TMPRSS2
Serin 2 transmembranska proteaza jest enzim koji je kod ljudi kodiran genom TMPRSS2 sa hromosoma 21.[5][6][7]
Aminokiselinska sekvenca
[uredi | uredi izvor]Dužina polipeptidnog lanca je 492 aminokiseline, a molekulska težina 53.859 Da.[6]
| 10 | 20 | 30 | 40 | 50 | ||||
|---|---|---|---|---|---|---|---|---|
| MALNSGSPPA | IGPYYENHGY | QPENPYPAQP | TVVPTVYEVH | PAQYYPSPVP | ||||
| QYAPRVLTQA | SNPVVCTQPK | SPSGTVCTSK | TKKALCITLT | LGTFLVGAAL | ||||
| AAGLLWKFMG | SKCSNSGIEC | DSSGTCINPS | NWCDGVSHCP | GGEDENRCVR | ||||
| LYGPNFILQV | YSSQRKSWHP | VCQDDWNENY | GRAACRDMGY | KNNFYSSQGI | ||||
| VDDSGSTSFM | KLNTSAGNVD | IYKKLYHSDA | CSSKAVVSLR | CIACGVNLNS | ||||
| SRQSRIVGGE | SALPGAWPWQ | VSLHVQNVHV | CGGSIITPEW | IVTAAHCVEK | ||||
| PLNNPWHWTA | FAGILRQSFM | FYGAGYQVEK | VISHPNYDSK | TKNNDIALMK | ||||
| LQKPLTFNDL | VKPVCLPNPG | MMLQPEQLCW | ISGWGATEEK | GKTSEVLNAA | ||||
| KVLLIETQRC | NSRYVYDNLI | TPAMICAGFL | QGNVDSCQGD | SGGPLVTSKN | ||||
| NIWWLIGDTS | WGSGCAKAYR | PGVYGNVMVF | TDWIYRQMRA | DG |
Funkcija gena TMPRSS2
[uredi | uredi izvor]Gen TMPRSS2 kodira protein koji pripada porodici serin-proteaza. Kodirani protein sadrži transmembranski tip II domen, domen klase receptora A, domen bogat cisteinom receptora za čišćenje i domen proteaze. Poznato je da su serinske proteaze uključene u mnoge fiziološke i patološke procese. Pokazalo se da je ovaj gen pojačano reguliran androgenim hormonima u ćelijama raka prostate i smanjeno u tkivu. kancera prostate nezavisnog od androgena Smatra se da se domen proteaze ovog proteina cijepa i izlučuje u ćelijski medij nakon autocijepanja.[6] TMPRSS2 učestvuje u proteolitskim kaskadama neophodnim za normalnu fiziološku funkciju prostate.[7] Nokaut-miševi kojima nedostaje gen TMPRSS2 ne pokazuje abnormalnosti.[8]
ERG genska fuzija
[uredi | uredi izvor]Funkcija proteina TMPRSS2 u karcinogenezi prostate oslanja se na prekomjernu ekspresiju transkripcijskog faktora ETS, kao što su ERG i ETV1, putem fuzije gena . TMPRSS2-ERG fuzioni gen je najčešći, prisutan u 40% – 80% karcinoma prostate kod ljudi. Prekomjerna ekspresija ERG-a doprinosi razvoju nezavisnosti od androgena kod raka prostate putem prekida signalizacije androgenih receptora.[9]
U korona virusima
[uredi | uredi izvor]Neki korona virusi, npr. sindrom koronavirusnog teškog akutnog respiratornog kovida (SARS-CoV-1), koronavirus Bliskoistočnog respiratornog sindroma (MERS-CoV) i koronavirus 2 teškog akutnog respiratornog sindroma (SARS-CoV-2) (prije omikron varijanta), aktiviraju se preko TMPRSS2 i stoga mogu biti spriječeni inhibitorima TMPRSS2.[10][11] SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming.[12]
Cepanje SARS-CoV-2 S2 bodljasti protein potrebnog za ulazak virusa u ćelije može se postići pomoću proteaza TMPRSS2 lociranih na ćelijskoj membrani ili pomoću katepsina (prvenstveno katepsina L) u endolizosomima.[13] Hidroksihloroikin inhibira djelovanje katepsina L u endolizosomima, ali budući da je cijepanje katepsina L neznatno u poređenju sa cijepanjem TMPRSS2, hidroksihlorokin čini malo da inhibira infekcije SARS-CoV-2.[13]
