TMPRSS6

Summary

TMPRSS6 (transmembrane serine protease 6, HGNC:16517) is a protein-coding gene on chromosome 22q12.3, encoding Transmembrane protease serine 6 (Q8IU80). Membrane-bound serine protease.

The protein encoded by this gene is a type II transmembrane serine proteinase that is found attached to the cell surface. The encoded protein may be involved in matrix remodeling processes in the liver. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 164656 — RefSeq curated summary.

At a glance

• Gene–disease (curated): IRIDA syndrome (Definitive, ClinGen)
• GWAS associations: 155
• Clinical variants (ClinVar): 412 total — 22 pathogenic, 10 likely-pathogenic
• Phenotypes (HPO): 13
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_001374504

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16517
Approved symbol	TMPRSS6
Name	transmembrane serine protease 6
Location	22q12.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ30744, MT2
Ensembl gene	ENSG00000187045
Ensembl biotype	protein_coding
OMIM	609862
Entrez	164656

Gene structure

Transcript identifiers

Ensembl transcripts: 37 — 37 protein_coding

ENST00000346753, ENST00000381792, ENST00000406725, ENST00000406856, ENST00000423761, ENST00000429068, ENST00000442782, ENST00000676104, ENST00000862824, ENST00000862826, ENST00000862827, ENST00000862829, ENST00000862830, ENST00000862832, ENST00000862835, ENST00000862836, ENST00000862837, ENST00000862838, ENST00000862839, ENST00000862840, ENST00000862841, ENST00000862842, ENST00000862843, ENST00000862844, ENST00000862845, ENST00000862846, ENST00000862847, ENST00000862848, ENST00000862849, ENST00000862850, ENST00000862851, ENST00000862852, ENST00000862853, ENST00000862854, ENST00000862855, ENST00000862856, ENST00000956781

RefSeq mRNA: 4 — MANE Select: NM_001374504 NM_001289000, NM_001289001, NM_001374504, NM_153609

CCDS: CCDS74856, CCDS74857

Canonical transcript exons

ENST00000676104 — 18 exons

Exon	Start	End
ENSE00000653772	37084295	37084404
ENSE00000880119	37066826	37066962
ENSE00000880125	37084727	37084839
ENSE00001174361	37070916	37071032
ENSE00001174370	37073532	37073645
ENSE00001174382	37074610	37074708
ENSE00001243834	37075135	37075280
ENSE00001338845	37069073	37069344
ENSE00001338847	37070484	37070652
ENSE00001350746	37065436	37066238
ENSE00001547540	37109503	37109713
ENSE00001612988	37095551	37095592
ENSE00001620707	37098416	37098549
ENSE00001646760	37086283	37086419
ENSE00001729124	37096648	37096715
ENSE00001778410	37095906	37096090
ENSE00001780110	37089578	37089782
ENSE00003595084	37103216	37103418

Expression profiles

Bgee: expression breadth ubiquitous, 142 present calls, max score 95.97.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.5205 / max 211.1762, expressed in 122 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
193998	0.3578	106
193996	0.1055	13
193995	0.0380	16
193997	0.0192	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	95.97	gold quality
liver	UBERON:0002107	92.32	gold quality
mammary duct	UBERON:0001765	90.40	silver quality
type B pancreatic cell	CL:0000169	89.93	gold quality
olfactory bulb	UBERON:0002264	89.67	gold quality
epithelium of mammary gland	UBERON:0003244	87.27	silver quality
diaphragm	UBERON:0001103	87.12	gold quality
pancreatic ductal cell	CL:0002079	84.86	silver quality
male germ cell	CL:0000015	82.87	gold quality
sperm	CL:0000019	82.06	gold quality
upper arm skin	UBERON:0004263	81.72	gold quality
pituitary gland	UBERON:0000007	79.17	gold quality
adenohypophysis	UBERON:0002196	78.45	gold quality
vastus lateralis	UBERON:0001379	78.29	gold quality
tongue squamous epithelium	UBERON:0006919	77.88	gold quality
thymus	UBERON:0002370	76.39	gold quality
right testis	UBERON:0004534	76.15	gold quality
cardia of stomach	UBERON:0001162	75.80	gold quality
left testis	UBERON:0004533	75.80	gold quality
myocardium	UBERON:0002349	75.59	gold quality
biceps brachii	UBERON:0001507	75.14	gold quality
epithelium of nasopharynx	UBERON:0001951	74.24	gold quality
testis	UBERON:0000473	73.73	gold quality
gluteal muscle	UBERON:0002000	73.64	gold quality
left ventricle myocardium	UBERON:0006566	73.04	gold quality
cardiac muscle of right atrium	UBERON:0003379	72.70	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	72.64	gold quality
putamen	UBERON:0001874	72.56	gold quality
mucosa of urinary bladder	UBERON:0001259	72.43	gold quality
triceps brachii	UBERON:0001509	72.11	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.09

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
BMP6	Activation
TFRC	Repression

miRNA regulators (miRDB)

16 targeting TMPRSS6, 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-4692	100.00	67.32	2066
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-378G	99.71	64.90	1106
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-6727-3P	99.49	65.92	1333
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-6081	99.48	66.07	1446
HSA-MIR-3612	99.45	66.02	1333
HSA-MIR-650	99.45	65.77	1309
HSA-MIR-3191-3P	99.45	63.94	356
HSA-MIR-4722-3P	99.35	65.22	1099
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-6511A-5P	98.13	67.47	1770

