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Information on EC 3.4.21.B60 - transmembrane protease serine 2 and Organism(s) Homo sapiens and UniProt Accession O15393

for references in articles please use BRENDA:EC3.4.21.B60
deleted, replaced by EC 3.4.21.122
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EC Tree
     3 Hydrolases
         3.4 Acting on peptide bonds (peptidases)
             3.4.21 Serine endopeptidases
                3.4.21.B60 transmembrane protease serine 2
Synonyms
TMPRSS2, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
10-hydroxyusambarensine
binding energy -10.4 kcal/mol, additionally binds to ACE2 and SARS-CoV-2 spike protein
-
6-carbamimidoylnaphthalen-2-yl 2-chloro-4-[(diaminomethylidene)amino]benzoate
variant of inhibitors nafamostat, predicted binding energy -174.16 kcal/mol. EC50 value for inhibition of cytopathic effect caused by SARS-CoV-2 infection is 8 nM
-
6-carbamimidoylnaphthalen-2-yl 4-[(diaminomethylidene)amino]-2-methylbenzoate
variant of inhibitors nafamostat, predicted binding energy -172.38 kcal/mol. EC50 value for inhibition of cytopathic effect caused by SARS-CoV-2 infection is 15 nM
-
6-carbamimidoylnaphthalen-2-yl 4-[(diaminomethylidene)amino]-3-methylbenzoate
variant of inhibitors nafamostat, predicted binding energy -178.94 kcal/mol. EC50 value for inhibition of cytopathic effect caused by SARS-CoV-2 infection is 9.6 nM
-
alpha-1-antitrypsin
the reactive center loop of alpha-1-antitrypsin adopts an inhibitory-competent conformation compared with the crystal structure of TMPRSS2 bound to nafamostat or HAI-2 TMPRSS2 inhibitor. Negatively-charged heparin bridges adjacent electropositive patches at the TMPRSS2-alpha-1-antitrypsin interface, neutralizing otherwise repulsive forces. Heparinoid enoxaparin enhances alpha-1-antitrypsin inhibition of both TMPRSS2 activity and infection of human airway epithelial cells with coronavirus HCoV-229E
-
caffeic acid phenethyl ester
binds and stably interacts at the catalytic site of TMPRSS2, binding energy -6.2 kcal/mol, Gly464 and Ser436 are involved in hydrogen bond interactions
calmostat
topical TMPRSS2 inhibition when delivered in a clinically relevant and achievable dose to differentiated airways cells markedly restricts SARC-CoV-2 cellular infection
-
camostat
residues Asp435 and Glu299 significantly contribute to the binding. EC50 value for inhibition of cytopathic effect caused by SARS-CoV-2 infection is 66 nM
camostat mesylate
cryptoquindoline
binding energy -9.7 kcal/mol, additionally binds to ACE2 and SARS-CoV-2 spike protein
-
cryptospirolepine
binding energy -9.9 kcal/mol, additionally binds to ACE2 and SARS-CoV-2 spike protein
-
enoxaparin
heparinoid enoxaparin enhances alpha-1-antitrypsin inhibition of both TMPRSS2 activity and infection of human airway epithelial cells with coronavirus HCoV-229E
isocryptolepine
-
-
N-(6-carbamimidoylnaphthalen-2-yl)-4-[(diaminomethylidene)amino]benzamide
variant of inhibitors nafamostat, predicted binding energy -179.65 kcal/mol. EC50 value for inhibition of cytopathic effect caused by SARS-CoV-2 infection is 17 nM
-
N-(6-cyanonaphthalen-2-yl)-4-[(diaminomethylidene)amino]benzamide
variant of inhibitors nafamostat, predicted binding energy -127.92 kcal/mol
-
Nafamostat
strychnopentamine
binding energy -8.8 kcal/mol, additionally binds to ACE2 and SARS-CoV-2 spike protein
-
withaferin A
binds and stably interacts at the catalytic site of TMPRSS2, binding energy -5.6 kcal/mol, residues Glu299 and Lys342 are mainly involved in polar interactions
withanone
binds and stably interacts at the catalytic site of TMPRSS2 and is able to induce changes in its allosteric site. Docking score is -4.3 kcal/nmol, Gly462 of TMPRSS2 is involved in the polar interactions. Withanone downregulates the expression of TMPRSS2 in MCF7 cells
