dysfunction

GWAS associations

15 associations:

Study	Trait	p-value
GCST006585_2105	Blood protein levels	4e-212
GCST006585_2158	Blood protein levels	5e-166
GCST009597_153	Multiple sclerosis	9e-17
GCST000258_3	Type 1 diabetes	3e-15
GCST009873_10	Autoimmune traits (pleiotropy)	1e-14
GCST005536_34	Type 1 diabetes	9e-14
GCST009875_13	Type 1 diabetes	1e-11
GCST90011899_50	Aspartate aminotransferase levels	4e-11
GCST005522_2	Narcolepsy	1e-9
GCST008871_41	Basal cell carcinoma	3e-9
GCST005531_8	Multiple sclerosis	1e-8
GCST000392_4	Type 1 diabetes	8e-8
GCST008870_7	Keratinocyte cancer (MTAG)	2e-7
GCST009874_33	Celiac disease	2e-6
GCST001164_3	Bipolar disorder	9e-6

EFO canonical traits (from GWAS)

2 canonical traits:

EFO ID	Trait name
EFO:0010176	keratinocyte carcinoma
EFO:0004736	aspartate aminotransferase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2111441 (SELECTIVITY GROUP), CHEMBL2225 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 75 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

1 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL5095230	ATUZAGINSTAT	2	75

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — C1: Papain

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
compound 1b [PMID: 16290936]	Inhibition	7.4	pKi
compound 1e [PMID: 27285276]	Inhibition	6.36	pIC50

Binding affinities (BindingDB)