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Single Nucleotide Polymorphisms in TMPRSS6 is associated with breast cancer (PMID:16533768)
• Matriptase-2 suppresses breast tumor development in vivo, displays prognostic value for breast cancer patients, inhibits both breast cancer cell invasion and motility in vitro, and may play a contrasting role to matriptase-1 in breast cancer (PMID:17575220)
• identification, structural features, enzymology, expression pattern and potential roles of TMPRSS6 [review] (PMID:17981570)
• These findings demonstrate that TMPRSS6 is essential for normal systemic iron homeostasis in humans. (PMID:18408718)
• Data show that genetic upregulation of matriptase-2 reduces the aggressiveness of prostate cancer cells in vitro and in vivo and affects FAK and paxillin localisation. (PMID:18449907)
• TMPRSS6 mutation leads to overproduction of hepcidin and, in turn, to defective iron absorption and utilization (PMID:18603562)
• TMPRSS6 role in iron metabolism and its interaction with HJV (PMID:18976966)
• Transmembrane protease serine 6 cleaves hemojuvelin a regulator of hepcidin, on plasma membrane; transmembrane protease serine 6 shows no cleavage activity and the human mutant only partial cleavage capacity. (PMID:18976966)
• Article summarized the functional relevance of matriptase-2 in iron metabolism. (PMID:19377077)
• TMPRSS6 mutations are associated with iron-refractory iron deficiency anemia. (PMID:19592582)
• 2 new cases of iron-refractory iron deficiency anaemia show the importance of LDLR-1/-2 & CUB1 domains in TMPRSS6 function and its role in hepcidin regulation. (PMID:19708871)
• investigation of genetic variations in TMPRSS6: polymorphisms & mutations in iron deficiency anemia; 3 uncommon non-synonymous polymorphisms were identified, G228D, R446W, & V795I; R446W polymorphism appeared to be overrepresented in the anemic population (PMID:19818657)
• findings suggest that TMPRSS6, a regulator of hepcidin synthesis and iron handling, is crucial in hemoglobin level maintenance. (PMID:19820698)
• findings demonstrate the involvement of TMPRSS6 in control of iron homeostasis and in normal erythropoiesis. (PMID:19820699)
• A key biologically relevant substrate for the proteolytic activity of matriptase-2/TMPRSS6 was found to be hemojuvelin, a cell surface protein that regulates hepcidin expression through a BMP/SMAD pathway (PMID:19907145)
• Results extend the pattern of TMPRSS6 mutations associated with IRIDA and propose a model of causality for some of the novel missense mutation. (PMID:20232450)
• showed that it localizes to similar subcellular compartments as wild-type TMPRSS6 and binds HJV, but fails to auto-catalytically activate itself. (PMID:20704562)
• in 16 subjects with iron-refractory iron deficiency anaemia (IRIDA), identified 27 polymorphisms in TMPRSS6 gene; 8 snps and 4 haplotypes were associated with iron-refractory anaemia (PMID:20738301)
• Matriptase-2- and proprotein convertase-cleaved forms of hemojuvelin have different roles in the down-regulation of hepcidin expression (PMID:20937842)
• Cryptic splice site usage leading to truncated TMPRSS6 is responsible for iron refractory iron deficiency anaemia in an Italian Family (PMID:20964721)
• Regulation of type II transmembrane serine proteinase TMPRSS6 by hypoxia-inducible factors: new link between hypoxia signaling and iron homeostasis (PMID:20966077)
• Novel genetic forms of iron-related microcytic anemia have been identified, due to defects of iron transport/utilization or to TMPRSS6 deficiency and hepcidin hyperproduction. (PMID:21150441)
• A novel mutation Gly603Arg of TMPRSS6 in a Korean female with iron-refractory iron deficiency anemia (PMID:21618415)
• Modulation of TMPRSS6 expression could serve as a negative feedback inhibitor to avoid excessive hepcidin increases by iron to help maintain tight homeostatic balance of systemic iron levels. (PMID:21622652)
• the importance of TMPRSS6 trafficking at the plasma membrane in the regulation of hepcidin expression, an event that is essential for iron homeostasis. (PMID:21724843)
• HFE rs1800562 C282Y variant exerts a direct pleiotropic effect on the iron parameters, in part independent of hepcidin. (PMID:21785125)
• Data indicate that TMPRSS6 rs855791 has a functional role in determining protease activity and regulating hepcidin expression in normal subjects. (PMID:21873547)
• We observed no other significant relationship of TMPRSS6 K253E, A736V, or Y739Y with iron, erythrocyte, or pica phenotypes. (PMID:22265928)
• TMPRSS6 variants were significantly associated with plasma ferritin, hemoglobin, risk of iron overload, and type 2 diabetes in Chinese Hans. (PMID:22301935)
• TF, TFR2 and TMPRSS6 polymorphisms are significantly associated with decreased iron status, but only variants in TMPRSS6 are genetic risk factors for iron deficiency and iron-deficiency anemia. (PMID:22323359)
• sequenced exons and exon-intron boundaries of SLC11A2 and TMPRSS6 in all 6 family members with iron-refractory iron deficiency anaemia; cannot exclude or confirm a gene-gene interaction between SLC11A2 and TMPRSS6; gene sequencing did not reveal causative rare mutations (PMID:22509377)
• TMPRSS6 missense mutant proteins are targeted to the plasma membrane. (PMID:22581667)
• action of HIF-1alpha on TMPRSS6 promoter activity (PMID:22628316)
• Single nucleotide polymorphisms in TMPRSS6 gene is associated with iron overload. (PMID:22761678)
• 2 new TMPRSS6 variants associated, in the heterozygous form, with iron-refractory iron-deficiency anaemia (IRDA) in 2 unrelated families; data suggest although heterozygous TMPRSS6 mutations may not be able to induce a clear IRIDA phenotype, some may increase susceptibility to iron deficiency (PMID:22765023)
• matriptase-2 protects against the development and progression of prostate cancer by regulating the motility and invasive capabilities of prostate cancer cells (PMID:22858929)
• The p.A736V TMPRSS6 polymorphism is likely a modifier of Hereditary hemochromatosis (HH) expression. (PMID:22885719)
• neogenin forms a ternary complex with both MT2 and HJV at the plasma membrane. The complex facilitates HJV cleavage by MT2, and release of the cleaved HJV from the cell occurs after a retrograde trafficking through the TGN/Golgi compartments. (PMID:22893705)
• The p.Ala736Val TMPRSS6 variant influences secondary hepatic iron accumulation in patients with nonalcoholic fatty liver disease (NAFLD). (PMID:23144979)
• Matriptase-2 could have a potential role in prostate and breast tumour suppression through its anti-angiogenic properties. (PMID:23238872)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Tmprss6	ENSMUSG00000016942
rattus_norvegicus	Tmprss6	ENSRNOG00000000184
drosophila_melanogaster	Sb	FBGN0003319
drosophila_melanogaster	CG17242	FBGN0250841

Paralogs (17): PRSS22 (ENSG00000005001), PRSS21 (ENSG00000007038), TMPRSS11E (ENSG00000087128), HPN (ENSG00000105707), TMPRSS13 (ENSG00000137747), ST14 (ENSG00000149418), TMPRSS11D (ENSG00000153802), TMPRSS15 (ENSG00000154646), TMPRSS3 (ENSG00000160183), TMPRSS5 (ENSG00000166682), TMPRSS7 (ENSG00000176040), TMPRSS9 (ENSG00000178297), TMPRSS2 (ENSG00000184012), TMPRSS11B (ENSG00000185873), TMPRSS11A (ENSG00000187054), TMPRSS11F (ENSG00000198092), PRSS41 (ENSG00000215148)

Protein

Protein identifiers

Transmembrane protease serine 6 — Q8IU80 (reviewed: Q8IU80)

Alternative names: Matriptase-2

All UniProt accessions (4): B0QYB3, B0QYB6, Q8IU80, X6REP5

UniProt curated annotations — full annotation on UniProt →

Function. Membrane-bound serine protease. Through the cleavage of cell surface hemojuvelin (HJV), a regulator of the expression of the iron absorption-regulating hormone hepicidin/HAMP, plays a role in iron homeostasis.

Subunit / interactions. Interacts with HJV.

Subcellular location. Cell membrane.

Post-translational modifications. The single-chain zymogen undergoes autoproteolytic processing. This results in TMPRSS6 shedding from the cell surface and conversion into an activated two-chains form which is released extracellularly. The process involves a trans-activation mechanism that requires TMPRSS6 oligomerization.

