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 (top 1% of genes corpus-wide)
• Clinical variants (ClinVar): 446 total — 22 pathogenic, 19 likely-pathogenic (top 7% of genes corpus-wide)
• GTEx eGene: eQTL in 11 tissues, sQTL in 4 (q < 0.05)
• Phenotypes (HPO): 13
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.82 (unconstrained)
• 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: 48 — 41 protein_coding, 7 nonsense_mediated_decay

MANE Select: ENST00000676104

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

ENST00000676104, ENST00000346753, ENST00000381792, ENST00000406725, ENST00000406856, ENST00000423761, ENST00000429068, ENST00000442782, 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, ENST00000985021, ENST00000985022, ENST00000985024, ENST00000985025, ENST00000985026, ENST00000985027, ENST00000985028, ENST00000985030, ENST00000985031, ENST00001101696, ENST00001135196

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.

Highest expression (Bgee): lobe of liver, liver, mammary duct, type B pancreatic cell, olfactory bulb.

Genetic regulation across tissues (GTEx eQTL / sQTL)

TMPRSS6 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 11 tissues and its splicing (sQTL) in 4 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

15 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Testis	eqtl	1.1e-22	-0.25	22:37098380:T:C
Brain Nucleus accumbens basal ganglia	eqtl	2.2e-13	+0.33	22:37071352:G:C
Stomach	eqtl	3.1e-11	+0.36	22:37100807:C:T
Liver	sqtl	6.9e-10	+0.79	22:37068584:T:C
Skin Sun Exposed Lower leg	eqtl	1.3e-08	+0.27	22:37105030:A:G
Lung	eqtl	1.2e-06	+0.42	22:37113804:T:C
Testis	sqtl	2.2e-03	-0.24	22:37088334:T:G
Liver	eqtl	2.2e-03	-0.22	22:37114993:A:G
Pituitary	sqtl	2.6e-03	-0.45	22:37068584:T:C
Skin Not Sun Exposed Suprapubic	eqtl	1.1e-02	+0.28	22:37109512:C:T
Skin Sun Exposed Lower leg	sqtl	2.2e-02	+0.28	22:37068584:T:C
Brain Anterior cingulate cortex BA24	eqtl	2.3e-02	+0.46	22:36563692:A:C
Pancreas	eqtl	2.4e-02	+0.83	22:37095164:C:T
Artery Aorta	eqtl	4.0e-02	+0.23	22:37281678:G:A
Brain Cerebellum	eqtl	4.6e-02	-0.89	22:37581605:G:C