-
(3R)-1-[(3-[(1R)-1-amino-2-[(3S,4R)-1-[[4-(aminomethyl)phenyl]methyl]-4-methylpyrrolidin-3-yl]ethyl]phenyl)methyl]piperidin-3-ol
-
inhibitor developed by fragment-based drug design
-
(3R,4R)-1-[[4-(aminomethyl)phenyl]methyl]-4-(2-[(1R,2Z)-2-[(5-hydroxy-2-methoxyphenyl)methylidene]cyclobutyl]ethyl)pyrrolidin-3-ol
-
inhibitor developed by fragment-based drug design
-
(3S)-1-[(3-[(1S)-1-amino-3-[(3S,4R)-1-[[4-(aminomethyl)phenyl]methyl]-4-methylpyrrolidin-3-yl]propyl]phenyl)methyl]piperidin-3-ol
-
inhibitor developed by fragment-based drug design
-
(3S)-3-(aminomethyl)-5-[(3R,4S)-1-[[4-(aminomethyl)phenyl]methyl]-4-methylpyrrolidin-3-yl]-1-(3,4-dihydroisoquinolin-2(1H)-yl)pentan-1-one
-
inhibitor developed by fragment-based drug design
-
(3S)-4-[(3R)-3-amino-3-(4-[[(3S)-3-hydroxypyrrolidin-1-yl]methyl]phenyl)propyl]-1-[[4-(aminomethyl)phenyl]methyl]pyrrolidin-3-ol
-
inhibitor developed by fragment-based drug design
-
(4S)-4-amino-5-[(3R,4S)-1-[[4-(aminomethyl)phenyl]methyl]-4-hydroxypyrrolidin-3-yl]-1-(1,4-dihydro-3H-2,3-benzoxazin-3-yl)pentan-1-one
-
inhibitor developed by fragment-based drug design
-
(4S)-4-amino-7-[(3R,4R)-1-[[4-(aminomethyl)phenyl]methyl]-4-hydroxypyrrolidin-3-yl]-1-(1,4-dihydro-3H-2,3-benzoxazin-3-yl)heptan-1-one
-
inhibitor developed by fragment-based drug design
-
2,6-dimethoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]quinolin-8-amine
-
compound exhibits a nearly effective TMPRSS2 inhibitory activity relative to tafenoquine , while it is deficient in SARS-CoV-2 main protease inhibition
-
3-[(Z)-[(2R,3R)-3-amino-2-[3-[(3S)-1-[[4-(aminomethyl)phenyl]methyl]pyrrolidin-3-yl]propyl]cyclobutylidene]methyl]-4-methoxyphenol
-
inhibitor developed by fragment-based drug design
-
5-[(1R,3R)-3-[[(3S)-3-acetamidopiperidin-1-yl]methyl]-1-aminocyclobutyl]-N-(2,3-dihydro-1H-isoindol-4-yl)-N2-methyl-D-norvalinamide
-
inhibitor developed by fragment-based drug design
-
5-[(1r,3S)-1-amino-3-[(2-methylpyridin-4-yl)amino]cyclobutyl]-N-[(1R)-4,6-difluoro-2,3-dihydro-1H-inden-1-yl]-D-norvalinamide
-
inhibitor developed by fragment-based drug design
-
tafenoquine
-
inhibits TMPRSS2 protease activity, tafenoquine may block SARS-CoV-2 by inhibiting enzymatic activities of both SARS-CoV-2 main protease and host TMPRSS2
-
additional information
-
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0032
10-hydroxyusambarensine
pH not specified in the publication, temperature not specified in the publication
-
0.0034
cryptoquindoline
pH not specified in the publication, temperature not specified in the publication
-
0.00655
cryptospirolepine
pH not specified in the publication, temperature not specified in the publication
-
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
ACE2 and TMPRSS2 are expressed in capillaries
Manually annotated by BRENDA team
ACE2 and TMPRSS2 are stained in the neuronal cell body of trigeminal ganglia
Manually annotated by BRENDA team
ACE2 and TMPRSS2 are strongly expressed in the intermediate layer of the squamous epithelia of tongue papillae and buccal mucosa
Manually annotated by BRENDA team
ACE2 and TMPRSS2 are coexpressed in the ductal epithelium and acinar cells of salivary glands
Manually annotated by BRENDA team
ACE2- and TMPRSS2-positive cells are observed in the taste buds of the tongue
Manually annotated by BRENDA team
ACE2- and TMPRSS2-positive cells are observed in the taste buds of the tongue
Manually annotated by BRENDA team
additional information
no expression in Schwann cells or in venules/arterioles
Manually annotated by BRENDA team
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION?
