MTOR

S Wikipedije, slobodne enciklopedije
MTOR
Dostupne strukture
PDBPretraga ortologa: PDBe RCSB
Spisak PDB ID kodova

4JT6, 1AUE, 1FAP, 1NSG, 2FAP, 2GAQ, 2NPU, 2RSE, 3FAP, 4DRH, 4DRI, 4DRJ, 4FAP, 4JSN, 4JSP, 4JSV, 4JSX, 4JT5, 5FLC

Identifikatori
AliasiMTOR
Vanjski ID-jeviOMIM: 601231 MGI: 1928394 HomoloGene: 3637 GeneCards: MTOR
Lokacija gena (čovjek)
Hromosom 1 (čovjek)
Hrom.Hromosom 1 (čovjek)[1]
Hromosom 1 (čovjek)
Genomska lokacija za MTOR
Genomska lokacija za MTOR
Bend1p36.22Početak11,106,535 bp[1]
Kraj11,262,551 bp[1]
Lokacija gena (miš)
Hromosom 4 (miš)
Hrom.Hromosom 4 (miš)[2]
Hromosom 4 (miš)
Genomska lokacija za MTOR
Genomska lokacija za MTOR
Bend4 E2|4 78.76 cMPočetak148,533,068 bp[2]
Kraj148,642,140 bp[2]
Obrazac RNK ekspresije
Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija protein domain specific binding
TFIIIC-class transcription factor complex binding
kinase activity
ATP binding
protein serine/threonine kinase activity
transferase activity
ribosome binding
GO:0001948, GO:0016582 protein binding
protein kinase binding
nucleotide binding
phosphoprotein binding
protein kinase activity
GO:0032403 protein-containing complex binding
identical protein binding
translation regulator activity
Ćelijska komponenta citoplazma
citosol
phosphatidylinositol 3-kinase complex
membrana
mitohondrija
TORC1 complex
organelle membrane
GO:0009327 protein-containing complex
mitochondrial outer membrane
Endoplazmatski retikulum
TORC2 complex
Golđijev aparat
intracellular membrane-bounded organelle
Nukleoplazma
neuronal cell body
PML body
endoplasmic reticulum membrane
Golđijeva membrana
lysosomal membrane
dendrit
Endomembranski sistem
Jedro
Lizozom
glutamatergic synapse
postsynaptic cytosol
Biološki proces germ cell development
positive regulation of protein phosphorylation
response to amino acid
positive regulation of lipid biosynthetic process
positive regulation of actin filament polymerization
positive regulation of skeletal muscle hypertrophy
positive regulation of granulosa cell proliferation
regulation of carbohydrate utilization
post-embryonic development
positive regulation of dendritic spine development
positive regulation of translation
positive regulation of eating behavior
protein phosphorylation
mRNA stabilization
cell projection organization
regulation of glycogen biosynthetic process
positive regulation of cell growth involved in cardiac muscle cell development
positive regulation of neuron maturation
positive regulation of glial cell proliferation
cellular response to hypoxia
negative regulation of cell size
response to cocaine
positive regulation of protein kinase B signaling
cardiac muscle contraction
maternal process involved in female pregnancy
ruffle organization
GO:0043087, GO:0032313, GO:0032319, GO:0032314, GO:0043088 regulation of GTPase activity
cardiac muscle cell development
positive regulation of transcription of nucleolar large rRNA by RNA polymerase I
regulation of membrane permeability
response to insulin
regulation of myelination
regulation of fatty acid beta-oxidation
regulation of osteoclast differentiation
positive regulation of cholangiocyte proliferation
regulation of protein kinase B signaling
spinal cord development
positive regulation of peptidyl-tyrosine phosphorylation
socijalno ponašanje
protein autophosphorylation
negative regulation of cholangiocyte apoptotic process
regulation of brown fat cell differentiation
regulation of protein kinase activity
GO:0033128 negative regulation of protein phosphorylation
positive regulation of oligodendrocyte differentiation
regulation of carbohydrate metabolic process
regulation of actin cytoskeleton organization
voluntary musculoskeletal movement
Fosforilacija
multicellular organism growth
negative regulation of muscle atrophy
Zarastanje rana
positive regulation of neurogenesis
response to morphine
positive regulation of sensory perception of pain
GO:0044257 protein catabolic process
'de novo' pyrimidine nucleobase biosynthetic process
cellular response to nutrient levels
energy reserve metabolic process
peptidyl-threonine phosphorylation
positive regulation of transcription by RNA polymerase III
positive regulation of smooth muscle cell proliferation
visual learning
positive regulation of myotube differentiation
positive regulation of cell death
positive regulation of endothelial cell proliferation
negative regulation of iodide transmembrane transport
cardiac muscle tissue development
positive regulation of nitric oxide biosynthetic process
regulation of response to food
heart morphogenesis
positive regulation of neuron death
cardiac cell development
negative regulation of protein ubiquitination
brain development
GO:1901313 positive regulation of gene expression
Dugoročno pamćenje
heart valve morphogenesis
GO:0035404 peptidyl-serine phosphorylation
positive regulation of neuron projection development
regulation of cellular response to heat
positive regulation of lamellipodium assembly
positive regulation of stress fiber assembly
GO:0072468 Transdukcija signala
regulation of protein phosphorylation
negative regulation of macroautophagy
anoikis
TOR signaling
GO:0100026 Popravka DNK
regulation of cell size
negative regulation of autophagy
positive regulation of epithelial to mesenchymal transition
regulation of macroautophagy
cellular response to amino acid starvation
positive regulation of keratinocyte migration
cellular response to amino acid stimulus
cellular response to leucine
positive regulation of wound healing, spreading of epidermal cells
cellular response to leucine starvation
cellular response to starvation
TORC1 signaling
growth
regulation of cell growth
response to nutrient
activation of protein kinase B activity
T-helper 1 cell lineage commitment
response to activity
positive regulation of phosphoprotein phosphatase activity
negative regulation of calcineurin-NFAT signaling cascade
regulation of translation at synapse, modulating synaptic transmission
positive regulation of cytoplasmic translational initiation
response to nutrient levels
Izvori:Amigo / QuickGO
Ortolozi
VrsteČovjekMiš
Entrez
Ensembl
UniProt
RefSeq (mRNK)