Disease relevance. Iron-refractory iron deficiency anemia (IRIDA) [MIM:206200] Key features include congenital hypochromic microcytic anemia, very low mean corpuscular erythrocyte volume, low transferrin saturation, abnormal iron absorption characterized by no hematologic improvement following treatment with oral iron, and abnormal iron utilization characterized by a sluggish, incomplete response to parenteral iron. The disease is caused by variants affecting the gene represented in this entry. Mutations leading to abrogation of TMPRSS6 activity are associated with IRIDA due to elevated levels of hepcidin, a negative regulator of plasma iron pool.

Domain organisation. Cytoplasmic domain mediates HAMP suppression via proximal promoter element(s).

Similarity. Belongs to the peptidase S1 family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q8IU80-4	1	yes
Q8IU80-1	2
Q8IU80-2	3
Q8IU80-5	4

RefSeq proteins (4): NP_001275929, NP_001275930, NP_001361433, NP_705837 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000082	SEA_dom	Domain
IPR000859	CUB_dom	Domain
IPR001254	Trypsin_dom	Domain
IPR001314	Peptidase_S1A	Family
IPR002172	LDrepeatLR_classA_rpt	Repeat
IPR009003	Peptidase_S1_PA	Homologous_superfamily
IPR017118	Pept_S1A_matriptase-2	Family
IPR018114	TRYPSIN_HIS	Active_site
IPR033116	TRYPSIN_SER	Active_site
IPR035914	Sperma_CUB_dom_sf	Homologous_superfamily
IPR036055	LDL_receptor-like_sf	Homologous_superfamily
IPR036364	SEA_dom_sf	Homologous_superfamily
IPR043504

Pfam: PF00057, PF00089, PF01390

Enzyme classification (BRENDA):

• EC 3.4.21.109 — matriptase (BRENDA: 9 organisms, 282 substrates, 322 inhibitors, 62 Km, 40 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
BOC-GLN-ALA-ARG-4-NITROANILIDE	0.024–1	8
METHYLSULFONYL-D-CYCLOHEXYLTYROSYLGLYCYL-ARGININ	0.164–0.228	4
BUTYLOXYCARBONYL-L-GLN-L-ALA-L-ARG-4-NITROANILID	0.159–0.381	3
ALPHAEBETA7 INTEGRIN	0.1–0.111	2
FILAGGRIN	0.03–0.046	2
ILE-PRO-ARG-P-NITROANILIDE	0.256–0.387	2
MATRIPTASE	0.104–0.126	2
METHYLSULFONYL-D-CYCLOHEXYLTYROSYL-GLYCYL-ARGINI	0.17–0.19	2
N-TERT-BUTOXYCARBONYL-GLN-ALA-ARG 7-AMIDO-4-METH	0.0049–0.0335	2
PROTEASE-ACTIVATED RECEPTOR-2	0.142–0.197	2
RQARAVGG	0.018–0.128	2
RQARVVGG	0.104–0.126	2
RRARVVGG	0.0033–0.012	2
SINGLE-CHAIN UROKINASE-TYPE PLASMINOGEN ACTIVATO	0.0035–0.006	2
T-BUTYLOXYCARBONYL-L-GLN-L-ALA-L-ARG-4-METHYL-CO	0.582–0.59	2

UniProt features (78 total): sequence variant 36, disulfide bond 14, domain 7, glycosylation site 7, splice variant 4, active site 3, topological domain 2, mutagenesis site 2, chain 1, transmembrane region 1, sequence conflict 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
9NRC	ELECTRON MICROSCOPY	3.29

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IU80-F1	84.69	0.48

Antibody-complex structures (SAbDab): 1 — 9NRC

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): 617 (charge relay system); 668 (charge relay system); 762 (charge relay system)

Disulfide bonds (14): 335–366, 458–470, 464–480, 474–489, 491–503, 497–516, 510–525, 531–543, 538–557, 551–566, 602–618, 702–768, 733–747, 758–787

Glycosylation sites (7): 136, 184, 216, 338, 433, 453, 518

Mutagenesis-validated functional residues (2):

Position	Phenotype
576	does not undergo proteolytic processing.
762	does not undergo proteolytic processing.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-1442490	Collagen degradation
R-HSA-1474228	Degradation of the extracellular matrix

MSigDB gene sets: 148 (showing top): GSE45365_NK_CELL_VS_CD11B_DC_UP, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOMF_METALLOPEPTIDASE_ACTIVITY, GNF2_GSTM1, GNF2_HPN, GOBP_INTRACELLULAR_IRON_ION_HOMEOSTASIS, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, VART_KSHV_INFECTION_ANGIOGENIC_MARKERS_UP, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_PROTEIN_MATURATION, GOBP_REGULATION_OF_TRANSMEMBRANE_RECEPTOR_PROTEIN_SERINE_THREONINE_KINASE_SIGNALING_PATHWAY, GNF2_LCAT, GOBP_NEGATIVE_REGULATION_OF_BMP_SIGNALING_PATHWAY, GNF2_HPX, GOBP_RESPONSE_TO_BMP

GO Biological Process (12): negative regulation of transcription by RNA polymerase II (GO:0000122), intracellular iron ion homeostasis (GO:0006879), extracellular matrix disassembly (GO:0022617), BMP signaling pathway (GO:0030509), negative regulation of BMP signaling pathway (GO:0030514), collagen catabolic process (GO:0030574), membrane protein proteolysis (GO:0033619), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of transcription by RNA polymerase II (GO:0045944), multicellular organismal-level iron ion homeostasis (GO:0060586), self proteolysis (GO:0097264), proteolysis (GO:0006508)

GO Molecular Function (6): metalloendopeptidase activity (GO:0004222), serine-type endopeptidase activity (GO:0004252), serine-type peptidase activity (GO:0008236), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787)

GO Cellular Component (3): obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Degradation of the extracellular matrix	1
Extracellular matrix organization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
inorganic ion homeostasis	2
proteolysis	2
endopeptidase activity	2
negative regulation of DNA-templated transcription	1
intracellular monoatomic cation homeostasis	1
cellular component disassembly	1
extracellular matrix organization	1
cellular response to BMP stimulus	1
transforming growth factor beta receptor superfamily signaling pathway	1
BMP signaling pathway	1
regulation of BMP signaling pathway	1
negative regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
negative regulation of cellular response to growth factor stimulus	1
catabolic process	1
collagen metabolic process	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
monoatomic cation homeostasis	1
multicellular organismal-level chemical homeostasis	1
protein metabolic process	1
metallopeptidase activity	1
serine-type peptidase activity	1
peptidase activity	1
serine hydrolase activity	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

891 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMPRSS6	HJV	Q6ZVN8	994
TMPRSS6	HAMP	P81172	961
TMPRSS6	NEO1	Q92859	955
TMPRSS6	HFE	Q30201	933
TMPRSS6	TFR2	Q9UP52	909
TMPRSS6	BMP6	P22004	889
TMPRSS6	TFRC	P02786	847
TMPRSS6	GDF15	P78360	722
TMPRSS6	EPO	P01588	719
TMPRSS6	CYBRD1	Q53TN4	708
TMPRSS6	SLC11A2	P49281	697
TMPRSS6	CREB3L3	Q68CJ9	694
TMPRSS6	SLC40A1	Q9NP59	608
TMPRSS6	ERFE	Q4G0M1	581
TMPRSS6	FURIN	P09958	510