60 measured of 92 human assays (95 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(1S)-2-cyclohexyl-1-methylethyl 2-cyano-2-methylhydrazinecarboxylate	KI	0.077 nM
cis-4-(2,3-dimethylphenoxy)-6-oxa-1-aza-bicyclo[3.2.1]octan-7-one	IC50	1 nM
(1S)-2-cyclohexyl-1-methylethyl 2-cyano-2-isopropylhydrazinecarboxylate	KI	1.3 nM
(1R,2S)-2-(benzyloxy)-7-oxa-5-aza-bicyclo[3.2.1]octan-6-one	IC50	2 nM
(2S)-1-cyclohexylpropan-2-yl 1-cyanoazetidine-2-carboxylate	IC50	2.4 nM
CHEMBL4292287	KI	3 nM
(1R,2S)-2-phenoxy-7-oxa-5-aza-bicyclo[3.2.1]octan-6-one	IC50	5 nM
(1R,2S)-2-isobutoxy-7-oxa-5-aza-bicyclo[3.2.1]octan-6-one	IC50	8 nM
CHEMBL4287663	KI	9 nM
{(S)-1-[(morpholine-4-carbonyl)-hydrazonomethyl]-pentyl}-carbamic acid (R)-1-benzyl-2-methyl-propyl ester	IC50	18 nM
((S)-1-Formyl-pentyl)-carbamic acid (R)-1-benzyl-2-methyl-propyl ester	IC50	27 nM
[(S)-1-(1-Benzyl-2-oxo-ethylcarbamoyl)-2-methyl-propyl]-carbamic acid benzyl ester	IC50	40 nM
CHEMBL570897	EC50	41 nM
rac-trans4-(2,3-dimethylphenoxy)-6-oxa-1-aza-bicyclo[3.2.1]octan-7-one	IC50	46 nM
N2-(MORPHOLIN-4-YLCARBONYL)-N1-[(1S,2E)-1-(2-PHENYLETHYL)-3-(PHENYLSULFONYL)PROP-2-ENYL]-D-LEUCINAMIDE	KI	64 nM
(1S,2S)-2-bromo-7-oxa-5-aza-bicyclo[3.2.1]octan-6-one	IC50	158 nM
{(S)-1-[(morpholine-4-carbonyl)-hydrazonomethyl]-pentyl}-carbamic acid (S)-1-methyl-2-phenyl-ethyl ester	IC50	270 nM
3-acetyl-8-chloro-2-(2,4-dibromophenylamino)-5-methylquinolin-4(1H)-one	IC50	277 nM
(2R)-2-{[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]amino}-N-(1-cyanocyclopropyl)-3-methanesulfonylpropanamide	IC50	280 nM
(1S)-2-cyclohexyl-1-methylethyl (2S)-1-cyanopyrrolidine-2-carboxylate	IC50	310 nM
BDBM453327	IC50	380 nM	US-10730826: Ketone inhibitors of lysine gingipain
N-[7-amino-2-oxo-1-(2,3,6-trifluorophenoxy)heptan-3-yl]cyclopentanecarboxamide	IC50	380 nM	US-11325884: Ketone inhibitors of lysine gingipain
(S)-1-phenylpropan-2-yl (S)-1-oxohexan-2-ylcarbamate	IC50	460 nM
N-[(3S)-7-amino-2-oxo-1-(2,3,5,6-tetrafluorophenoxy)heptan-3-yl]cyclopentanecarboxamide	IC50	485 nM	US-10730826: Ketone inhibitors of lysine gingipain
(1R,2S)-2-phenoxy-7-oxa-5-aza-bicyclo[3.2.1]octane-6-thione	IC50	519 nM
TCMDC-138496	IC50	680 nM
benzyl (S)-1-((S)-4-fluoro-3-oxo-1-phenylbutan-2-ylamino)-1-oxo-3-phenylpropan-2-ylcarbamate	IC50	680 nM
1-(PHENYLMETHYL)CYCLOPENTYL[(1S)-1-FORMYLPENTYL]CARBAMATE	IC50	810 nM
MK-0822	IC50	1030 nM
(S)-2-amino-N-((S)-5-phenyl-1-(phenylsulfonyl)pent-1-en-3-yl)pentanamide	KI	1100 nM
[(S)-1-((R)-1-Phenyl-ethylaminooxalyl)-pentyl]-carbamic acid (S)-4,4-dimethyl-2-oxo-pyrrolidin-3-yl ester	IC50	1400 nM
3-acetyl-5,8-dibromo-2-(4-bromophenylamino)quinolin-4(1H)-one	IC50	1690 nM
Gallinamide A	IC50	1700 nM
{(S)-1-[(2,3-dihydro-indole-1-carbonyl)-hydrazonomethyl]-pentyl}-carbamic acid 1-benzyl-cyclopentyl ester	IC50	1800 nM
3-acetyl-6-chloro-2-(2-chloro-4-methylphenylamino)-8-nitroquinolin-4(1H)-one	IC50	2390 nM
(Cyano-methyl-amino)-acetic acid (S)-2-cyclohexyl-1-methyl-ethyl ester	KI	2600 nM
2-Amino-N-[(S)-3-diazo-1-(4-iodo-benzyl)-2-oxo-propyl]-acetamide	IC50	2940 nM
3-acetyl-6-chloro-2-(2,4-dichlorophenylamino)-8-nitroquinolin-4(1H)-one	IC50	3160 nM
3-acetyl-5,8-dichloro-2-(2,4-dichlorophenylamino)quinolin-4(1H)-one	IC50	3170 nM
3-acetyl-8-bromo-5-chloro-2-(4-chlorophenylamino)quinolin-4(1H)-one	IC50	3530 nM
[(S)-1-((R)-1-Phenyl-ethylaminooxalyl)-pentyl]-carbamic acid 1-benzyl-cyclobutylmethyl ester	IC50	3600 nM
3-acetyl-2-(4-tert-butylphenylamino)-8-chloro-6-nitroquinolin-4(1H)-one	IC50	3690 nM
3-acetyl-8-chloro-2-(4-chlorophenylamino)-6-nitroquinolin-4(1H)-one	IC50	4560 nM
[(S)-1-((R)-1-Phenyl-ethylaminooxalyl)-pentyl]-carbamic acid 2-methyl-2-phenyl-propyl ester	IC50	5000 nM
Grassystatin A	IC50	5000 nM
[(S)-1-((R)-1-Phenyl-ethylaminooxalyl)-pentyl]-carbamic acid 1,3,3-trimethyl-bicyclo[2.2.1]hept-2-yl ester	IC50	12000 nM
CHEMBL4228921	KI	13000 nM
[(S)-1-(4-Bromo-1H-pyrazol-3-ylaminooxalyl)-pentyl]-carbamic acid 1-isopropyl-2-methyl-propyl ester	IC50	32000 nM
{(S)-1-[(morpholine-4-carbonyl)-hydrazonomethyl]-pentyl}-carbamic acid tert-butyl ester	IC50	32000 nM
{(S)-1-[(2,3-dihydro-indole-1-carbonyl)-hydrazonomethyl]-pentyl}-carbamic acid tert-butyl ester	IC50	35000 nM