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

showing 100 of 248 tissues 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
heart right ventricle	UBERON:0002080	71.62	gold quality
cervix epithelium	UBERON:0004801	71.37	gold quality
Brodmann (1909) area 46	UBERON:0006483	70.92	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	70.89	gold quality
endometrium epithelium	UBERON:0004811	70.64	gold quality
secondary oocyte	CL:0000655	70.53	silver quality
cervix squamous epithelium	UBERON:0006922	70.00	gold quality
vena cava	UBERON:0004087	69.70	gold quality
pylorus	UBERON:0001166	69.58	gold quality
trachea	UBERON:0003126	69.46	gold quality
pons	UBERON:0000988	69.44	silver quality
caudate nucleus	UBERON:0001873	69.35	gold quality
hair follicle	UBERON:0002073	69.28	gold quality
tongue	UBERON:0001723	69.21	gold quality
islet of Langerhans	UBERON:0000006	69.20	gold quality
kidney epithelium	UBERON:0004819	69.00	gold quality
superior surface of tongue	UBERON:0007371	68.98	silver quality
skeletal muscle tissue	UBERON:0001134	68.80	gold quality
nucleus accumbens	UBERON:0001882	68.80	gold quality
CA1 field of hippocampus	UBERON:0003881	68.80	gold quality
body of tongue	UBERON:0011876	68.69	gold quality
deltoid	UBERON:0001476	68.44	gold quality
lower lobe of lung	UBERON:0008949	68.38	silver quality
saphenous vein	UBERON:0007318	68.29	gold quality
ileal mucosa	UBERON:0000331	68.15	silver quality
trigeminal ganglion	UBERON:0001675	68.12	silver quality
layer of synovial tissue	UBERON:0007616	68.11	gold quality
periodontal ligament	UBERON:0008266	67.97	silver quality
pericardium	UBERON:0002407	67.93	gold quality
nipple	UBERON:0002030	67.83	gold quality
lateral globus pallidus	UBERON:0002476	67.66	gold quality
lateral nuclear group of thalamus	UBERON:0002736	67.44	gold quality
metanephric glomerulus	UBERON:0004736	67.30	gold quality
substantia nigra pars compacta	UBERON:0001965	67.22	gold quality
synovial joint	UBERON:0002217	67.11	silver quality
duodenum	UBERON:0002114	67.07	gold quality
tibia	UBERON:0000979	67.05	gold quality
parotid gland	UBERON:0001831	66.99	gold quality
nephron tubule	UBERON:0001231	66.79	gold quality
endothelial cell	CL:0000115	66.61	gold quality
penis	UBERON:0000989	66.53	gold quality
cerebellar vermis	UBERON:0004720	66.50	gold quality
superficial temporal artery	UBERON:0001614	66.34	gold quality
squamous epithelium	UBERON:0006914	65.98	gold quality
renal glomerulus	UBERON:0000074	65.68	gold quality
urethra	UBERON:0000057	65.08	gold quality
gingival epithelium	UBERON:0001949	65.08	gold quality
tibialis anterior	UBERON:0001385	64.70	silver quality
mammary gland	UBERON:0001911	64.65	gold quality
decidua	UBERON:0002450	64.58	silver quality
thoracic mammary gland	UBERON:0005200	64.53	gold quality
jejunal mucosa	UBERON:0000399	64.15	silver quality
upper leg skin	UBERON:0004262	64.09	gold quality
gingiva	UBERON:0001828	64.04	gold quality
epithelium of esophagus	UBERON:0001976	63.79	gold quality
placenta	UBERON:0001987	63.57	gold quality
inferior olivary complex	UBERON:0002127	62.94	gold quality
esophagus squamous epithelium	UBERON:0006920	62.70	gold quality
Brodmann (1909) area 23	UBERON:0013554	62.52	gold quality
germinal epithelium of ovary	UBERON:0001304	62.21	gold quality
nasal cavity mucosa	UBERON:0001826	62.11	silver quality
cartilage tissue	UBERON:0002418	61.95	gold quality
globus pallidus	UBERON:0001875	61.93	gold quality
zone of skin	UBERON:0000014	61.86	gold quality
entorhinal cortex	UBERON:0002728	61.83	gold quality
granulocyte	CL:0000094	61.77	gold quality
skin of abdomen	UBERON:0001416	61.75	gold quality
orbitofrontal cortex	UBERON:0004167	61.62	gold quality
skin of leg	UBERON:0001511	61.51	gold quality
oviduct epithelium	UBERON:0004804	61.51	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