IntAct

4 interactions, top by confidence:

A	B	Type	Score
TEPSIN	AP4M1	psi-mi:“MI:0914”(association)	0.700
TMPRSS6	HJV	psi-mi:“MI:0915”(physical association)	0.400
CFTR	TMPRSS6	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (2): TMPRSS6 (Affinity Capture-RNA), TMPRSS6 (PCA)

ESM2 similar proteins: A1L0T3, A1L4H1, D3ZTE0, G3V801, O08762, O43866, O75636, O95428, O97507, P00748, P22457, P56730, P58215, P69525, P69526, P85521, P98140, Q02853, Q04756, Q04962, Q24K22, Q2VL90, Q2VLG4, Q2VLG6, Q2VLH6, Q499S5, Q4G0T1, Q5G265, Q5G268, Q5G269, Q5G270, Q5G271, Q5IJ48, Q6QNF4, Q70UZ7, Q769J6, Q76LX8, Q7Z410, Q80YA8, Q80YC5

Diamond homologs: A0A1B0GVH4, A1L453, A2VE36, E5RG02, F2YMG0, O35205, O35453, O60235, O97370, P03952, P05981, P06868, P08001, P08709, P10323, P14272, P19236, P20231, P22457, P23578, P26262, P29293, P29786, P35035, P35036, P35038, P35039, P35040, P35041, P39675, P49275, P49864, P50342, P69526, P70375, P83748, P98139, Q05511, Q14B25, Q14BX2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	22
Likely pathogenic	10
Uncertain significance	219
Likely benign	59
Benign	51

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1297560	NM_001374504.1(TMPRSS6):c.470del (p.Leu157fs)	Pathogenic
1399	NM_001374504.1(TMPRSS6):c.1877_1878dup (p.Lys627fs)	Pathogenic
1400	NM_001374504.1(TMPRSS6):c.1786del (p.Ala596fs)	Pathogenic
1401	NM_001374504.1(TMPRSS6):c.1555+1G>A	Pathogenic
1402	NM_001374504.1(TMPRSS6):c.2113+1G>C	Pathogenic
1407	NM_001374504.1(TMPRSS6):c.1152T>G (p.Tyr384Ter)	Pathogenic
1409	NM_001374504.1(TMPRSS6):c.2028_2031dup (p.Val678fs)	Pathogenic
1410	NM_001374504.1(TMPRSS6):c.326C>A (p.Ala109Asp)	Pathogenic
2412690	NM_001374504.1(TMPRSS6):c.1055C>A (p.Ser352Ter)	Pathogenic
2427433	NC_000022.10:g.(?37480315)(37485842_?)del	Pathogenic
2791461	NM_001374504.1(TMPRSS6):c.930C>G (p.Tyr310Ter)	Pathogenic
30802	NM_001374504.1(TMPRSS6):c.1537G>A (p.Glu513Lys)	Pathogenic
3347407	NM_001374504.1(TMPRSS6):c.939del (p.Phe314fs)	Pathogenic
3355691	NM_001374504.1(TMPRSS6):c.120del (p.Tyr41fs)	Pathogenic
3380919	NM_001374504.1(TMPRSS6):c.1655C>A (p.Ser552Ter)	Pathogenic
3658350	NM_001374504.1(TMPRSS6):c.355_361del (p.Ser119fs)	Pathogenic
3723975	NM_001374504.1(TMPRSS6):c.2074_2081dup (p.Trp694fs)	Pathogenic
4686736	NM_001374504.1(TMPRSS6):c.1687_1697del (p.Gly563fs)	Pathogenic
617552	NM_001374504.1(TMPRSS6):c.207C>G (p.Tyr69Ter)	Pathogenic
627580	NM_001374504.1(TMPRSS6):c.2134C>T (p.Gln712Ter)	Pathogenic
917402	NM_001374504.1(TMPRSS6):c.336+2T>G	Pathogenic
917403	NM_001374504.1(TMPRSS6):c.1310_1315del (p.Arg437_Val438del)	Pathogenic
1180681	NM_001374504.1(TMPRSS6):c.1620_1627del (p.Gln541fs)	Likely pathogenic
1299579	NM_001374504.1(TMPRSS6):c.1547G>A (p.Cys516Tyr)	Likely pathogenic
1404	NM_001374504.1(TMPRSS6):c.1534G>A (p.Asp512Asn)	Likely pathogenic
1405	NM_001374504.1(TMPRSS6):c.1038C>A (p.Tyr346Ter)	Likely pathogenic
1406	NM_001374504.1(TMPRSS6):c.1355del (p.Glu452fs)	Likely pathogenic
1675886	NM_001374504.1(TMPRSS6):c.2407T>G (p.Ter803Gly)	Likely pathogenic
2637038	NM_001374504.1(TMPRSS6):c.909G>A (p.Trp303Ter)	Likely pathogenic
3648546	NM_001374504.1(TMPRSS6):c.1442-2A>G	Likely pathogenic

SpliceAI

3384 predictions. Top by Δscore:

Variant	Effect	Δscore
22:37066237:CC:C	acceptor_gain	1.0000
22:37066238:CC:C	acceptor_gain	1.0000
22:37066822:TCA:T	donor_loss	1.0000
22:37066823:CA:C	donor_loss	1.0000
22:37066824:A:AC	donor_gain	1.0000
22:37066825:C:CC	donor_gain	1.0000
22:37066825:C:G	donor_loss	1.0000
22:37066825:CCTG:C	donor_gain	1.0000
22:37066825:CCTGA:C	donor_gain	1.0000
22:37066959:GGGC:G	acceptor_gain	1.0000
22:37066963:C:CA	acceptor_loss	1.0000
22:37066963:C:CC	acceptor_gain	1.0000
22:37066967:CCG:C	acceptor_gain	1.0000
22:37066968:C:CT	acceptor_gain	1.0000
22:37066968:C:T	acceptor_gain	1.0000
22:37066974:C:CT	acceptor_gain	1.0000
22:37066975:A:T	acceptor_gain	1.0000
22:37070910:GCTCA:G	donor_loss	1.0000
22:37070911:CTCA:C	donor_loss	1.0000
22:37070912:TCACC:T	donor_loss	1.0000
22:37070913:CA:C	donor_loss	1.0000
22:37070915:CCA:C	donor_gain	1.0000
22:37073534:T:A	donor_gain	1.0000
22:37074606:TCA:T	donor_loss	1.0000
22:37074607:CA:C	donor_loss	1.0000
22:37074608:A:AC	donor_gain	1.0000
22:37074609:C:CT	donor_gain	1.0000
22:37074609:CCG:C	donor_gain	1.0000
22:37074609:CCGCA:C	donor_gain	1.0000
22:37074728:C:CT	acceptor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000002651 (22:37075828 G>C), RS1000057240 (22:37111781 T>A,C), RS1000063661 (22:37100890 G>A), RS1000065012 (22:37077455 G>C,T), RS1000249191 (22:37086718 C>G,T), RS1000270700 (22:37104956 G>A,C), RS1000305950 (22:37069134 G>C), RS1000315554 (22:37094471 A>G,T), RS1000332838 (22:37110787 A>C,G), RS1000434317 (22:37075051 T>G), RS1000524006 (22:37096924 A>G), RS1000693673 (22:37085500 G>A), RS1000720452 (22:37108254 T>A), RS1000850339 (22:37070699 G>A), RS1000931150 (22:37077515 C>G)

