TMPRSS2

TMPRSS2
Identifikatori
Aliasi	TMPRSS2
Vanjski ID-jevi	OMIM: 602060 MGI: 1354381 HomoloGene: 4136 GeneCards: TMPRSS2
Lokacija gena (čovjek) Hrom. Hromosom 21 (čovjek)[1] Bend 21q22.3 Početak 41,464,300 bp[1] Kraj 41,531,116 bp[1]
Lokacija gena (miš) Hrom. Hromosom 16 (miš)[2] Bend 16 C4|16 57.53 cM Početak 97,365,882 bp[2] Kraj 97,412,395 bp[2]
Obrazac RNK ekspresije Više referentnih podataka o ekspresiji
Ontologija gena Molekularna funkcija • scavenger receptor activity • GO:0070122 peptidase activity • serine-type peptidase activity • GO:0001948, GO:0016582 vezivanje za proteine • hydrolase activity • serine-type endopeptidase activity Ćelijska komponenta • integral component of membrane • extracellular region • ćelijska membrana • integral component of plasma membrane • Egzosom • membrana Biološki proces • positive regulation of viral entry into host cell • protein autoprocessing • receptor-mediated endocytosis • Proteoliza • vesicle-mediated transport • Endocitoza Izvori:Amigo / QuickGO
Ortolozi
Vrste	Čovjek	Miš
Entrez	7113	50528
Ensembl	ENSG00000184012	ENSMUSG00000000385
UniProt	O15393	Q9JIQ8
RefSeq (mRNK)	NM_001135099 NM_005656 NM_001382720	NM_015775
RefSeq (bjelančevina)	NP_001128571 NP_005647 NP_001369649	NP_056590
Lokacija (UCSC)	Chr 21: 41.46 – 41.53 Mb	Chr 16: 97.37 – 97.41 Mb
PubMed pretraga	[3]	[4]
Wikipodaci
Pogledaj/uredi – čovjek Pogledaj/uredi – miš

Serin 2 transmembranska proteaza jest enzim koji je kod ljudi kodiran genom TMPRSS2 sa hromosoma 21.^[5][6][7]

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 492 aminokiseline, a molekulska težina 53.859 Da.^[6]

• C: Cistein
• D: Asparaginska kiselina
• E: Glutaminska kiselina
• F: Fenilalanin
• G: Glicin
• H: Histidin
• I: Izoleucin
• K: Lizin
• L: Leucin
• M: Metionin
• N: Asparagin
• P: Prolin
• Q: Glutamin
• R: Arginin
• S: Serin
• T: Treonin
• V: Valin
• W: Triptofan
• Y: Tirozin

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

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

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

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

1. GRCh38: Ensembl release 89: ENSG00000184012 - Ensembl, maj 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000000385 - Ensembl, maj 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. 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.
6. "Entrez Gene: TMPRSS2 transmembrane protease, serine 2".
7. "UniProt Protein: TMPS2_HUMAN transmembrane protease".
8. 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).
9. 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.
10. 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.
11. 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.
12. 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.
13. 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).
14. 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.
15. 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.
16. 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.
17. 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.
18. 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).

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Vanjski linkovi