NM_004958
NM_001386500
NM_001386501

NM_020009

RefSeq (bjelančevina)

NP_004949

NP_064393

Lokacija (UCSC)Chr 1: 11.11 – 11.26 MbChr 4: 148.53 – 148.64 Mb
PubMed pretraga[3][4]
Wikipodaci
Pogledaj/uredi – čovjekPogledaj/uredi – miš

Sisarski cilj za rapamicin (mTOR),[5] znan i kao mehanistički cilj rapamicina, a ponekad i kao FK506-vezujući protein 12-rapamicinu pridruženi protein 1 (FRAP1), jest kinaza koji je kod ljudi kodiran genom MTOR sa hromosoma 1.[6][7] mTOR je član porodice protein-kinaza, fosfatidilinozitol 3-kinaza-vezane kinaze.[8]

mTOR se povezuje sa drugim proteinima i služi kao osnovna komponenta dva različita proteinska kompleksa, mTOR kompleksa 1 i mTOR kompleksa 2, koji regulišu različite ćelijske procese. Konkretno, kao ključna komponenta oba kompleksa, mTOR funkcionira kao serin/treonin protein-kinaza koja regulira ćelijski rast, proliferaciju ćelija, ćelijski motilitet, preživljavanje ćelije, sintezu proteina, autofagiju i transkripciju.[9][10] Kao jezgarna komponenta mTORC2, mTOR također funkcionira kao tirozin protein-kinaza koja promovira aktivaciju insulinskih receptora i insulinolikog receptora faktora rasta 1.[11] mTORC2 je također uključen u kontrolu i održavanje aktinskog citoskeleta.[9][12]

Aminokiselinska sekvenca[uredi | uredi izvor]

Dužina polipeptidnog lanca je 2.549 aminokiselina, a molekulska težina 288.892 Da.[11]