Disease associations

OMIM: gene MIM:609862 | disease phenotypes: MIM:206200

GenCC curated gene-disease

Disease	Classification	Inheritance
IRIDA syndrome	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
IRIDA syndrome	Definitive	AR

Mondo (2): microcytic anemia (MONDO:0001245), IRIDA syndrome (MONDO:0008788)

Orphanet (1): IRIDA syndrome (Orphanet:209981)

HPO phenotypes

13 total (14 of 13 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001017	Anemic pallor
HP:0001596	Alopecia
HP:0001598	Concave nail
HP:0001891	Iron deficiency anemia
HP:0004447	Poikilocytosis
HP:0004840	Hypochromic microcytic anemia
HP:0011273	Anisocytosis
HP:0012464	Decreased transferrin saturation
HP:0025066	Decreased mean corpuscular volume
HP:0030318	Angular cheilitis
HP:0031877	Elevated circulating hepcidin concentration
HP:0040303	Decreased circulating iron concentration
HP:0001935	Microcytic anemia

GWAS associations

155 associations (top):

Study	Trait	p-value
GCST000301_18	Iron status biomarkers	6.000000e-06
GCST000498_5	Hematological parameters	1.000000e-09
GCST000499_1	Hemoglobin	3.000000e-25
GCST000501_2	Hemoglobin	2.000000e-13
GCST000502_6	Hematocrit	2.000000e-13
GCST000503_4	Mean corpuscular volume	3.000000e-41
GCST000504_3	Mean corpuscular hemoglobin	9.000000e-34
GCST000505_2	Iron status biomarkers	5.000000e-07
GCST000505_3	Iron status biomarkers	1.000000e-10
GCST000517_1	Iron levels	5.000000e-09
GCST000582_3	Mean corpuscular hemoglobin concentration	8.000000e-14
GCST000583_25	Hematological and biochemical traits	2.000000e-10
GCST000583_7	Hematological and biochemical traits	5.000000e-06
GCST000585_6	Mean corpuscular volume	1.000000e-15
GCST000587_4	Mean corpuscular hemoglobin	5.000000e-25
GCST000803_7	Glycated hemoglobin levels	3.000000e-14
GCST000814_10	Red blood cell traits	1.000000e-12
GCST000814_11	Red blood cell traits	5.000000e-09
GCST000814_4	Red blood cell traits	1.000000e-12
GCST000913_4	Iron status biomarkers	2.000000e-15
GCST000935_3	Iron status biomarkers	4.000000e-11
GCST001174_5	Hepcidin levels	5.000000e-07
GCST001174_7	Hepcidin levels	9.000000e-11
GCST001174_8	Hepcidin levels	4.000000e-09
GCST001765_30	Red blood cell traits	1.000000e-69
GCST001779_9	Hematology traits	3.000000e-08
GCST001780_4	Mean corpuscular hemoglobin	2.000000e-06
GCST001780_5	Mean corpuscular hemoglobin	5.000000e-14
GCST001780_7	Mean corpuscular hemoglobin	7.000000e-19
GCST001781_4	Mean corpuscular volume	2.000000e-09

EFO canonical traits (26, from GWAS)

EFO ID	Trait name
EFO:0004461	iron biomarker measurement
EFO:0004527	mean corpuscular hemoglobin
EFO:0004509	hemoglobin measurement
EFO:0004348	hematocrit
EFO:0004528	mean corpuscular hemoglobin concentration
EFO:0004541	HbA1c measurement
EFO:0004460	soluble transferrin receptor measurement
EFO:0004459	ferritin measurement
EFO:0006341	transferrin measurement
EFO:0006333	transferrin saturation measurement
EFO:0004297	clinical laboratory measurement
EFO:0007901	hepcidin:ferritin ratio
EFO:0007902	hepcidin:transferrin saturation ratio
EFO:0004305	erythrocyte count
EFO:0004309	platelet count
EFO:0007985	platelet crit
EFO:0007986	reticulocyte count
EFO:0009188	Red cell distribution width
EFO:0004570	bilirubin measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004530	triglyceride measurement
EFO:0006845	liver disease biomarker
EFO:0010821	liver fat measurement
EFO:0006334	total iron binding capacity
EFO:0004531	urate measurement
EFO:0007984	platelet component distribution width

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C562385	Iron-Refractory Iron Deficiency Anemia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1795139 (SINGLE PROTEIN)

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs4820268	TMPRSS6		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — S1: Chymotrypsin

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

Ligand	Action	Affinity	Parameter
inhibitor 1 [Colombo et al., 2012]	Inhibition	8.48	pKi
MD5	Inhibition	8.47	pKi

Binding affinities (BindingDB)

1 measured of 1 human assays (1 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL4093566	KI	6 nM

ChEMBL bioactivities

121 potent at pChembl≥5 of 147 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.96	Ki	0.011	nM	CHEMBL2086421
10.06	Ki	0.088	nM	CHEMBL2089123
9.87	Ki	0.134	nM	CHEMBL5982921
9.40	Ki	0.4	nM	CHEMBL4081543
9.30	Ki	0.506	nM	CHEMBL5557224
9.22	Ki	0.6	nM	CHEMBL4081543
9.13	Ki	0.74	nM	CHEMBL3354675
8.99	Ki	1.03	nM	CHEMBL3354683
8.96	Ki	1.1	nM	CHEMBL4093487
8.92	Ki	1.2	nM	CHEMBL4103740
8.92	Ki	1.2	nM	CHEMBL5562941
8.92	Ki	1.2	nM	CHEMBL4081543
8.85	Ki	1.4	nM	CHEMBL3354676
8.85	Ki	1.4	nM	CHEMBL5590035
8.85	Ki	1.4	nM	CHEMBL5573803
8.82	Ki	1.5	nM	CHEMBL4101897
8.82	Ki	1.5	nM	CHEMBL5574204
8.76	Ki	1.74	nM	CHEMBL4091809
8.70	Ki	1.98	nM	CHEMBL3354685
8.68	Ki	2.1	nM	CHEMBL4100506
8.66	Ki	2.2	nM	CHEMBL5575948
8.64	Ki	2.3	nM	CHEMBL4083908
8.61	Ki	2.48	nM	CHEMBL3354686
8.59	Ki	2.56	nM	CHEMBL3354684
8.59	Ki	2.6	nM	CHEMBL3354684
8.59	Ki	2.6	nM	CHEMBL4104560
8.58	Ki	2.63	nM	CHEMBL5532456
8.51	Ki	3.1	nM	CHEMBL4103673
8.51	Ki	3.1	nM	CHEMBL4086405
8.48	Ki	3.3	nM	CHEMBL2086421
8.47	Ki	3.4	nM	CHEMBL5569457
8.46	Ki	3.5	nM	CHEMBL4073691
8.43	Ki	3.7	nM	CHEMBL5571372
8.41	Ki	3.9	nM	CHEMBL5569773
8.40	Ki	4	nM	CHEMBL4101235
8.36	IC50	4.4	nM	CHEMBL4081543
8.34	Ki	4.6	nM	CHEMBL5592173
8.30	Ki	5	nM	CHEMBL4099552
8.30	Ki	5	nM	CHEMBL4089262
8.30	Ki	5	nM	CHEMBL4074504
8.28	Ki	5.3	nM	CHEMBL4065870
8.28	Ki	5.2	nM	CHEMBL4084785
8.28	Ki	5.3	nM	CHEMBL4073533
8.28	Ki	5.3	nM	CHEMBL5569457
8.28	Ki	5.2	nM	CHEMBL5562937
8.25	Ki	5.6	nM	CHEMBL5595012
8.22	Ki	6	nM	CHEMBL4093566
8.22	Ki	6	nM	CHEMBL4065964
8.22	Ki	6	nM	CHEMBL4085747
8.20	Ki	6.3	nM	CHEMBL3354677