HPA expression

RNA tissue specificity: Tissue enriched

showing 60 of 63 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Liver	tissue	71.7
Pituitary gland	tissue	12.4
Nucleus accumbens	tissue	4.9
Putamen	tissue	4.7
Testis	tissue	4.3
Stomach 1	tissue	3.4
Basal ganglia	tissue	3.0
Skin 1	tissue	2.1
Duodenum	tissue	2.1
Cerebellum	tissue	1.7
Ventral forebrain	tissue	1.6
Periaqueductal gray	tissue	1.6
Olfactory bulb	tissue	1.6
Cerebral cortex	tissue	1.4
Corpus callosum	tissue	1.4
Retrosplenial cortex	tissue	1.4
Occipital cortex	tissue	1.4
Insular cortex	tissue	1.4
Prefrontal cortex	tissue	1.3
Amygdala	tissue	1.3
Hippocampal formation	tissue	1.3
Entorhinal cortex	tissue	1.3
Retrosplenial and cingulate cortex	tissue	1.3
Septum	tissue	1.3
Temporal cortex	tissue	1.3
Pancreas	tissue	1.2
Hypothalamus	tissue	1.2
Somatosensory cortex	tissue	1.2
Motor cortex	tissue	1.1
Medulla oblongata	tissue	1.1
Pons	tissue	1.0
Thalamus	tissue	1.0
Superior colliculi	tissue	1.0
Small intestine	tissue	1.0
Spinal cord	tissue	1.0
Midbrain	tissue	0.9
Substantia nigra	tissue	0.9
Postcentral gyrus	tissue	0.9
Epididymis	tissue	0.8
Gallbladder	tissue	0.8
Choroid plexus	tissue	0.7
Placenta	tissue	0.7
Locus coeruleus	tissue	0.7
Hippocampus	tissue	0.7
Colon	tissue	0.6
Caudate putamen	tissue	0.6
Rectum	tissue	0.5
Lung	tissue	0.5
Fallopian tube	tissue	0.5
Lymph node	tissue	0.3
Breast	tissue	0.3
Thymus	tissue	0.3
Esophagus	tissue	0.2
Bone marrow	tissue	0.2
Appendix	tissue	0.2
Retina	tissue	0.1
Vagina	tissue	0.1
Adipose tissue	tissue	0.1
Endometrium 1	tissue	0.1
Thyroid gland	tissue	0.1

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Caudate nucleus (7.0), Nucleus basalis of Meynert (6.1), Centromedial thalamic nucleus (3.7), Ventromedial nucleus (3.5), Pulvinar (2.8).

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets:

Target	Regulation
BMP6	Activation
TFRC	Repression

miRNA regulators (miRDB)

Targeting TMPRSS6 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

16 miRNAs:

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

gnomAD constraint: pLI 7.56e-14, LOEUF 0.821, missense Z 0.545 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000676104 — one region, missense o/e 0.95. 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)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1919003) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 60 distinct phenotype terms.

Mouse phenotype (MP)	Records
alopecia	6
decreased circulating iron level	6
decreased mean corpuscular volume	4
decreased hemoglobin content	4
decreased hematocrit	2
decreased body size	2
abnormal iron level	2
female infertility	2
abnormal erythrocyte morphology	2
microcytic anemia	2
decreased mean corpuscular hemoglobin	2
abnormal iron homeostasis	2
decreased mean corpuscular hemoglobin concentration	2
decreased liver iron level	2
decreased spleen iron level	2
progressive hair loss	2
increased circulating calcium level	1
extramedullary hematopoiesis	1
abnormal coat/ hair morphology	1
abnormal hair follicle morphology	1
sparse hair	1
focal hair loss	1
decreased locomotor activity	1
decreased exploration in new environment	1
abnormal coat appearance	1

+35 more (showing top 25).

