Wikipedia

MTOR

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
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
• aktivnost sa transferazom
• ribosome binding
• GO:0001948, GO:0016582 vezivanje za proteine
• protein kinase binding
• nucleotide binding
• phosphoprotein binding
• protein kinase activity
• GO:0032403 protein-containing complex binding
• vezivanje identičnih proteina
• translation regulator activity
Ćelijska komponenta• citoplazma
• citosol
• phosphatidylinositol 3-kinase complex
• membrana
• mitohondrija
• TORC1 complex
• organelle membrane
• GO:0009327 makromolekulani kompleks
• mitochondrial outer membrane
• Endoplazmatski retikulum
• TORC2 complex
• Golđijev aparat
• intracellular membrane-bounded organelle
• nukleoplazma
• soma
• 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

2475

56717

Ensembl

ENSG00000198793

ENSMUSG00000028991

UniProt

P42345

Q9JLN9

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

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

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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

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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 FKBP12–rapamicin vezuje se direktno za FKBP12-rapamicinvezujući (FRB) domen mTOR, inhibirajući njegovu aktivnost.[18]

Kompleksi

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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

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Starenje

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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

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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

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Glavni članak: Poremećaj centralnog nervnog sistema

Autizam

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

Alzheimerova bolest

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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

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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

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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]

 
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

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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

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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

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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

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

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

Reference

uredi
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    mTOR function is mediated through two large biochemical complexes defined by their respective protein composition and have been extensively reviewed elsewhere(Dibble and Manning, 2013; Laplante and Sabatini, 2012)(Figure 1B). In brief, common to both mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) are: mTOR itself, mammalian lethal with sec13 protein 8 (mLST8; also known as GβL), and the inhibitory DEP domain containing mTOR-interacting protein (DEPTOR). Specific to mTORC1 is the regulator-associated protein of the mammalian target of rapamycin (Raptor) and proline-rich Akt substrate of 40 kDa (PRAS40)(Kim et al., 2002; Laplante and Sabatini, 2012). Raptor is essential to mTORC1 activity. The mTORC2 complex includes the rapamycin insensitive companion of mTOR (Rictor), mammalian stress activated MAP kinase-interacting protein 1 (mSIN1), and proteins observed with rictor 1 and 2 (PROTOR 1 and 2)(Jacinto et al., 2006; Jacinto et al., 2004; Pearce et al., 2007; Sarbassov et al., 2004)(Figure 1B). Rictor and mSIN1 are both critical to mTORC2 function.
    Figure 1: Domain structure of the mTOR kinase and components of mTORC1 and mTORC2
    Figure 2: The mTOR Signaling Pathway
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