TMPS2_HUMAN
492
0
53859
Swiss-Prot
other Location (Reliability: 2)
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
?
x * 55000, full length protein, x * 20000, fully autocleaved form, SDS-PAGE
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
proteolytic modification
full-length enzyme of 55000 Da is autocleaved at residue R255 to an active fragment of 22000 Da
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
in silico binding analysis and molecular docking between TMPRSS2 and SARS-CoV-2 spike protein. TMPRSS2 binds in close proximity to two cleavage sites of the spike glycoprotein. Inhibitor camostat mesylate binds to the central cleft of TMPRSS2 via hydrogen bonding interactions with the residues C281, C297, V280, S436, W461 and G462. Inhibitor nafamostat forms 3 hydrogen bonds
homology modeling of TMPRSS2 protein and application of the fragment-based drug design technique to develop effective TMPRSS2 inhibitors. Catalytic residues are His 296 Asp 345, and Ser 441, and residues Asp435, Ser460, Gly462 are invorlved in substrate binding
-
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
C297S
mutant is predicted to show altered interactions with the inhibitors, camostat mesylate and nafamostat
G462D
variant is predicted to be less susceptible to the SARS-CoV-2 infection and to show altered interactions with the inhibitors, camostat mesylate and nafamostat
G462S
variant is predicted to be less susceptible to the SARS-CoV-2 infection
Q438E
mutation is predicted to increase susceptibility to the SARS-CoV-2 infection
R255Q
mutant is unable to autocleave
R255Q/V160M
mutant does not autocleave and shows a significantly reduced ability to promote SARS-CoV-2 spike protein-expressing pseudovirus
S339F
mutation is predicted to increase susceptibility to the SARS-CoV-2 infection
S441A
inactive
S460R
mutant is predicted to show altered interactions with the inhibitors, camostat mesylate and nafamostat
V160M
naturally-occurring TMPRSS2 genetic variant, non-synonymous variant predicted to be damaging. V160M is associated with a reduced likelihood of developing severe COVID-19. This association is stronger in homozygous individuals when compared to the general population. In vitro the mutation affects the catalytic activity of TMPRSS2, the mutant is less able to support SARS-CoV-2 spike-mediated entry into cells. Mutant protein is present in significantly higher proportion of full-length (55 kDa), and a significantly lower proportion of fully cleaved protein
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expression in in the avian fibroblast cell line, DF1
overexpression in HEK-293T cell
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
the expression of ACE2 and TMPRSS2 increases significantly in differentiated cells cultured at air-liquid interface compared with submerged standard culture
treatment of A-549 lung epithelial cells with 17-beta-estradiol reduces the cellular mRNA levels of ACE2 and TMPRSS2 mRNA, while not affecting FURIN expression
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
David, A.; Parkinson, N.; Peacock, T.; Pairo-Castineira, E.; Khanna, T.; Cobat, A.; Tenesa, A.; Sancho-Shimizu, V.; Casanova, J.; Abel, L.; Barclay, W.; Baillie, J.; Sternberg, M.
A common TMPRSS2 variant has a protective effect against severe COVID-19
Curr. Res. Transl. Med.
70
103333
2022
Homo sapiens (O15393)
Manually annotated by BRENDA team
Baristaite, G.; Gurwitz, D.
Estradiol reduces ACE2 and TMPRSS2 mRNA levels in A549 human lung epithelial cells
Drug Dev. Res.
2022
1-6
2022
Homo sapiens (O15393)
Manually annotated by BRENDA team
Alzain, A.A.; Elbadwi, F.A.; Alsamani, F.O.
Discovery of novel TMPRSS2 inhibitors for COVID-19 using in silico fragment-based drug design, molecular docking, molecular dynamics, and quantum mechanics studies
Inform. Med. Unlocked
29
100870
2022
Homo sapiens
Manually annotated by BRENDA team
Schneider, M.A.; Richtmann, S.; Gruending, A.R.; Wrenger, S.; Welte, T.; Meister, M.; Kriegsmann, M.; Winter, H.; Muley, T.; Janciauskiene, S.
Transmembrane serine protease 2 is a prognostic factor for lung adenocarcinoma
Int. J. Oncol.
60
39
2022
Homo sapiens (O15393)
Manually annotated by BRENDA team
Chen, Y.; Yang, W.; Chen, H.; Huang, L.; Gao, J.; Lin, C.; Wang, Y.; Yang, C.; Liu, Y.; Hou, M.; Tsai, C.; Chou, Y.; Huang, B.; Hung, C.; Hung, Y.; Wang, W.; Su, W.; Kumar, V.; Wu, Y.; Chao, S.; Chang, C.; Chen, J.; Chiang, Y.; Cho, D.; Jeng, L.; Tsai, C.