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
Phytophthora sojae strain P6497	G5AE35	100.0%	Diamond
Tropidechis carinatus	P81428	99.3%	Diamond
Notechis scutatus scutatus	P82807	99.3%	Diamond
Pan troglodytes	Q5R1W3	99.3%	Diamond
Pongo abelii	Q5R5E8	99.3%	Diamond
Pan paniscus	Q2F9P4	98.7%	Diamond
Nomascus leucogenys	Q5G268	98.5%	Diamond
Gorilla gorilla gorilla	Q5G270	98.5%	Diamond
Trachypithecus phayrei	Q5G266	98.3%	Diamond
Macaca mulatta	Q5G267	98.3%	Diamond
Hoplocephalus stephensii	P83370	97.6%	Diamond
Tachypleus tridentatus	P28175	97.2%	Diamond
Carcinoscorpius rotundicauda	Q26422	97.2%	Diamond
Bos taurus	P00741	96.8%	Diamond
Ovis aries	P16291	96.8%	Diamond
Pongo pygmaeus	Q5G269	96.7%	Diamond
Macaca fascicularis	Q4R577	96.3%	Diamond
Manduca sexta	P35045	96.1%	Diamond
Saguinus labiatus	Q5G265	95.5%	Diamond
Oxyuranus microlepidotus	Q58L95	95.1%	Diamond
Oxyuranus scutellatus	Q58L96	95.1%	Diamond
Pseudonaja textilis	Q1L659	93.6%	Diamond
Papio cynocephalus	P16227	92.6%	Diamond
Lucilia cuprina	P35044	91.5%	Diamond
Rhinella arenarum	Q66TN7	90.6%	Diamond
Desmodus rotundus	P15638	89.9%	Diamond
Cryptophis nigrescens	B5G6G5	89.2%	Diamond
Canis lupus familiaris	P19540	88.5%	Diamond
Acropora millepora	B8V7S0	87.4%	Diamond
Oryctolagus cuniculus	Q28661	86.3%	Diamond
Pseudechis porphyriacus	Q58L93	86.1%	Diamond
Felis catus	Q28412	86.0%	Diamond
Demansia vestigiata	A6MFK7	85.8%	Diamond
Sus scrofa	Q19AZ8	85.0%	Diamond
Meriones unguiculatus	P50342	84.7%	Diamond
Equus caballus	Q28380	84.7%	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
IL2RB-AS1	ncRNA	139281655
IL2RB	protein-coding	3560
MPST	protein-coding	4357
TST	protein-coding	7263
KCTD17	protein-coding	79734
C1QTNF6	protein-coding	114904
SSTR3	protein-coding	6753
CIMIP4	protein-coding	339669
RAC2	protein-coding	5880

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 (148 total): strand 47, sequence variant 36, helix 18, disulfide bond 14, domain 7, glycosylation site 7, turn 5, splice variant 4, active site 3, topological domain 2, mutagenesis site 2, chain 1, sequence conflict 1, transmembrane region 1

Structure

Experimental structures (PDB)

1 structures by resolution:

PDB	Title	Method	Resolution (Å)
9NRC	TMPRSS6 in complex with REGN7999 Fab and REGN8023 Fab	ELECTRON MICROSCOPY	3.29

Predicted structure (AlphaFold)

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

Antibody-complex structures (SAbDab)

1 antibodies co-crystallized with this protein: 9NRC

Human Protein Atlas

Protein class: Enzymes, Peptidases, Serine-type peptidases, Predicted membrane proteins, Predicted intracellular proteins, Plasma proteins, Disease related genes, Potential drug targets, Human disease related genes

Protein evidence: Evidence at protein level

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
617	charge relay system
668	charge relay system
762	charge relay system

Disulfide bonds (14)

Type	Positions
Disulfide bond	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)

Type	Positions
N-linked (glcnac…) asparagine	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

0 curated (TAS) of 3; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

3 pathways:

ID	Pathway	Evidence
R-HSA-1442490	Collagen degradation	electronic
R-HSA-1474228	Degradation of the extracellular matrix	electronic
R-HSA-1474244	Extracellular matrix organization	—

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 (11): negative regulation of transcription by RNA polymerase II (GO:0000122), intracellular iron ion homeostasis (GO:0006879), protein processing (GO:0016485), extracellular matrix disassembly (GO:0022617), 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 (1): plasma membrane (GO:0005886)

Reactome top-level categories

2 top-level categories:

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

GO top-level categories

29 GO namespaces:

Category	Terms
proteolysis	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
inorganic ion homeostasis	2
endopeptidase activity	2
negative regulation of DNA-templated transcription	1
intracellular monoatomic cation homeostasis	1
protein maturation	1
cellular component disassembly	1
extracellular matrix organization	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

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 5 of 19 annotations. The rest are phylogenetic / computational / electronic (IEA).