1020304050
MLGTGPAAATTAATTSSNVSVLQQFASGLKSRNEETRAKAAKELQHYVTM
ELREMSQEESTRFYDQLNHHIFELVSSSDANERKGGILAIASLIGVEGGN
ATRIGRFANYLRNLLPSNDPVVMEMASKAIGRLAMAGDTFTAEYVEFEVK
RALEWLGADRNEGRRHAAVLVLRELAISVPTFFFQQVQPFFDNIFVAVWD
PKQAIREGAVAALRACLILTTQREPKEMQKPQWYRHTFEEAEKGFDETLA
KEKGMNRDDRIHGALLILNELVRISSMEGERLREEMEEITQQQLVHDKYC
KDLMGFGTKPRHITPFTSFQAVQPQQSNALVGLLGYSSHQGLMGFGTSPS
PAKSTLVESRCCRDLMEEKFDQVCQWVLKCRNSKNSLIQMTILNLLPRLA
AFRPSAFTDTQYLQDTMNHVLSCVKKEKERTAAFQALGLLSVAVRSEFKV
YLPRVLDIIRAALPPKDFAHKRQKAMQVDATVFTCISMLARAMGPGIQQD
IKELLEPMLAVGLSPALTAVLYDLSRQIPQLKKDIQDGLLKMLSLVLMHK
PLRHPGMPKGLAHQLASPGLTTLPEASDVGSITLALRTLGSFEFEGHSLT
QFVRHCADHFLNSEHKEIRMEAARTCSRLLTPSIHLISGHAHVVSQTAVQ
VVADVLSKLLVVGITDPDPDIRYCVLASLDERFDAHLAQAENLQALFVAL
NDQVFEIRELAICTVGRLSSMNPAFVMPFLRKMLIQILTELEHSGIGRIK
EQSARMLGHLVSNAPRLIRPYMEPILKALILKLKDPDPDPNPGVINNVLA
TIGELAQVSGLEMRKWVDELFIIIMDMLQDSSLLAKRQVALWTLGQLVAS
TGYVVEPYRKYPTLLEVLLNFLKTEQNQGTRREAIRVLGLLGALDPYKHK
VNIGMIDQSRDASAVSLSESKSSQDSSDYSTSEMLVNMGNLPLDEFYPAV
SMVALMRIFRDQSLSHHHTMVVQAITFIFKSLGLKCVQFLPQVMPTFLNV
IRVCDGAIREFLFQQLGMLVSFVKSHIRPYMDEIVTLMREFWVMNTSIQS
TIILLIEQIVVALGGEFKLYLPQLIPHMLRVFMHDNSPGRIVSIKLLAAI
QLFGANLDDYLHLLLPPIVKLFDAPEAPLPSRKAALETVDRLTESLDFTD
YASRIIHPIVRTLDQSPELRSTAMDTLSSLVFQLGKKYQIFIPMVNKVLV
RHRINHQRYDVLICRIVKGYTLADEEEDPLIYQHRMLRSGQGDALASGPV
ETGPMKKLHVSTINLQKAWGAARRVSKDDWLEWLRRLSLELLKDSSSPSL
RSCWALAQAYNPMARDLFNAAFVSCWSELNEDQQDELIRSIELALTSQDI
AEVTQTLLNLAEFMEHSDKGPLPLRDDNGIVLLGERAAKCRAYAKALHYK
ELEFQKGPTPAILESLISINNKLQQPEAAAGVLEYAMKHFGELEIQATWY
EKLHEWEDALVAYDKKMDTNKDDPELMLGRMRCLEALGEWGQLHQQCCEK
WTLVNDETQAKMARMAAAAAWGLGQWDSMEEYTCMIPRDTHDGAFYRAVL
ALHQDLFSLAQQCIDKARDLLDAELTAMAGESYSRAYGAMVSCHMLSELE
EVIQYKLVPERREIIRQIWWERLQGCQRIVEDWQKILMVRSLVVSPHEDM
RTWLKYASLCGKSGRLALAHKTLVLLLGVDPSRQLDHPLPTVHPQVTYAY
MKNMWKSARKIDAFQHMQHFVQTMQQQAQHAIATEDQQHKQELHKLMARC
FLKLGEWQLNLQGINESTIPKVLQYYSAATEHDRSWYKAWHAWAVMNFEA
VLHYKHQNQARDEKKKLRHASGANITNATTAATTAATATTTASTEGSNSE
SEAESTENSPTPSPLQKKVTEDLSKTLLMYTVPAVQGFFRSISLSRGNNL
QDTLRVLTLWFDYGHWPDVNEALVEGVKAIQIDTWLQVIPQLIARIDTPR
PLVGRLIHQLLTDIGRYHPQALIYPLTVASKSTTTARHNAANKILKNMCE
HSNTLVQQAMMVSEELIRVAILWHEMWHEGLEEASRLYFGERNVKGMFEV
LEPLHAMMERGPQTLKETSFNQAYGRDLMEAQEWCRKYMKSGNVKDLTQA
WDLYYHVFRRISKQLPQLTSLELQYVSPKLLMCRDLELAVPGTYDPNQPI
IRIQSIAPSLQVITSKQRPRKLTLMGSNGHEFVFLLKGHEDLRQDERVMQ
LFGLVNTLLANDPTSLRKNLSIQRYAVIPLSTNSGLIGWVPHCDTLHALI
RDYREKKKILLNIEHRIMLRMAPDYDHLTLMQKVEVFEHAVNNTAGDDLA
KLLWLKSPSSEVWFDRRTNYTRSLAVMSMVGYILGLGDRHPSNLMLDRLS
GKILHIDFGDCFEVAMTREKFPEKIPFRLTRMLTNAMEVTGLDGNYRITC
HTVMEVLREHKDSVMAVLEAFVYDPLLNWRLMDTNTKGNKRSRTRTDSYS
AGQSVEILDGVELGEPAHKKTGTTVPESIHSFIGDGLVKPEALNKKAIQI
INRVRDKLTGRDFSHDDTLDVPTQVELLIKQATSHENLCQCYIGWCPFW

