PIKFYVE
FYVE prst s fosfoinozitid-kinazom (PIKfyve) je enzim koji je kod ljudi kodiran genom PIKFYVE.[5]
Funkcija
[uredi | uredi izvor]Glavna enzimska aktivnost PIKfyve je fosforilacija PtdIns3P-a u PtdIns (3,5) P2. Aktivnost PIKfyve-a odgovorna je za proizvodnju i PtdIns (3,5) P2 i fosfatidilinozitol 5-fosfata (PtdIns5P).[6][7][8][9] PIKfyve je veliki protein koji sadrži brojne funkcijske domene i izražen je u nekoliko spojenih oblika. Prijavljeni klonovi miša pune dužine i ljudske cDNK, kodiraju proteine 2052, odnosno 2098 aminokiselinskih ostataka.[7][10][11][12] Direktnim vezanjem membrane PtdIns(3)P,[13] Domen FYVE prsta PIKfyve je presudan za lokalizaciju proteina u citosolnom listiću endosoma.[10][13] Rasparena enzimska aktivnost PIKfyve dominantno ometajućim mutantima, ablacija posredovana putem siRNK ili farmakološka inhibicija uzrokuju povećanje lizosoma i citoplazmatsku vakuolaciju zbog poremećene sinteze PtdIns (3,5) P2 i oštećenog procesa fisije lizosoma i homeostaze.[14] Dakle, putem proizvodnje PtdIns (3,5) P2, PIKfyve učestvuje u nekoliko aspekata vezikulske dinamike,[15][16], čime utiče na brojne puteve prometa koji potiču iz ili prelaze u endosomni sistem na putu do trans-Golgijeve mreže ili kasnijih odjeljaka duž endocitoznog puta.[17][18][19][20][21][22]
Medicinski značaj
[uredi | uredi izvor]PIKfyve mutacije koje pogađaju jedan od dva PIKFYVE alela pronađene su u 8 od 10 porodica sa Francois-Neetens distrofija rožnjačine fleke. Poremećaj oba PIKFYVE alela kod miša je smrtonosan u fazi predimplantacijskog embriona. Uloga PIKfyve u invaziji patogena utvrđena je dokazima iz ćelijskih studija koje impliciraju aktivnost PIKfyve u replikaciji HIV-a i bakterija]] roda Salmonella. Na vezu PIKfyve-a sa dijabetesom tipa 2 upućuju zapažanja da PIKfyve perturbacije inhibiraju unos glukoze reguliran insulinom.[23][24] Sukladno tome, miševi sa selektivnim poremećajem gena Pikfyve u skeletnim mišićima, tkivo koje je uglavnom odgovorno za smanjenje šećera u krvi nakon jela, ispoljavajući sistemsku otpornost na insulin, netoleranciju glukoze, hiperinsulinemiju i povećanu adipoznost, tj. tipske simptome za predijabetes.[25]
Inhibitori PIKfyve-a kao potencijalni antikancerski lijekovi
[uredi | uredi izvor]Nekoliko inhibitora PIKfyve-ovih malih molekula pokazalo se obećavajućim kao terapija za rak u pretkliničkim studijama, zbog selektivne toksičnosti u B-ćelijama ne-Hodgkinovog limfoma.[26] or in U-251 glioblastoma cells.[27] Inhibitori PIKfyve-a uzrokuju ćelijsku smrt i u ćelijama melanoma A-375, koje za rast i proliferaciju ovise o autofagiji, uslijed oštećene homeostaze lizozoma.[14]
Ove interakcije povezuju PIKfyve sa na mikrotubulama baziranim endosomom na trans-Golgijevoj mreži prometa. Pod kontinuiranom aktivacijom glutamatnog receptora, PIKfyve veže se i olakšava razgradnju lizosomskog Cav1.2, naponski zavisnog kalcijskog kanal tipa 1.2, štiteći tako neurone od eksitotoksičnosti.[28] PIKfyve negativno regulira Ca2+ ovisnu egzocitozu u neuroendokrinim ćelijama, bez uticaja na naponske kanale.
Evoluciijska biologija
[uredi | uredi izvor]PIKFYVE pripada velikoj porodici evolucijski očuvanih lipidnih kinaza. Geni za pojedinačne kopije kodiraju slično strukturirane fosfoinozitidne kinaze, koje sadrže domen FYVE, postoje u većini genoma, od kvasaca do čovjeka. Biljka Arabidopsis thaliana ima nekoliko kopija tog enzima. Viši eukarioti (prema Drosophila melanogaster), stiču dodatni DEP domen. Enzim Fab1p S. cerevisiae potreban je za sintezu PtdIns (3,5) P2 u baznim uvjetima i kao odgovor na hiperosmotski šok. PtdIns5P, stvoren PIKfyve-om kinaznom aktivnošću u ćelijama sisara, nije otkriven u pupajućem kvascu. Kvasac Fab1p veže se na Vac14p (ortolog ljudskog ArPIKfyve) i Fig4p (ortolog Sac3). Kompleks kvasca Fab1 također uključuje Vac7p i vjerovatno Atg18p, proteine koji nisu otkriveni u PIKfyve-u sisarskog kompleksa.[5] S. cerevisiae mogao bi preživjeti bez Fab1. Nasuprot tome, nokaut enzima koji sadrže domen FYVE u A. thaliana, D. melanogaster, C. elegans i M. musculus dovodi do smrtnosti embriona, što ukazuje da su fosfoinozitidne kinaze koje sadrže domen FYVE postale ključne u embrionskom razvoju vi��ećelijskih organizama.[29][30][31][32] Tako, tokom evolucije, fosfoinozitidne kinaze koje sadrže FYVE domen zadržavaju nekoliko aspekata strukturne organizacije, enzimske aktivnosti i interakcija proteina iz pupajućeg kvasca. Kod viših eukariota, enzimi stiču jedan dodatni domen, sa ulogom u proizvodnji PtdIns5P, nove grupe interaktivnih proteina i postaju bitni u razvoju embriona.[5]
Reference
[uredi | uredi izvor]- ^ a b c GRCh38: Ensembl release 89: ENSG00000115020 - Ensembl, maj 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000025949 - 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.
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Dopunska literatura
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