5 experimentally-supported GO terms:

GO term	NS	Evidence
membrane protein proteolysis	BP	mutant phenotype
multicellular organismal-level iron ion homeostasis	BP	mutant phenotype
negative regulation of DNA-templated transcription	BP	mutant phenotype
self proteolysis	BP	mutant phenotype
plasma membrane	CC	direct assay

Protein interactions and networks

STRING

showing 15 of 622 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMPRSS6	HAMP	P81172	960
TMPRSS6	HJV	Q6ZVN8	958
TMPRSS6	HFE	Q30201	902
TMPRSS6	BMP6	P22004	818
TMPRSS6	TFR2	Q9UP52	804
TMPRSS6	TFRC	P02786	747
TMPRSS6	EPO	P01588	697
TMPRSS6	GDF15	P78360	697
TMPRSS6	CYBRD1	Q53TN4	692
TMPRSS6	CREB3L3	Q68CJ9	685
TMPRSS6	SLC11A2	P49281	684
TMPRSS6	NEO1	Q92859	629
TMPRSS6	SLC40A1	Q9NP59	576
TMPRSS6	ERFE	Q4G0M1	570
TMPRSS6	TWSG1	Q9GZX9	487

IntAct

Human interaction partners of TMPRSS6 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

2 partners by confidence:

Partner	Interaction type	MIscore	Records
HJV	physical association	0.400	1
CFTR	physical association	0.370	1

BioGRID (5 interactions; top human partners by supporting records): CFTR (PCA), HNRNPL (Affinity Capture-RNA), PARP3 (Proximity Label-MS), POLI (Reconstituted Complex), TRIM71 (Affinity Capture-RNA)

Disease & clinical

Genetic variants

Variant evidence for TMPRSS6: 446 ClinVar records (41 pathogenic / likely pathogenic); 155 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	22
Likely pathogenic	19
Uncertain significance	230
Likely benign	73
Benign	28

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 41 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
3380919	NM_001374504.1(TMPRSS6):c.1655C>A (p.Ser552Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	4
1404	NM_001374504.1(TMPRSS6):c.1534G>A (p.Asp512Asn)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	5
1405	NM_001374504.1(TMPRSS6):c.1038C>A (p.Tyr346Ter)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	5
4056834	NM_001374504.1(TMPRSS6):c.208A>T (p.Lys70Ter)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
1297560	NM_001374504.1(TMPRSS6):c.470del (p.Leu157fs)	Pathogenic	criteria provided, single submitter	3
617552	NM_001374504.1(TMPRSS6):c.207C>G (p.Tyr69Ter)	Pathogenic	criteria provided, single submitter	1
627580	NM_001374504.1(TMPRSS6):c.2134C>T (p.Gln712Ter)	Pathogenic	criteria provided, single submitter	1
2412690	NM_001374504.1(TMPRSS6):c.1055C>A (p.Ser352Ter)	Pathogenic	criteria provided, single submitter	1
2791461	NM_001374504.1(TMPRSS6):c.930C>G (p.Tyr310Ter)	Pathogenic	criteria provided, single submitter	1
3658350	NM_001374504.1(TMPRSS6):c.355_361del (p.Ser119fs)	Pathogenic	criteria provided, single submitter	1
3723975	NM_001374504.1(TMPRSS6):c.2074_2081dup (p.Trp694fs)	Pathogenic	criteria provided, single submitter	1
4686736	NM_001374504.1(TMPRSS6):c.1687_1697del (p.Gly563fs)	Pathogenic	criteria provided, single submitter	1
1406	NM_001374504.1(TMPRSS6):c.1355del (p.Glu452fs)	Likely pathogenic	criteria provided, single submitter	2
1180681	NM_001374504.1(TMPRSS6):c.1620_1627del (p.Gln541fs)	Likely pathogenic	criteria provided, single submitter	1
1299579	NM_001374504.1(TMPRSS6):c.1547G>A (p.Cys516Tyr)	Likely pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore TMPRSS6’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 22 predictions of 1,860):