Funkcija[uredi | uredi izvor]

mTOR integrira ulaz iz uzvodnih puteva||transdukcija signala|transdukcije signala]], uključujući insulin, faktore rasta (kao što su IGF-1 i IGF-2), i [ [aminokiselina]].[10] mTOR takođe osjeća nivoe ćelijskih hranljivih materija, kisika i energije.[13] mTOR-ski put je centralni regulator metabolizma i fiziologije sisara, s važnom ulogom u funkciji tkiva, uključujući jetru, mišiće, bijelo i smeđe masno tkivo,[14] i mozak; disreguliran je kod ljudskih bolesti, kao što su dijabetes, gojaznost, depresija i određeni karcinomi.[15][16] Rapamicin inhibira mTOR povezujući se sa njegovim unutarčelijskim receptorom FKBP12.[17][18] Kompleks FKBP12rapamicin vezuje se direktno za FKBP12-rapamicinvezujući (FRB) domen mTOR, inhibirajući njegovu aktivnost.[18]

Kompleksi[uredi | uredi izvor]

Komponente mTOR kompleksa, mTORC1 (lijevo) i mTORC2 (desno). FKBP12, biološka meta za koju se rapamicin vezuje, je neobvezna komponenta proteina mTORC1.[9]

mTOR je katalitska podjedinica dva strukturno različita kompleksa: mTORC1 i mTORC2.[19] The two complexes localize to different subcellular compartments, thus affecting their activation and function.[20] Nakon aktivacije Rheb-om, mTORC1 se lokalizira na Ragulator-Rag kompleks na površini lizosoma gdje tada postaje aktivan, u prisustvu dovoljno aminokiselina.[21][22]

Klinički značaj[uredi | uredi izvor]

Starenje[uredi | uredi izvor]

mTOR signalni put.[1]

Utvrđeno je da smanjena aktivnost TOR produžava životni vijek u S. cerevisiae, C. elegans, i D. melanogaster.[23][24][25][26] Potvrđeno je da mTOR-ov inhibitor, rapamicin produžava životni vijek miševa.[27][28][29][30][31]