PubChem BioAssay actives

89 with measured affinity, of 208 total; 50 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)-2-[[(2S)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]-N-[(2S)-1-[[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]pentanediamide	1806088: TMPRSS2 pericellular activity screening assay from Article 10.1038/s41586-022-04661-w: “A TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic.”	ki	0.0001	uM
(2S)-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-3-methyl-2-[[(2S)-2-(3-phenylpropanoylamino)-3-(1,3-thiazol-4-yl)propanoyl]amino]butanamide	1441767: Inhibition of recombinant human C-terminal V5-His-tagged matriptase-2 expressed in Drosophila S2 cells using Boc-Gln-Ala-ArgAMC as substrate measured for 1200 mins by fluorescence assay	ki	0.0004	uM
(2S)-2-acetamido-N-[(2S)-1-[[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]pentanediamide	1806088: TMPRSS2 pericellular activity screening assay from Article 10.1038/s41586-022-04661-w: “A TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic.”	ki	0.0005	uM
(2S)-2-[[(2S)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]-N-[(2S)-1-[[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]pentanediamide	1170923: Inhibition of human recombinant matriptase-2 using Boc-Gln-Ala-Arg-AMC as substrate by microplate reader analysis	ki	0.0007	uM
(2S)-2-[[(2R)-2-[[(2S)-2-amino-3-(1H-indol-3-yl)propanoyl]amino]-3-sulfanylpropanoyl]amino]-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-3-(4-hydroxyphenyl)propanamide	1170923: Inhibition of human recombinant matriptase-2 using Boc-Gln-Ala-Arg-AMC as substrate by microplate reader analysis	ki	0.0010	uM
(2S)-2-amino-N-[(2S)-1-[[(2S)-1-[[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]-3-(4-hydroxyphenyl)propanamide	1441767: Inhibition of recombinant human C-terminal V5-His-tagged matriptase-2 expressed in Drosophila S2 cells using Boc-Gln-Ala-ArgAMC as substrate measured for 1200 mins by fluorescence assay	ki	0.0011	uM
(4S)-4-[[(2S)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]-5-[[(2S)-1-[[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-5-oxopentanoic acid	1806088: TMPRSS2 pericellular activity screening assay from Article 10.1038/s41586-022-04661-w: “A TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic.”	ki	0.0011	uM
(2S)-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-2-[[(2S)-3-(4-hydroxyphenyl)-2-[3-(4-hydroxyphenyl)propanoylamino]propanoyl]amino]-3-methylbutanamide	1441767: Inhibition of recombinant human C-terminal V5-His-tagged matriptase-2 expressed in Drosophila S2 cells using Boc-Gln-Ala-ArgAMC as substrate measured for 1200 mins by fluorescence assay	ki	0.0012	uM
(2S,3S)-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-3-methyl-2-[[(2S)-2-(3-phenylpropanoylamino)-3-(1,3-thiazol-4-yl)propanoyl]amino]pentanamide	2110361: Binding affinity to recombinant human TMPRSS6 using Boc-QAR-AMC as substrate assessed as inhibition constant by fluorescence based analysis	ki	0.0012	uM
(2S,3R)-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-3-methyl-2-[[(2S)-2-(3-phenylpropanoylamino)-3-(1,3-thiazol-4-yl)propanoyl]amino]pentanamide	2110361: Binding affinity to recombinant human TMPRSS6 using Boc-QAR-AMC as substrate assessed as inhibition constant by fluorescence based analysis	ki	0.0014	uM
(2S)-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-3-phenyl-2-[[(2S)-2-(3-phenylpropanoylamino)-3-(1,3-thiazol-4-yl)propanoyl]amino]propanamide	2110361: Binding affinity to recombinant human TMPRSS6 using Boc-QAR-AMC as substrate assessed as inhibition constant by fluorescence based analysis	ki	0.0014	uM
(2S)-N-[(2S)-1-[[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxobutan-2-yl]-4-phenyl-2-(3-phenylpropanoylamino)butanamide	1441767: Inhibition of recombinant human C-terminal V5-His-tagged matriptase-2 expressed in Drosophila S2 cells using Boc-Gln-Ala-ArgAMC as substrate measured for 1200 mins by fluorescence assay	ki	0.0015	uM
(2S)-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-4-methyl-2-[[(2S)-2-(3-phenylpropanoylamino)-3-(1,3-thiazol-4-yl)propanoyl]amino]pentanamide	2110361: Binding affinity to recombinant human TMPRSS6 using Boc-QAR-AMC as substrate assessed as inhibition constant by fluorescence based analysis	ki	0.0015	uM
(2S)-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-2-[[(2S)-3-(4-hydroxyphenyl)-2-(3-phenylpropanoylamino)propanoyl]amino]-3-methylbutanamide	1441767: Inhibition of recombinant human C-terminal V5-His-tagged matriptase-2 expressed in Drosophila S2 cells using Boc-Gln-Ala-ArgAMC as substrate measured for 1200 mins by fluorescence assay	ki	0.0017	uM
(2S)-2-amino-N-[(2S)-1-[[(2S)-1-[[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]-4-methylpentanamide	1170923: Inhibition of human recombinant matriptase-2 using Boc-Gln-Ala-Arg-AMC as substrate by microplate reader analysis	ki	0.0020	uM
(2S)-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-3-methyl-2-[[(2S)-4-phenyl-2-(3-phenylpropanoylamino)butanoyl]amino]butanamide	1441767: Inhibition of recombinant human C-terminal V5-His-tagged matriptase-2 expressed in Drosophila S2 cells using Boc-Gln-Ala-ArgAMC as substrate measured for 1200 mins by fluorescence assay	ki	0.0021	uM
(2S)-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-4-phenyl-2-[[(2S)-2-(3-phenylpropanoylamino)-3-(1,3-thiazol-4-yl)propanoyl]amino]butanamide	2110361: Binding affinity to recombinant human TMPRSS6 using Boc-QAR-AMC as substrate assessed as inhibition constant by fluorescence based analysis	ki	0.0022	uM
(2S)-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-2-[[(2S)-4-phenyl-2-(3-phenylpropanoylamino)butanoyl]amino]pentanamide	1441767: Inhibition of recombinant human C-terminal V5-His-tagged matriptase-2 expressed in Drosophila S2 cells using Boc-Gln-Ala-ArgAMC as substrate measured for 1200 mins by fluorescence assay	ki	0.0023	uM
(2S)-2-[[(2S)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]-N-[(2S)-1-[[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]-4-methylpentanamide	1170923: Inhibition of human recombinant matriptase-2 using Boc-Gln-Ala-Arg-AMC as substrate by microplate reader analysis	ki	0.0025	uM
(2S)-2-[[(2S)-2-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-3-methylbutanamide	1170923: Inhibition of human recombinant matriptase-2 using Boc-Gln-Ala-Arg-AMC as substrate by microplate reader analysis	ki	0.0026	uM
(2S)-N-[(2S)-1-[[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]-2-(methanesulfonamido)pentanediamide	1806088: TMPRSS2 pericellular activity screening assay from Article 10.1038/s41586-022-04661-w: “A TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic.”	ki	0.0026	uM
(2S,3R)-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-3-methyl-2-[[(2S)-4-phenyl-2-(3-phenylpropanoylamino)butanoyl]amino]pentanamide	1441767: Inhibition of recombinant human C-terminal V5-His-tagged matriptase-2 expressed in Drosophila S2 cells using Boc-Gln-Ala-ArgAMC as substrate measured for 1200 mins by fluorescence assay	ki	0.0026	uM
(2S,3S)-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-3-hydroxy-2-[[(2S)-4-phenyl-2-(3-phenylpropanoylamino)butanoyl]amino]butanamide	1441767: Inhibition of recombinant human C-terminal V5-His-tagged matriptase-2 expressed in Drosophila S2 cells using Boc-Gln-Ala-ArgAMC as substrate measured for 1200 mins by fluorescence assay	ki	0.0031	uM
(2S)-2-amino-N-[(2S)-1-[[(2S)-1-[[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]-3-(4-hydroxyphenyl)propanamide	1441767: Inhibition of recombinant human C-terminal V5-His-tagged matriptase-2 expressed in Drosophila S2 cells using Boc-Gln-Ala-ArgAMC as substrate measured for 1200 mins by fluorescence assay	ki	0.0031	uM
(2S)-2-[[(2S)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]-N-[(2S)-1-[[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]pentanediamide	682985: Tight binding inhibition of human matriptase2 expressed in Drosophila melanogaster S2 cells using Boc-QAR-AMC as substrate incubated for 15 mins prior to substrate addition measured for 30 mins by fluorimetric analysis	ki	0.0033	uM
(2S)-N-[(1S)-2-[[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-cyclohexyl-2-oxoethyl]-2-(3-phenylpropanoylamino)-3-(1,3-thiazol-4-yl)propanamide	2110361: Binding affinity to recombinant human TMPRSS6 using Boc-QAR-AMC as substrate assessed as inhibition constant by fluorescence based analysis	ki	0.0034	uM