Tafenoquine and its derivatives as inhibitors for the severe acute respiratory syndrome coronavirus 2
J. Biol. Chem.
298
101658
2022
Homo sapiens
Manually annotated by BRENDA team
Kumar, V.; Dhanjal, J.; Bhargava, P.; Kaul, A.; Wang, J.; Zhang, H.; Kaul, S.; Wadhwa, R.; Sundar, D.
Withanone and Withaferin-A are predicted to interact with transmembrane protease serine 2 (TMPRSS2) and block entry of SARS-CoV-2 into cells
J. Biomol. Struct. Dyn.
40
1-13
2022
Homo sapiens (O15393)
Manually annotated by BRENDA team
Gyebi, G.A.; Adegunloye, A.P.; Ibrahim, I.M.; Ogunyemi, O.M.; Afolabi, S.O.; Ogunro, O.B.
Prevention of SARS-CoV-2 cell entry insight from in silico interaction of drug-like alkaloids with spike glycoprotein, human ACE2, and TMPRSS2
J. Biomol. Struct. Dyn.
40
2121-2145
2022
Homo sapiens (O15393)
Manually annotated by BRENDA team
Lee, J.H.; Lee, C.E.; Yoo, Y.; Shin, E.; An, J.; Park, S.Y.; Song, W.J.; Kwon, H.S.; Cho, Y.S.; Moon, H.B.; Kim, T.B.
Soluble ACE2 and TMPRSS2 levels in the serum of asthmatic patients
J. Korean Med. Sci.
37
e65
2022
Homo sapiens (O15393)
Manually annotated by BRENDA team
Salleh, M.Z.; Deris, Z.Z.
In silico molecular characterization of human TMPRSS2 protease polymorphic variants and associated SARS-CoV-2 susceptibility
Life
12
231
2022
Homo sapiens (O15393)
Manually annotated by BRENDA team
Guo, W.; Porter, L.M.; Crozier, T.W.; Coates, M.; Jha, A.; McKie, M.; Nathan, J.A.; Lehner, P.J.; Greenwood, E.J.; McCaughan, F.
Topical TMPRSS2 inhibition prevents SARS-CoV-2 infection in differentiated human airway cultures
Life Sci. Alliance
5
e202101116
2022
Homo sapiens (O15393)
Manually annotated by BRENDA team
Park, G.C.; Bang, S.Y.; Lee, H.W.; Choi, K.U.; Kim, J.M.; Shin, S.C.; Cheon, Y.I.; Sung, E.S.; Lee, M.; Lee, J.C.; Kim, H.S.; Lee, B.J.
ACE2 and TMPRSS2 immunolocalization and oral manifestations of COVID-19
Oral Dis.
2022
1-9
2022
Homo sapiens (O15393)
Manually annotated by BRENDA team
Bai, X.; Buckle, A.M.; Vladar, E.K.; Janoff, E.N.; Khare, R.; Ordway, D.; Beckham, D.; Fornis, L.B.; Majluf-Cruz, A.; Fugit, R.V.; Freed, B.M.; Kim, S.; Sandhaus, R.A.; Chan, E.D.
Enoxaparin augments alpha-1-antitrypsin inhibition of TMPRSS2, a promising drug combination against COVID-19
Sci. Rep.
12
5207
2022
Homo sapiens (O15393)
Manually annotated by BRENDA team
Kapczynski, D.R.; Sweeney, R.; Spackman, E.; Pantin-Jackwood, M.; Suarez, D.L.
Development of an in vitro model for animal species susceptibility to SARS-CoV-2 replication based on expression of ACE2 and TMPRSS2 in avian cells
Virology
569
1-12
2022
Capra hircus (A0A452FYA6), Felis catus (Q56H28), Homo sapiens (O15393), Mesocricetus auratus
Manually annotated by BRENDA team
Fujimoto, K.J.; Hobbs, D.C.F.; Umeda, M.; Nagata, A.; Yamaguchi, R.; Sato, Y.; Sato, A.; Ohmatsu, K.; Ooi, T.; Yanai, T.; Kimura, H.; Murata, T.
In silico analysis and synthesis of nafamostat derivatives and evaluation of their anti-SARS-CoV-2 activity
Viruses
14
389
2022
Homo sapiens (O15393)
Manually annotated by BRENDA team