Pretpostavlja se da neki režimi ishrane, kao što su ograničenje kalorija i ograničenje metionina, uzrokuju produženje životnog vijeka, smanjenjem mTOR-ske aktivnosti.[23][24] Neke studije sugerirale su da se signalizacija mTOR-a može povećati tokom starenja, barem u specifičnim tkivima kao što je masno tkivo, a rapamicin može djelovati, djelimično blokirajući ovo povećanje.[32] Alternativna teorija je da je mTOR signalizacija primjer antagonističke plejotropije, a dok je visoka signalizacija mTOR dobra tokom ranog života, održava se na neprikladno visokom nivou u starosti. Restrikcija kalorija i restrikcija metionina mogu djelomično djelovati ograničavanjem nivoa esencijalnih aminokiselina, uključujući leucin i metionin, koji su snažni aktivatori mTOR-a.[33] Pokazalo se da davanje leucina u mozak pacova smanjuje unos hrane i tjelesnu težinu putem aktivacije mTOR puta u hipotalamusu.[34]

Kancer[uredi | uredi izvor]

Prekomjerna aktivacija signalizacije mTOR-a značajno doprinosi započinjanju i razvoju tumora, a otkriveno je da je aktivnost mTOR deregulirana kod mnogih tipova karcinoma uključujući karcinome dojke, pluća, prostate, melanoma, mjehura, mozga i bubrega.[35] Ima nekoliki razloga za konstitutivnu aktivaciju. Među najčešćim su mutacije tumor supresorskog gena PTEN. PTEN-ova fosfataza negativno utiče na signalizaciju mTOR, ometanjem efekta PI3K, uzvodnog efektora mTOR. Osim toga, aktivnost mTOR je deregulirana kod mnogih karcinoma, kao posljedica povećane aktivnosti PI3K ili Akt.[36] Slično tome, prekomjerna ekspresija nizvodnih mTOR efektora 4E-BP1, S6K i eIF4E dovodi do loše prognoze raka.[37] Također, mutacije TSC proteina koje inhibiraju aktivnost mTOR-a mogu dovesti do stanja pod nazivom kompleksne gomoljasate skleroze, koje se ispoljava kao benigne lezije i povećava rizik od karcinomskih ćelija bubrežne skleroze.[38]

Pokazalo se da povećanje aktivnosti mTOR-a pokreće progresiju ćelijskog ciklusa i povećava ćelijsku proliferaciju uglavnom zbog njegovog efekta na sintezu proteina. Štaviše, aktivni mTOR podržava rast tumora takođe indirektno inhibirajući autofagiju.[39] Konstitutivno aktivirani mTOR funkcionira u opskrbi karcinomskih ćelija kisikom i hranjivim tvarima, povećanjem translacije HIF1A i podržavanjem angiogeneze.[40] mTOR također pomaže u još jednoj metaboličkoj adaptaciji kancerogenih ćelija, kako bi podržao njihovu povećanu stopu rasta – aktivaciju glikolitskog metabolizma. Akt2, supstrat mTOR-a, posebno mTORC2, pojačava ekspresiju glikolitskog enzima PKM2 doprinoseći tako Warburgovom efektu.[41]

Poremećaji centralnog nervnog sistema / Funkcija mozga[uredi | uredi izvor]

Autizam[uredi | uredi izvor]

mTOR je umiješan u neuspjeh mehanizma 'orezivanja' ekscitatornih sinapsi kod poremećaja iz autističkog spektra.[42]

Alzheimerova bolest[uredi | uredi izvor]