(2S)-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-3-methyl-2-[[(2S)-3-(4-phenylmethoxyphenyl)-2-(3-phenylpropanoylamino)propanoyl]amino]butanamide	1441767: Inhibition of recombinant human C-terminal V5-His-tagged matriptase-2 expressed in Drosophila S2 cells using Boc-Gln-Ala-ArgAMC as substrate measured for 1200 mins by fluorescence assay	ki	0.0035	uM
(2S)-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-3-naphthalen-1-yl-2-[[(2S)-2-(3-phenylpropanoylamino)-3-(1,3-thiazol-4-yl)propanoyl]amino]propanamide	2110361: Binding affinity to recombinant human TMPRSS6 using Boc-QAR-AMC as substrate assessed as inhibition constant by fluorescence based analysis	ki	0.0037	uM
(2S)-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-3-cyclohexyl-2-[[(2S)-2-(3-phenylpropanoylamino)-3-(1,3-thiazol-4-yl)propanoyl]amino]propanamide	2110361: Binding affinity to recombinant human TMPRSS6 using Boc-QAR-AMC as substrate assessed as inhibition constant by fluorescence based analysis	ki	0.0039	uM
(2S,3S)-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-3-methyl-2-[[(2S)-4-phenyl-2-(3-phenylpropanoylamino)butanoyl]amino]pentanamide	1441767: Inhibition of recombinant human C-terminal V5-His-tagged matriptase-2 expressed in Drosophila S2 cells using Boc-Gln-Ala-ArgAMC as substrate measured for 1200 mins by fluorescence assay	ki	0.0040	uM
(2S)-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-4,4-dimethyl-2-[[(2S)-2-(3-phenylpropanoylamino)-3-(1,3-thiazol-4-yl)propanoyl]amino]pentanamide	2110361: Binding affinity to recombinant human TMPRSS6 using Boc-QAR-AMC as substrate assessed as inhibition constant by fluorescence based analysis	ki	0.0046	uM
(2R,3R)-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-3-methyl-2-[[(2S)-4-phenyl-2-(3-phenylpropanoylamino)butanoyl]amino]pentanamide	1441767: Inhibition of recombinant human C-terminal V5-His-tagged matriptase-2 expressed in Drosophila S2 cells using Boc-Gln-Ala-ArgAMC as substrate measured for 1200 mins by fluorescence assay	ki	0.0050	uM
(2S)-2-amino-N-[(2S)-1-[[(2S)-1-[[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-(3,4-dihydroxyphenyl)-1-oxopropan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]-3-(4-hydroxyphenyl)propanamide	1441767: Inhibition of recombinant human C-terminal V5-His-tagged matriptase-2 expressed in Drosophila S2 cells using Boc-Gln-Ala-ArgAMC as substrate measured for 1200 mins by fluorescence assay	ki	0.0050	uM
(2S)-2-[[(2S)-2-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]-3-(3-chlorophenyl)propanoyl]amino]-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-3-methylbutanamide	1441767: Inhibition of recombinant human C-terminal V5-His-tagged matriptase-2 expressed in Drosophila S2 cells using Boc-Gln-Ala-ArgAMC as substrate measured for 1200 mins by fluorescence assay	ki	0.0050	uM
(2S)-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-4-methyl-2-[[(2S)-4-phenyl-2-(3-phenylpropanoylamino)butanoyl]amino]pentanamide	1441767: Inhibition of recombinant human C-terminal V5-His-tagged matriptase-2 expressed in Drosophila S2 cells using Boc-Gln-Ala-ArgAMC as substrate measured for 1200 mins by fluorescence assay	ki	0.0052	uM
(2S)-N-[(1S)-2-[[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-cyclohexyl-2-oxoethyl]-4-phenyl-2-(3-phenylpropanoylamino)butanamide	2110368: Competitive tight binding inhibition of recombinant human TMPRSS6 using Boc-QAR-AMC as substrate assessed as inhibition constant by fluorescence based analysis	ki	0.0052	uM
(2S)-2-amino-N-[(2S)-1-[[(2S)-1-[[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-naphthalen-2-yl-1-oxopropan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]-3-(4-hydroxyphenyl)propanamide	1441767: Inhibition of recombinant human C-terminal V5-His-tagged matriptase-2 expressed in Drosophila S2 cells using Boc-Gln-Ala-ArgAMC as substrate measured for 1200 mins by fluorescence assay	ki	0.0053	uM
(2S,3R)-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-3-hydroxy-2-[[(2S)-4-phenyl-2-(3-phenylpropanoylamino)butanoyl]amino]butanamide	1441767: Inhibition of recombinant human C-terminal V5-His-tagged matriptase-2 expressed in Drosophila S2 cells using Boc-Gln-Ala-ArgAMC as substrate measured for 1200 mins by fluorescence assay	ki	0.0053	uM
(2S)-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-3-(4-phenylmethoxyphenyl)-2-[[(2S)-2-(3-phenylpropanoylamino)-3-(1,3-thiazol-4-yl)propanoyl]amino]propanamide	2110361: Binding affinity to recombinant human TMPRSS6 using Boc-QAR-AMC as substrate assessed as inhibition constant by fluorescence based analysis	ki	0.0056	uM
[4-[2-[2-(dimethylamino)-2-oxoethoxy]-2-oxoethyl]phenyl] 4-(diaminomethylideneamino)benzoate	1806088: TMPRSS2 pericellular activity screening assay from Article 10.1038/s41586-022-04661-w: “A TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic.”	ki	0.0056	uM
N-[(2S)-1-[[(2S)-1-[[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]-4-methylpentanamide	1441767: Inhibition of recombinant human C-terminal V5-His-tagged matriptase-2 expressed in Drosophila S2 cells using Boc-Gln-Ala-ArgAMC as substrate measured for 1200 mins by fluorescence assay	ki	0.0060	uM
(2S)-2-amino-N-[(2S)-1-[[(2S)-1-[[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxo-3-thiophen-2-ylpropan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]-3-(4-hydroxyphenyl)propanamide	1441767: Inhibition of recombinant human C-terminal V5-His-tagged matriptase-2 expressed in Drosophila S2 cells using Boc-Gln-Ala-ArgAMC as substrate measured for 1200 mins by fluorescence assay	ki	0.0060	uM
(2S)-2-[[(2S)-2-[[2-(1-adamantyl)acetyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-3-methylbutanamide	1441767: Inhibition of recombinant human C-terminal V5-His-tagged matriptase-2 expressed in Drosophila S2 cells using Boc-Gln-Ala-ArgAMC as substrate measured for 1200 mins by fluorescence assay	ki	0.0060	uM
(2S)-2-amino-N-[(2S)-1-[[(2S)-1-[[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]-5-(diaminomethylideneamino)pentanamide	1170923: Inhibition of human recombinant matriptase-2 using Boc-Gln-Ala-Arg-AMC as substrate by microplate reader analysis	ki	0.0063	uM
(2R)-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-3-methyl-2-[[(2S)-4-phenyl-2-(3-phenylpropanoylamino)butanoyl]amino]butanamide	1441767: Inhibition of recombinant human C-terminal V5-His-tagged matriptase-2 expressed in Drosophila S2 cells using Boc-Gln-Ala-ArgAMC as substrate measured for 1200 mins by fluorescence assay	ki	0.0070	uM
(2S)-1-[(2S)-5-amino-2-[[(2S)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]-5-oxopentanoyl]-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]pyrrolidine-2-carboxamide	1170923: Inhibition of human recombinant matriptase-2 using Boc-Gln-Ala-Arg-AMC as substrate by microplate reader analysis	ki	0.0078	uM
(2S)-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-3-naphthalen-2-yl-2-[[(2S)-2-(3-phenylpropanoylamino)-3-(1,3-thiazol-4-yl)propanoyl]amino]propanamide	2110361: Binding affinity to recombinant human TMPRSS6 using Boc-QAR-AMC as substrate assessed as inhibition constant by fluorescence based analysis	ki	0.0079	uM
(2S)-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-4-cyclohexyl-2-[[(2S)-2-(3-phenylpropanoylamino)-3-(1,3-thiazol-4-yl)propanoyl]amino]butanamide	2110361: Binding affinity to recombinant human TMPRSS6 using Boc-QAR-AMC as substrate assessed as inhibition constant by fluorescence based analysis	ki	0.0083	uM
(2S)-2-[[(2S)-2-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]-3-phenylpropanoyl]amino]-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-3-methylbutanamide	1441767: Inhibition of recombinant human C-terminal V5-His-tagged matriptase-2 expressed in Drosophila S2 cells using Boc-Gln-Ala-ArgAMC as substrate measured for 1200 mins by fluorescence assay	ki	0.0090	uM
(2S)-N-[(1S)-2-[[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-2-oxo-1-phenylethyl]-2-(3-phenylpropanoylamino)-3-(1,3-thiazol-4-yl)propanamide	2110361: Binding affinity to recombinant human TMPRSS6 using Boc-QAR-AMC as substrate assessed as inhibition constant by fluorescence based analysis	ki	0.0125	uM