ChEMBL bioactivities

37 potent at pChembl≥5 of 46 total, top 28 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.34	Ki	0.46	nM	CHEMBL371420
8.85	Ki	1.4	nM	CHEMBL190121
7.75	IC50	18	nM	CHEMBL113948
7.40	IC50	40	nM	CHEMBL183812
7.40	IC50	40	nM	CHEMBL114161
6.96	IC50	110	nM	CHEMBL5848986
6.90	IC50	125.9	nM	CHEMBL567341
6.86	Ki	137	nM	CHEMBL514348
6.84	IC50	145	nM	CHEMBL492175
6.72	IC50	190	nM	CHEMBL203663
6.72	IC50	190	nM	E-64
6.64	IC50	230	nM	CHEMBL204605
6.25	IC50	560	nM	ATUZAGINSTAT
6.25	IC50	560	nM	CHEMBL5783659
6.24	IC50	580	nM	CHEMBL180839
6.19	IC50	645.6	nM	CHEMBL567134
5.89	Ki	1300	nM	CHEMBL4287663
5.85	Ki	1400	nM	CHEMBL486232
5.81	IC50	1550	nM	CHEMBL5870472
5.58	IC50	2653	nM	CHEMBL390474
5.43	Ki	3700	nM	CHEMBL212521
5.30	IC50	5000	nM	CHEMBL426611
5.18	IC50	6591	nM	CHEMBL230474
5.16	Ki	7000	nM	CHEMBL4292287
5.08	IC50	8300	nM	CHEMBL183660
5.04	Ki	9200	nM	LEUPEPTIN
5.01	IC50	9800	nM	CHEMBL450997
5.00	IC50	1e+04	nM	GRASSYSTATIN A