mTOR signalizacija se ukršta sa nekoliko aspekata patoloških prfomjena kod Alzhemerovw bolesti (AD), sugerirajući njegovu potencijalnu ulogu kao doprinosa progresiji bolesti. Općenito, nalazi pokazuju hiperaktivnost signalizacije mTORa u mozgu sa AD. Naprimjer, postmortem studije ljudskog mozga sa AD otkrivaju disregulaciju u PTEN, Akt, S6K i mTOR.[43][44][45] Signalizacija mTOR-a povezana je usko s prisustvom rastvorljivih beta (Aβ) i tau proteina, koji se agregiraju i formiraju dva obilježja bolesti, Aβ plakove i neurofibrilne čvorove.[46] In vitro studije pokazale su da je Aβ aktivator PI3K/AKT put, koji zauzvrat aktivira mTOR.[47] Osim toga, primjena Aβ na N2K ćelije povećava ekspresiju p70S6K, nizvodne mete mTOR-a, za koju se zna da ima veću ekspresiju u neuronima koji na kraju razvijaju neurofibrilske zaplete.[48][49] Ćelije jajnika kineskog hrčka transficirane 7PA2 porodičnom AD mutacijom također pokazuju povećanu aktivnost mTOR-a u odnosu na kontrole, a hiperaktivnost je blokirana pomoću inhibitora gama-sekretaze.[50][51] Ove in vitro studije ukazuju na to da povećanje koncentracije Aβ povećava signalizaciju mTOR-a; međutim, smatra se da značajno velike, citotoksične koncentracije Aβ smanjuju tu signalizaciju.[52]

U skladu sa podacima uočenim in vitro, pokazalo se da su aktivnost mTOR-a i aktivirani p70S6K značajno povećani u korteksu i hipokampusu životinjskih modela AD, u poređenju sa kontrolama.[51][53] Farmakološko ili genetičko uklanjanje Aβ u životinjskim modelima AD eliminira poremećaj normalne aktivnosti mTOR-a, ukazujući na direktnu uključenost Aβ u njegovu signalizaciju.[53] Osim toga, ubrizgavanjem Aβ oligomera u hipokampus normalnih miševa, uočena je hiperaktivnost mTOR-a.[53] Čini se da su kognitivna oštećenja karakteristična za AD posredovana fosforilacijom PRAS-40, koja se odvaja od mTOR-ovoj hiperaktivnosti i omogućava mTOR-sku hiperaktivnost kada je fosforiliran; inhibiranje fosforilacije PRAS-40 sprečava hiperaktivnost mTOR-a izazvanu putem Aβ.[53][54][55] S obzirom na ove nalaze, čini se da je signalni put mTOR-a jedan od mehanizama Aβ-indukovane toksičnosti u AD. .

Limfoproliferativne bolesti[uredi | uredi izvor]

Hiperaktivni putevi mTOR-a su identificirani kod određenih limfoproliferativnih bolesti, kao što su autoimunski limfoproliferativni sindrom (ALPS),[56] multicentrična Castlemanova bolest,[57] i posttransplantacijski limfoproliferativni poremećaj (PTLD).[58]

Sinteza proteina i rast ćelija[uredi | uredi izvor]

Aktivacija mTORC1 potrebna je za sintezu proteina mišićnih miofibrila i skeletnu hipertrofiju mišića kod ljudi. kao odgovor i na fizičke vježbe i uzimanje određenih aminokiselina ili njihovih derivata.[59][60] Trajna inaktivacija signalizacije mTORC1 u skeletnim mišićima olakšava gubitak mišićne mase i snage tokom gubljenja mišića u starosti, kaheksije raka i atrofije zbog fizičke neaktivnosti.[59][60][61] Čini se da aktivacija mTORC2 posreduje u izrastanj neurita u diferenciranoj neuro2a ćeliji miša.[62] Intermitentna aktivacija mTOR-a u prefrontalnim neuronima pomoću β-hidroksi β-metilbutirata inhibira kognitivni pad koji je povezan sa starenjem i povezan sa dendritskim orezivanjem kod životinja, što je fenomen koji se također primjećuje kod ljudi.[63]

Signaling cascade diagram
Dijagram molekulsekih signalnih kascada koje su uključeni u miofibrilsku sintezu mišićnih proteina i mitohondrijsku biogenezu, kao odgovor na fizičku vježbu i specifične aminokiseline ili njihove derivate (prvenstveno leucin i HMB).[59]