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	5
Iron	affects abundance	2
Aflatoxin B1	decreases methylation, decreases expression	2
aristolochic acid I	increases expression	1
methyleugenol	decreases expression	1
sodium arsenite	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
CGP 52608	affects binding, increases reaction	1
bisphenol S	decreases methylation	1
Rosiglitazone	decreases expression	1
Acetaminophen	decreases expression	1
Ascorbic Acid	affects cotreatment, decreases expression	1
Endosulfan	decreases expression	1
Formaldehyde	increases expression	1
Lipopolysaccharides	increases expression, affects response to substance	1
Methapyrilene	decreases expression	1
N-Nitrosopyrrolidine	decreases expression	1
Phenobarbital	affects expression	1
Quercetin	affects cotreatment, decreases expression	1
Selenium	increases expression	1
Valproic Acid	decreases expression	1
Vitamin E	increases expression	1
Okadaic Acid	decreases expression	1
Raloxifene Hydrochloride	affects response to substance	1

ChEMBL screening assays

21 unique, capped per target: 21 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1218918	Binding	Inhibition of human recombinant matriptase 2 expressed in HEK293 cells in conditioned medium after 20 mins	Identification of the first low-molecular-weight inhibitors of matriptase-2. — J Med Chem

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2IW	Abcam HeLa TMPRSS6 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02905981	PHASE2	TERMINATED	Triferic IRIDA (Iron-Refractory Iron-Deficiency Anemia) Protocol