TMPRSS2
Serin 2 transmembranska proteaza jest enzim koji je kod ljudi kodiran genom TMPRSS2 sa hromosoma 21.[5][6][7]
Aminokiselinska sekvenca
urediDužina 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
urediGen 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
urediFunkcija 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
urediNeki 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- ^ a b c GRCh38: Ensembl release 89: ENSG00000184012 - Ensembl, maj 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000000385 - Ensembl, maj 2017
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- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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- ^ 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.
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- ^ 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
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Dopunska literatura
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