SLC22A5
SLC22A5 je membranski transportni protein pridružen primarnom nedostatku karnitina. To jest protein koji je kod ljudi kodiran genom SLC22A5 sa hromosoma 5.Ovaj protein je uključen u aktivno ćelijsko preuzimanje karnitina. Djeluje kao simporter, pomičući natrijeve ione i druge organske katikone preko membrane, zajedno s karnitinom. Takvi polispecifični organski kationski transporteri u jetri, bubrezima, crijevima i drugim organima kritični su za uklanjanje mnogih endogenih malih organskih kationa, kao i širokog spektra lijekova i toksina iz okoliša.[5] Mutacije u genu SLC22A5 uzrokuju sistemski primarni nedostatak karnitina, što može dovesti do zatajenja srca.[6]
Aminokiselinska sekvenca
Dužina polipeptidnog lanca je 557 aminokiselina, а molekulska težina 62.752 Da.[7]
| 10 | 20 | 30 | 40 | 50 | ||||
|---|---|---|---|---|---|---|---|---|
| MRDYDEVTAF | LGEWGPFQRL | IFFLLSASII | PNGFTGLSSV | FLIATPEHRC | ||||
| RVPDAANLSS | AWRNHTVPLR | LRDGREVPHS | CRRYRLATIA | NFSALGLEPG | ||||
| RDVDLGQLEQ | ESCLDGWEFS | QDVYLSTIVT | EWNLVCEDDW | KAPLTISLFF | ||||
| VGVLLGSFIS | GQLSDRFGRK | NVLFVTMGMQ | TGFSFLQIFS | KNFEMFVVLF | ||||
| VLVGMGQISN | YVAAFVLGTE | ILGKSVRIIF | STLGVCIFYA | FGYMVLPLFA | ||||
| YFIRDWRMLL | VALTMPGVLC | VALWWFIPES | PRWLISQGRF | EEAEVIIRKA | ||||
| AKANGIVVPS | TIFDPSELQD | LSSKKQQSHN | ILDLLRTWNI | RMVTIMSIML | ||||
| WMTISVGYFG | LSLDTPNLHG | DIFVNCFLSA | MVEVPAYVLA | WLLLQYLPRR | ||||
| YSMATALFLG | GSVLLFMQLV | PPDLYYLATV | LVMVGKFGVT | AAFSMVYVYT | ||||
| AELYPTVVRN | MGVGVSSTAS | RLGSILSPYF | VYLGAYDRFL | PYILMGSLTI | ||||
| LTAILTLFLP | ESFGTPLPDT | IDQMLRVKGM | KHRKTPSHTR | MLKDGQERPT | ||||
| ILKSTAF |
Struktura
Gen SLC22A5 ima 10 egzona,[8] nalazi se na q kraku hromosoma 5 u poziciji 31.1 i obuhvata 25.910 parova baza.[5] Gen proizvodi protein od 63 kDa sa 557 aminokiselina.[9][10] Protein ima 12 pretpostavljenih transmembranskih domena, sa dugom vanćelijskom petljom od 107 aminokiselina, između prve dva transmembranska domena i unutarćelijskom petljom između četvrtog i petog transmembranskog domena. Ova duga vanćelijska petlja ima tri potencijalna mjesta za N-glikozilaciju, a unutarćelijska petlja ima ATP/GTP vezujući motiv. U pretpostavljenim unutarćelijskim domenima postoji pet potencijalnih mjesta za fosforilaciju ovisne o protein-kinazi C i jedno za fosforilaciju ovisnu o protein-kinazi A.[11]
Funkcija
Gen SLC22A5 kodira plazmatski integralni membranski protein koji funkcionira i kao transporter organskih kationa i transporter visokog afiniteta karnitina ovisnog o natriju.[5] Kodirani protein uključen je u aktivno ćelijsko preuzimanje karnitina, prenoseći jedan natrijev ion s jednom molekulom karnitina. Organski kationi koji se prenose ovim proteinom uključuju tetraetilamonij (TEA) bez uključivanja natrija. Odnos relativne aktivnosti preuzimanja karnitina i TEA je 11,3.[12]
Klinički značaj
Glavni fenotipski učinak autosomno recesivnih mutacija, bilo složena heterozigotna ili homozigotna,[6] u genu SLC22A5 je sistemski primarni nedostatak karnitina,[8] karakterizirana je smanjenim transportom karnitina, gubitkom karnitina u urinu, niskim koncentracijama karnitina u serumu, smanjenom unutarćelijskom akumulacijom karnitina, smanjenom beta-oksidacijom i citosolnim masnimm kiselinama.[6] Pacijenti često pokazuju metaboličku dekompenzaciju, hipoketonsku hipoglikemija, jetrenu encefalopatiju, Reyeov sindrom i iznenadnu smrt novorođenčadi u prvoj godini, nakon čega jeslijedi kasniji početak kardiomiopatija ili skeletnih miopatija, aritmije, slabost mišića i zatajenje srca u ranom djetinjstvu.[6][13][14]
Pacijenti mogu biti asimptomski, pri čemu oko 70% takvih pacijenata ima misens mutacije ili delecije; učestalost nonsens mutacija je povećana kod simptomskih pacijenata.[15] Simptomi i ishod bolesti mogu se drastično poboljšati zamjenskom terapijom, uzimanjem L-karnitina.[16] Procijenjena incidencija primarnog nedostatka karnitina u novorođenčadi je oko 1/40.000.[17]
Interakcije
SLC22A5 ima interakcije sa PDZK1.[12]
Također pogledajte
References
Dopunska literatura
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- Kinali M, Olpin SE, Clayton PT, Daubeney PE, Mercuri E, Manzur AY, Tein I, Leonard J, Muntoni F (2004). "Diagnostic difficulties in a case of primary systemic carnitine deficiency with idiopathic dilated cardiomyopathy". European Journal of Paediatric Neurology. 8 (4): 217–9. doi:10.1016/j.ejpn.2004.03.007. PMID 15261886.