PubChem BioAssay actives

25 with measured affinity, of 178 total; 24 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
[(2S)-1-cyclohexylpropan-2-yl] N-[cyano(propan-2-yl)amino]carbamate	238907: Inhibition constant against human cathepsin H using L-Arg-b-naphthalamide	ki	0.0005	uM
[(2S)-1-cyclohexylpropan-2-yl] N-[cyano(methyl)amino]carbamate	238891: Inhibition constant against human cathepsin H using L-Arg-b-naphthalamide	ki	0.0014	uM
[(2R)-3-methyl-1-phenylbutan-2-yl] N-[(2S)-1-oxohexan-2-yl]carbamate	260672: Inhibition of recombinant human cathepsin H in a fluorescence assay	ic50	0.0180	uM
[(2S)-1-phenylpropan-2-yl] N-[(2S)-1-oxohexan-2-yl]carbamate	260672: Inhibition of recombinant human cathepsin H in a fluorescence assay	ic50	0.0400	uM
[(2S)-1-cyclohexylpropan-2-yl] 1-cyanoazetidine-2-carboxylate	242157: Inhibitory concentration against human cathepsin H using 50 uM L-Arg-beta-naphthalamide	ic50	0.0400	uM
6-(3,5-difluoroanilino)-9-ethylpurine-2-carbonitrile	444705: Inhibition of human Cathepsin H	ic50	0.1259	uM
(2S)-2-amino-N-[(E,3S)-1-(benzenesulfonyl)-5-phenylpent-1-en-3-yl]pentanamide	370548: Inhibition of human recombinant cathepsin H by fluorescence assay	ki	0.1370	uM
3-acetyl-8-chloro-2-(4-chloroanilino)-6-nitro-1H-quinolin-4-one	350739: Inhibition of human liver cathepsin H after 30 mins by fluorometric end-point assay	ic50	0.1450	uM
(2S,3S)-3-[[(2S)-1-[4-(diaminomethylideneamino)butylamino]-4-methyl-1-oxopentan-2-yl]carbamoyl]oxirane-2-carboxylic acid	360106: Inhibition of human recombinant cathepsin H after 10 mins	ic50	0.1900	uM
[(2R)-3-methyl-1-phenylbutan-2-yl] N-[(1E,2S)-1-(morpholine-4-carbonylhydrazinylidene)hexan-2-yl]carbamate	260672: Inhibition of recombinant human cathepsin H in a fluorescence assay	ic50	0.1900	uM
[(2S)-1-phenylpropan-2-yl] N-[(1E,2S)-1-(morpholine-4-carbonylhydrazinylidene)hexan-2-yl]carbamate	260672: Inhibition of recombinant human cathepsin H in a fluorescence assay	ic50	0.2300	uM
[(2S)-1-cyclohexylpropan-2-yl] 1-cyanopyrrolidine-2-carboxylate	242157: Inhibitory concentration against human cathepsin H using 50 uM L-Arg-beta-naphthalamide	ic50	0.5800	uM
9-(3,5-difluorophenyl)-6-(ethylamino)purine-2-carbonitrile	444705: Inhibition of human Cathepsin H	ic50	0.6456	uM
(2S)-1-[(2S)-2-[[(2S)-2-[[[(2S)-1-[(2S)-1-[(2S)-2-[(4-aminobenzoyl)amino]-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carbonyl]amino]carbamoylamino]-3-phenylpropanoyl]amino]-3-hydroxypropanoyl]-N-[(2S)-1-[[(2S)-1-[[(2S)-1-amino-3-(4-hydroxy-3-nitrophenyl)-1-oxopropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]pyrrolidine-2-carboxamide	1402875: Reversible competitive inhibition of human cathepsin H using fluorogenic AMC-derived peptide substrate assessed as reduction in residual activity preincubated for 30 mins followed by substrate addition	ki	1.3000	uM
N-[(2S)-1-[[(E,3S)-1-(benzenesulfonyl)-5-phenylpent-1-en-3-yl]amino]-4-methyl-1-oxopentan-2-yl]morpholine-4-carboxamide	370548: Inhibition of human recombinant cathepsin H by fluorescence assay	ki	1.4000	uM
(4S,5R)-4-(2,3-dimethylphenoxy)-6-oxa-1-azabicyclo[3.2.1]octan-7-one	290156: Inhibition of human recombinant cathepsin H	ic50	2.6530	uM
(2S)-2-amino-N-[(1S)-1-cyano-2-(4-phenylphenyl)ethyl]butanamide	370548: Inhibition of human recombinant cathepsin H by fluorescence assay	ki	3.7000	uM
(2-methyl-2-phenylpropyl) N-[(3S)-1,2-dioxo-1-[[(1R)-1-phenylethyl]amino]heptan-3-yl]carbamate	242263: Inhibition of 50 uM L-Arg-beta-naphthalamide binding to human cathepsin H in fluorescence assay	ic50	5.0000	uM
(4S,5R)-4-phenoxy-6-oxa-1-azabicyclo[3.2.1]octan-7-one	290156: Inhibition of human recombinant cathepsin H	ic50	6.5910	uM
(4S)-4-[[(2S)-2-[[(2S)-1-[(2S)-2-[[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-[(2-acetamidoacetyl)amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-3-(1H-imidazol-4-yl)propanoyl]pyrrolidine-2-carbonyl]amino]-4-methylsulfanylbutanoyl]amino]carbamoylamino]propanoyl]pyrrolidine-2-carbonyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-[[(2R)-1-[[(2R)-1-amino-5-carbamimidamido-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-5-oxopentanoic acid	1402875: Reversible competitive inhibition of human cathepsin H using fluorogenic AMC-derived peptide substrate assessed as reduction in residual activity preincubated for 30 mins followed by substrate addition	ki	7.0000	uM
[(2S)-1-cyclohexylpropan-2-yl] N-[(3S)-1-cyanopyrrolidin-3-yl]carbamate	242157: Inhibitory concentration against human cathepsin H using 50 uM L-Arg-beta-naphthalamide	ic50	8.3000	uM
(2S)-2-acetamido-N-[(2S)-1-[[(2S)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]-4-methylpentanamide	1125415: Inhibition of human liver cathepsin H	ki	9.2000	uM
2-amino-N-[(2S)-4-diazo-1-(4-iodophenyl)-3-oxobutan-2-yl]acetamide	360106: Inhibition of human recombinant cathepsin H after 10 mins	ic50	9.8000	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	448875: Inhibition of cathepsin H after 10 to 15 mins by fluorescence assay	ic50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	7
Estradiol	affects cotreatment, decreases expression	4
bisphenol A	affects expression, affects cotreatment, increases expression	2
sodium arsenite	decreases expression	2
Decitabine	affects expression, increases expression, affects cotreatment	2
Arsenic Trioxide	decreases expression, affects cotreatment	2
Lead	affects expression, decreases expression	2
Smoke	decreases expression	2
Cyclosporine	decreases expression	2
afuresertib	increases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
glycidyl methacrylate	decreases expression	1
sodium arsenate	decreases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
arsenite	decreases expression	1
sodium bichromate	decreases expression	1
afimoxifene	increases expression	1
butyraldehyde	increases expression	1
perfluorooctanoic acid	affects cotreatment, increases expression	1
cupric chloride	decreases expression	1
pentanal	increases expression	1
perfluorooctane sulfonic acid	increases expression	1
seocalcitol	decreases expression	1
entinostat	increases expression	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
nutlin 3	affects cotreatment, increases expression, increases secretion	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1

ChEMBL screening assays

58 unique, capped per target: 58 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL829917	Binding	Selectivity for human cathepsin H over human cathepsin K	Potent and selective ketoamide-based inhibitors of cysteine protease, cathepsin K. — *J Med Chem*

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2VE	Abcam HEK293T CTSH KO	Transformed cell line	Female

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for CTSH across ~30M SureChEMBL compounds — explore on Sugi Predict.