Enzim Adam17 ima sličnu aktivnost cijepanja ACE2 kao iTMPRSS2, ali formiranjem rastvorljivog ACE2, adam17 zapravo može imati zaštitni učinak blokiranja cirkulirajućih čestica virusa SARS-CoV-2.[14] Neoslobađanjem rastvorljivog ACE2, cijepanje TMPRSS2 je štetnije.[14]
Inhibitor TMPRSS2 kao što je camostat odobren za kliničku upotrebu blokirao je ulazak i mogao bi predstavljati opciju liječenja.[11][13] Još jedan eksperimentalni kandidat kao inhibitor TMPRSS2 za potencijalnu upotrebu protiv gripe i koronavirusnih infekcija općenito, uključujući i one prije pojave COVID-19, je OTC (u većini zemalja) mukolitski lijek protiv kašlja bromheksin,[15] koji se također istražuje kao mogući tretman i za sam COVID-19.[16] The fact that TMPRSS2 has no known irreplaceable function makes it a promising target for preventing SARS-CoV-2 virus transmission.[8]
Činjenica da je teška bolest i smrt od Sars-Cov-2 češća kod muškaraca nego kod žena, te da je TMPRSS2 nekoliko puta izraženiji u prostati epitelu nego u bilo kojem tkivu, sugerira ulogu TMPRSS2 u rodnoj razlici.[17][18] Pacijenti sa rakom prostate koji primaju terapiju deprivacije androgena imaju manji rizik od infekcije SARS-CoV-2 od onih koji ne primaju tu terapiju.[17][18]
Reference
[uredi | uredi izvor]- ^ a b c GRCh38: Ensembl release 89: ENSG00000184012 - Ensembl, maj 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000000385 - Ensembl, maj 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Paoloni-Giacobino A, Chen H, Peitsch MC, Rossier C, Antonarakis SE (September 1997). "Cloning of the TMPRSS2 gene, which encodes a novel serine protease with transmembrane, LDLRA, and SRCR domains and maps to 21q22.3". Genomics. 44 (3): 309–20. doi:10.1006/geno.1997.4845. PMID 9325052.
- ^ a b c "Entrez Gene: TMPRSS2 transmembrane protease, serine 2".
- ^ a b "UniProt Protein: TMPS2_HUMAN transmembrane protease".
- ^ a b Sarker J, Das P, Sarker S, Roy AK, Momen A (2021). "A Review on Expression, Pathological Roles, and Inhibition of TMPRSS2, the Serine Protease Responsible for SARS-CoV-2 Spike Protein Activation". List of Hindawi academic journals. 2021: 2706789. doi:10.1155/2021/2706789. PMC 8313365 Provjerite vrijednost parametra
|pmc=(pomoć). PMID 34336361 Provjerite vrijednost parametra|pmid=(pomoć). - ^ Yu J, Yu J, Mani RS, Cao Q, Brenner CJ, Cao X, et al. (May 2010). "An integrated network of androgen receptor, polycomb, and TMPRSS2-ERG gene fusions in prostate cancer progression". Cancer Cell. 17 (5): 443–54. doi:10.1016/j.ccr.2010.03.018. PMC 2874722. PMID 20478527.
- ^ Huggins, DJ (November 2020). "Structural analysis of experimental drugs binding to the SARS-CoV-2 target TMPRSS2". Journal of Molecular Graphics and Modelling. 100: 107710. doi:10.1016/j.jmgm.2020.107710. PMC 7417922. PMID 32829149.