- Silverberg MS (juni 2006). "OCTNs: will the real IBD5 gene please stand up?". World Journal of Gastroenterology. 12 (23): 3678–81. doi:10.3748/wjg.v12.i23.3678. PMC 4087460. PMID 16773684.
- Matsuishi T, Hirata K, Terasawa K, Kato H, Yoshino M, Ohtaki E, Hirose F, Nonaka I, Sugiyama N, Ohta K (februar 1985). "Successful carnitine treatment in two siblings having lipid storage myopathy with hypertrophic cardiomyopathy". Neuropediatrics. 16 (1): 6–12. doi:10.1055/s-2008-1052536. PMID 3974805.
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- Tamai I, Ohashi R, Nezu J, Yabuuchi H, Oku A, Shimane M, Sai Y, Tsuji A (august 1998). "Molecular and functional identification of sodium ion-dependent, high affinity human carnitine transporter OCTN2". The Journal of Biological Chemistry. 273 (32): 20378–82. doi:10.1074/jbc.273.32.20378. PMID 9685390.
- Nezu J, Tamai I, Oku A, Ohashi R, Yabuuchi H, Hashimoto N, Nikaido H, Sai Y, Koizumi A, Shoji Y, Takada G, Matsuishi T, Yoshino M, Kato H, Ohura T, Tsujimoto G, Hayakawa J, Shimane M, Tsuji A (januar 1999). "Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter". Nature Genetics. 21 (1): 91–4. doi:10.1038/5030. PMID 9916797. S2CID 20723174.
- Tang NL, Ganapathy V, Wu X, Hui J, Seth P, Yuen PM, Wanders RJ, Fok TF, Hjelm NM (april 1999). "Mutations of OCTN2, an organic cation/carnitine transporter, lead to deficient cellular carnitine uptake in primary carnitine deficiency". Human Molecular Genetics. 8 (4): 655–60. doi:10.1093/hmg/8.4.655. PMID 10072434.
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- Wu X, Huang W, Prasad PD, Seth P, Rajan DP, Leibach FH, Chen J, Conway SJ, Ganapathy V (septembar 1999). "Functional characteristics and tissue distribution pattern of organic cation transporter 2 (OCTN2), an organic cation/carnitine transporter". The Journal of Pharmacology and Experimental Therapeutics. 290 (3): 1482–92. PMID 10454528.
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- Seth P, Wu X, Huang W, Leibach FH, Ganapathy V (novembar 1999). "Mutations in novel organic cation transporter (OCTN2), an organic cation/carnitine transporter, with differential effects on the organic cation transport function and the carnitine transport function". The Journal of Biological Chemistry. 274 (47): 33388–92. doi:10.1074/jbc.274.47.33388. PMID 10559218.
- Mayatepek E, Nezu J, Tamai I, Oku A, Katsura M, Shimane M, Tsuji A (januar 2000). "Two novel missense mutations of the OCTN2 gene (W283R and V446F) in a patient with primary systemic carnitine deficiency". Human Mutation. 15 (1): 118. doi:10.1002/(SICI)1098-1004(200001)15:1<118::AID-HUMU28>3.0.CO;2-8. PMID 10612840.
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- Ohashi R, Tamai I, Inano A, Katsura M, Sai Y, Nezu J, Tsuji A (septembar 2002). "Studies on functional sites of organic cation/carnitine transporter OCTN2 (SLC22A5) using a Ser467Cys mutant protein". The Journal of Pharmacology and Experimental Therapeutics. 302 (3): 1286–94. doi:10.1124/jpet.102.036004. PMID 12183691. S2CID 1944987.
- Rahbeeni Z, Vaz FM, Al-Hussein K, Bucknall MP, Ruiter J, Wanders RJ, Rashed MS (septembar 2002). "Identification of two novel mutations in OCTN2 from two Saudi patients with systemic carnitine deficiency". Journal of Inherited Metabolic Disease. 25 (5): 363–9. doi:10.1023/A:1020143632011. PMID 12408185. S2CID 25824831.
- Elimrani I, Lahjouji K, Seidman E, Roy MJ, Mitchell GA, Qureshi I (maj 2003). "Expression and localization of organic cation/carnitine transporter OCTN2 in Caco-2 cells". American Journal of Physiology. Gastrointestinal and Liver Physiology. 284 (5): G863–71. doi:10.1152/ajpgi.00220.2002. PMID 12684216.
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Vanjski linkovi
- SLC22A5 protein, human na US National Library of Medicine Medical Subject Headings (MeSH)
- Primary Carnitine Deficiency (OCTN2 database)
Ovaj članak uključuje tekst iz Nacionalne medicinske biblioteke Sjedinjenih Država, koji je u javnom vlasništvu.