Mnoge aminokiseline izvedene iz proteina hrane podstiču aktivaciju mTORC1 i povećavaju sintezu proteina signalizacijom putem Rag GTPaza.
Skraćenice i prikazi:| • PLD: fosfolipaza D
 • PA: fosfatidna kiselina
 • mTOR: mehanička meta rapamicina
 • AMP: adenozin monofosfat
 • ATP: adenozin trifosfat
 • AMPK: AMP-aktivirana protein kinaza
 • PGC-1α: peroksizomski proliferator aktiviran receptor gama koaktivator-1α
 • S6K1: p70S6 kinaza
 • 4EBP1: eukariotski faktor inicijacije translacije 4E- vezujući protein 1
 • eIF4E: eukariotski faktor inicijacije translacije 4E
 • RPS6: ribosomalni protein S6
 • eEF2: eukariotski faktor elongacije 2
 • RE: vježba otpora; EE: vježba izdržljivosti
 • Mio: miofibrilski; Mito: mitohondrijel
 • AA: aminokiseline
 • HMB: β-hidroksi β-metilbuterna kiselina
 • ↑ predstavlja activaciju
 • T-inhibicije

Grapfikon simtže mišićni prorteina tokom vremena: Trening otpora stimuliše sintezu mišićnih proteina (MPS) u periodu do 48 sati nakon vježbanja (prikazano isprekidanom linijom). Unošenje obroka bogatog proteinima u bilo kom trenutku tokom ovog perioda će povećati povećanje sinteze mišićnih proteina izazvano vežbanjem (prikazano punim linijama).[64]

Sklerodermija[uredi | uredi izvor]

Skleroderma, također poznata kao sistemska skleroza, je hronična sistemska autoimunska bolest koju karakteriše otvrdnuće (sklero) kože (derma ) koje u težim oblicima zahvata unutrašnje organe.[65][66] mTOR ima ulogu u bolestima fibroza i autoimunosti, a blokada mTORC puta se istražuje kao tretman za sklerodermu.[8]

Bolest skladištenja glikogena[uredi | uredi izvor]

Neki članci navode da rapamicin može inhibirati mTORC1 tako da se fosforilacija GS (glikogen-sintaze) može povećati u skeletnim mišićima. Ovo otkriće predstavlja potencijalni novi terapijski pristup za bolest skladištenja glikogena koja uključuje akumulaciju glikogena u mišićima.

Anti-kancer[uredi | uredi izvor]

Postoje dva primarna nhibitoramTOR-a i koji se koriste u liječenju karcinoma kod ljudi, temsirolimus i everolimus. mTOR inhibitori su našli primenu u liječenju različitih malignosti, uključujući karcinom bubrežnih ćelija (temsirolimus) i rak gušterače, rak dojke i karcinom bubrežnih ćelija (everolimus).[67] Kompletan mehanizam ovih agenasa nije jasan, ali se smatra da funkcionišu tako što ometaju angiogenezu tumora i uzrokuju oštećenje G1/S tranzicije.[68]

Protiv starenja[uredi | uredi izvor]

Inhibitori mTOR-a mogu biti korisni za liječenje/prevenciju nekoliko stanja povezanih s godinama,[69] uključujući neurodegenerativne bolesti, kao što su Alzheimerova i Parkinsonova bolest.[70] Nakon kratkotrajnog tretmana inhibitorima mTORa, kao što su dactolisib i everolimus, kod starijih osoba (65 i više godina), liječeni su imali smanjen broj infekcija u toku jedne godine.[71]

Za razne prirodne spojeve, uključujući epigalokatehin-galat (EGCG), kofein, kurkumin, berberin, kvercetin, resveratrol i pterostilben, prijavljeno je da inhibiraju mTOR kada se primjenjuju na izolirane ćelije u kulturi.[72][73][74] Još uvijek ne postoje visokokvalitetni dokazi da ove tvari inhibiraju signalizaciju mTOR-a ili produžuju životni vijek kada ih ljudi uzimaju kao dodatke ishrani, uprkos ohrabrujućim rezultatima kod životinja kao što su vinske mušice i miševi. Razne prosudbe su u toku.[75][76]

Interakcije[uredi | uredi izvor]

Pokazalo se da mehancistička meta rapamicina reaguje sa:[77]

Reference[uredi | uredi izvor]

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    Figure 1: Domain structure of the mTOR kinase and components of mTORC1 and mTORC2
    Figure 2: The mTOR Signaling Pathway
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