- ^ a b Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. (March 2020). "SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor". Cell. 181 (2): 271–280.e8. doi:10.1016/j.cell.2020.02.052. PMC 7102627. PMID 32142651. Sažetak – Deutsches Primatenzentrum GmbH.
- ^ Rahman N, Basharat Z, Yousuf M, Castaldo G, Rastrelli L, Khan H (May 2020). "Virtual screening of natural products against type II transmembrane serine protease (TMPRSS2), the priming agent of Coronavirus 2 (SARS-CoV-2)". Molecules. 25 (10): 2271. doi:10.3390/molecules25102271. PMC 7287752. PMID 32408547.
- ^ a b c Jackson CB, Farzan M, Chen B, Choe H (Oct 2021). "Mechanisms of SARS-CoV-2 entry into cells". Nature Reviews Molecular Cell Biology. 23 (1): 3–20. doi:10.1038/s41580-021-00418-x. PMC 8491763 Provjerite vrijednost parametra
|pmc=(pomoć). PMID 34611326 Provjerite vrijednost parametra|pmid=(pomoć). - ^ a b Zipeto D, Argañaraz GA, Argañaraz ER (2020). "ACE2/ADAM17/TMPRSS2 Interplay May Be the Main Risk Factor for COVID-19". Frontiers in Immunology. 11: 576745. doi:10.3389/fimmu.2020.576745. PMC 7575774. PMID 33117379.
- ^ Shen, Li Wen; Mao, Hui Juan; Wu, Yan Ling; Tanaka, Yoshimasa; Zhang, Wen (November 2017). "TMPRSS2: A potential target for treatment of influenza virus and coronavirus infections". Biochimie. 142: 1–10. doi:10.1016/j.biochi.2017.07.016. PMC 7116903. PMID 28778717.
- ^ Depfenhart, Markus; de Villiers, Danielle; Lemperle, Gottfried; Meyer, Markus; Di Somma, Salvatore (August 2020). "Potential new treatment strategies for COVID-19: is there a role for bromhexine as add-on therapy?". Internal and Emergency Medicine. 15 (5): 801–812. doi:10.1007/s11739-020-02383-3. PMC 7249615. PMID 32458206.
- ^ a b Mollica V, Rizzo A, Massari F (2020). "The pivotal role of TMPRSS2 in coronavirus disease 2019 and prostate cancer". Future Oncology. 16 (27): 2029–2033. doi:10.2217/fon-2020-0571. PMC 7359420. PMID 32658591.
- ^ a b Epstein RJ (2021). "The secret identities of TMPRSS2: Fertility factor, virus trafficker, inflammation moderator, prostate protector and tumor suppressor". Tumor Biology. 43 (1): 159–176. doi:10.3233/TUB-211502. PMID 34420994 Provjerite vrijednost parametra
|pmid=(pomoć).
Dopunska literatura
[uredi | uredi izvor]- Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
- Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
- Lin B, Ferguson C, White JT, Wang S, Vessella R, True LD, et al. (September 1999). "Prostate-localized and androgen-regulated expression of the membrane-bound serine protease TMPRSS2". Cancer Research. 59 (17): 4180–4. PMID 10485450.
- Vaarala MH, Porvari KS, Kellokumpu S, Kyllönen AP, Vihko PT (January 2001). "Expression of transmembrane serine protease TMPRSS2 in mouse and human tissues". The Journal of Pathology. 193 (1): 134–40. doi:10.1002/1096-9896(2000)9999:9999<::AID-PATH743>3.0.CO;2-T. PMID 11169526.
- Afar DE, Vivanco I, Hubert RS, Kuo J, Chen E, Saffran DC, et al. (February 2001). "Catalytic cleavage of the androgen-regulated TMPRSS2 protease results in its secretion by prostate and prostate cancer epithelia". Cancer Research. 61 (4): 1686–92. PMID 11245484.