Position(s)	Effect	Δscore	Sites
22:37066825	donor_loss	1.0000	2
22:37066963	acceptor_loss	1.0000	2
22:37066968	acceptor_gain	1.0000
22:37066975	acceptor_gain	1.0000
22:37070914–37070915	donor_loss	1.0000	4
22:37073534	donor_gain	1.0000
22:37074608–37074609	donor_loss	1.0000	3
22:37084293	donor_loss	1.0000
22:37084405–37084406	acceptor_loss	1.0000	6
22:37066239	acceptor_gain	0.9900

HPA cancer prognostics

RNA cancer specificity: Group enriched (Liver Hepatocellular Carcinoma, Thyroid Carcinoma)

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

2 prognostic cancer types:

Cancer	Prognostic	p-value
Liver Hepatocellular Carcinoma (validation)	favorable	7.23e-06
Liver Hepatocellular Carcinoma (TCGA)	favorable	9.7e-06

Disease associations

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

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
IRIDA syndrome	Definitive	Autosomal recessive	5

ClinGen Gene-Disease Validity

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

1 validity classifications:

Disease	Classification	Inheritance
IRIDA syndrome	Definitive	AR

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (5 panels, 5 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

5 panels:

Panel	Rating
Cytopenias and congenital anaemias	green
DDG2P	green
Iron metabolism disorders - NOT common HFE mutations	green
Paediatric disorders	green
Rare anaemia	green

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

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

HPO phenotypes

13 phenotypes (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

GWAS associations

showing 30 of 155 associations:

Study	Trait	p-value
GCST004602_124	Mean corpuscular volume	0.000000e+00
GCST004630_166	Mean corpuscular hemoglobin	0.000000e+00
GCST90002384_227	Hemoglobin	0.000000e+00
GCST90002390_65	Mean corpuscular hemoglobin	0.000000e+00
GCST90002392_244	Mean corpuscular volume	0.000000e+00
GCST90002404_179	Red cell distribution width	0.000000e+00
GCST011366_9	Iron status biomarkers (transferrin saturation)	1e-300
GCST011367_4	Iron status biomarkers (iron levels)	1e-300
GCST90002391_253	Mean corpuscular hemoglobin concentration	7e-278
GCST004621_31	Red cell distribution width	1e-270
GCST006804_11	Red cell distribution width	1e-204
GCST90002383_482	Hematocrit	5e-202
GCST004605_57	Mean corpuscular hemoglobin concentration	5e-189
GCST010083_306	Hemoglobin levels	9e-173
GCST004615_120	Hemoglobin concentration	6e-169
GCST005993_65	Mean corpuscular hemoglobin	1e-158
GCST90002397_415	Mean spheric corpuscular volume	2e-149
GCST002679_4	Iron status biomarkers (iron levels)	1e-139
GCST002680_5	Iron status biomarkers (transferrin saturation)	6e-137
GCST004602_126	Mean corpuscular volume	3e-126
GCST004630_168	Mean corpuscular hemoglobin	7e-114
GCST004630_169	Mean corpuscular hemoglobin	3e-113
GCST004630_167	Mean corpuscular hemoglobin	4e-103
GCST004621_109	Red cell distribution width	2e-99
GCST006011_2	Mean corpuscular volume	2e-95
GCST90002406_177	Reticulocyte fraction of red cells	2e-83
GCST005992_39	Mean corpuscular hemoglobin concentration	5e-77
GCST004630_170	Mean corpuscular hemoglobin	4e-74
GCST004604_4	Hematocrit	4e-73
GCST004621_108	Red cell distribution width	6e-71

EFO canonical traits (from GWAS)

26 canonical traits:

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 disease descriptors:

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 (CPIC guideline: no)

PharmGKB variant annotations

Per-publication pharmacogenomic findings for this gene (significant associations).

2 published findings:

Variant	Drug(s)	Category	Finding	PMID
rs4820268		Other	Genotype AG is associated with decreased likelihood of Iron Overload in children with Anemia, Sickle Cell and Recent blood transfusion as compared to genotype GG.	PMID:40936486
rs4820268		Other	Genotype AG is associated with increased expression of HAMP as compared to genotype GG.	PMID:40936486

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)

125 measured of 148 human assays (159 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
Benzylsulfonyl-D-cyclohexylalanyl-proline-(2-aminomethyl-5-chlorobenzyl)amide Trifluoroacetate	KI	0.052 nM
CHEMBL3354674	KI	0.061 nM
CHEMBL3352840	KI	0.092 nM
Benzylsulfonyl-D-cyclohexylalanyl-proline-(4-amidinobenzyl)-amide Trifluoroacetate	KI	0.102 nM
CHEMBL3354677	KI	0.14 nM
CHEMBL3354679	KI	0.15 nM
CHEMBL3354675	KI	0.18 nM
Benzylsulfonyl-D-arginyl-proline-(2-aminomethyl-5-chlorobenzyl)-amide Bis(trifluoroacetate)	KI	0.29 nM
CHEMBL3354682	KI	0.45 nM
CHEMBL3354678	KI	0.72 nM
CHEMBL3354687	KI	0.89 nM
CHEMBL3354681	KI	0.91 nM
CHEMBL3623779	KI	1.2 nM
CHEMBL3354686	KI	1.4 nM
Benzylsulfonyl-D-argininyl-proline-(4-amidinobenzyl)amide Bis-(trifluoroacetate)	KI	2.4 nM
CHEMBL3354685	KI	3.2 nM
CHEMBL5575948	KI	3.3 nM
CHEMBL5573803	KI	4.1 nM
CHEMBL5574204	KI	5 nM
CHEMBL4103673	KI	5.6 nM
CHEMBL4093487	KI	7 nM
CHEMBL3354683	KI	8 nM
CHEMBL5590035	KI	8.8 nM
CHEMBL5569773	KI	9.1 nM
CHEMBL5562941	KI	11 nM
CHEMBL4089262	KI	12 nM
CHEMBL5566155	KI	12 nM
CHEMBL3354680	KI	15 nM
CHEMBL4085747	KI	19 nM
CHEMBL4085021	KI	20 nM
CHEMBL4101897	KI	20 nM
CHEMBL4083908	KI	26 nM
CHEMBL5595012	KI	27 nM
CHEMBL4065964	KI	28 nM
CHEMBL3354684	KI	32 nM
CHEMBL4103740	KI	34 nM
CHEMBL4099552	KI	34 nM
CHEMBL5596033	KI	34 nM
CHEMBL4093566	KI	39 nM
CHEMBL4091809	KI	43 nM
CHEMBL4065870	KI	44 nM
CHEMBL5571372	KI	45 nM
CHEMBL4062334	KI	48 nM
CHEMBL4104560	KI	51 nM
CHEMBL5592173	KI	51 nM
CHEMBL5574444	KI	53 nM
CHEMBL4070960	KI	63 nM
CHEMBL4100506	KI	65 nM
CHEMBL4073691	KI	71 nM
CHEMBL4084785	KI	120 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 211 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 expression, decreases methylation	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)

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

1 trials:

NCT	Phase	Status	Title
NCT02905981	Phase 2	TERMINATED	Triferic IRIDA (Iron-Refractory Iron-Deficiency Anemia) Protocol

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for TMPRSS6 across ~30M SureChEMBL compounds — explore on Sugi Predict.