- Jacquinet E, Rao NV, Rao GV, Zhengming W, Albertine KH, Hoidal JR (May 2001). "Cloning and characterization of the cDNA and gene for human epitheliasin". European Journal of Biochemistry. 268 (9): 2687–99. doi:10.1046/j.1432-1327.2001.02165.x. PMID 11322890.
- Teng DH, Chen Y, Lian L, Ha PC, Tavtigian SV, Wong AK (June 2001). "Mutation analyses of 268 candidate genes in human tumor cell lines". Genomics. 74 (3): 352–64. doi:10.1006/geno.2001.6551. PMID 11414763.
- Wilson S, Greer B, Hooper J, Zijlstra A, Walker B, Quigley J, Hawthorne S (June 2005). "The membrane-anchored serine protease, TMPRSS2, activates PAR-2 in prostate cancer cells". The Biochemical Journal. 388 (Pt 3): 967–72. doi:10.1042/BJ20041066. PMC 1183478. PMID 15537383.
- Soller MJ, Isaksson M, Elfving P, Soller W, Lundgren R, Panagopoulos I (July 2006). "Confirmation of the high frequency of the TMPRSS2/ERG fusion gene in prostate cancer". Genes, Chromosomes & Cancer. 45 (7): 717–9. doi:10.1002/gcc.20329. PMID 16575875. S2CID 86518137.
- Tomlins SA, Mehra R, Rhodes DR, Smith LR, Roulston D, Helgeson BE, et al. (April 2006). "TMPRSS2:ETV4 gene fusions define a third molecular subtype of prostate cancer". Cancer Research. 66 (7): 3396–400. doi:10.1158/0008-5472.CAN-06-0168. PMID 16585160.
- Yoshimoto M, Joshua AM, Chilton-Macneill S, Bayani J, Selvarajah S, Evans AJ, et al. (June 2006). "Three-color FISH analysis of TMPRSS2/ERG fusions in prostate cancer indicates that genomic microdeletion of chromosome 21 is associated with rearrangement". Neoplasia. 8 (6): 465–9. doi:10.1593/neo.06283. PMC 1601467. PMID 16820092.
- Böttcher E, Matrosovich T, Beyerle M, Klenk HD, Garten W, Matrosovich M (October 2006). "Proteolytic activation of influenza viruses by serine proteases TMPRSS2 and HAT from human airway epithelium". Journal of Virology. 80 (19): 9896–8. doi:10.1128/JVI.01118-06. PMC 1617224. PMID 16973594.
- Cerveira N, Ribeiro FR, Peixoto A, Costa V, Henrique R, Jerónimo C, Teixeira MR (October 2006). "TMPRSS2-ERG gene fusion causing ERG overexpression precedes chromosome copy number changes in prostate carcinomas and paired HGPIN lesions". Neoplasia. 8 (10): 826–32. doi:10.1593/neo.06427. PMC 1715930. PMID 17032499.
- Yoo NJ, Lee JW, Lee SH (March 2007). "Absence of fusion of TMPRSS2 and ETS transcription factor genes in gastric and colorectal carcinomas". APMIS. 115 (3): 252–3. doi:10.1111/j.1600-0463.2007.apm_652.x. PMID 17367471. S2CID 34487156.
- Winnes M, Lissbrant E, Damber JE, Stenman G (May 2007). "Molecular genetic analyses of the TMPRSS2-ERG and TMPRSS2-ETV1 gene fusions in 50 cases of prostate cancer". Oncology Reports. 17 (5): 1033–6. doi:10.3892/or.17.5.1033. PMID 17390040.
- Tu JJ, Rohan S, Kao J, Kitabayashi N, Mathew S, Chen YT (September 2007). "Gene fusions between TMPRSS2 and ETS family genes in prostate cancer: frequency and transcript variant analysis by RT-PCR and FISH on paraffin-embedded tissues". Modern Pathology. 20 (9): 921–8. doi:10.1038/modpathol.3800903. PMID 17632455.