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
urediDužina 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
urediGen 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
urediGen 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
urediGlavni 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
urediSLC22A5 ima interakcije sa PDZK1.[12]
Također pogledajte
urediReferences
uredi- ^ a b c GRCh38: Ensembl release 89: ENSG00000197375 - Ensembl, maj 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000018900 - 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.
- ^ a b c "Entrez Gene: SLC22A5 solute carrier family 22 (organic cation transporter), member 5". Pristupljeno 25. 7. 2018.
- ^ a b c d Lahrouchi N, Lodder EM, Mansouri M, Tadros R, Zniber L, Adadi N, Clur SB, van Spaendonck-Zwarts KY, Postma AV, Sefiani A, Ratbi I, Bezzina CR (juni 2017). "Exome sequencing identifies primary carnitine deficiency in a family with cardiomyopathy and sudden death". European Journal of Human Genetics. 25 (6): 783–787. doi:10.1038/ejhg.2017.22. PMC 5477358. PMID 28295041.
- ^ "UniProt, O76082" (jezik: engleski). Pristupljeno 20. 10. 2021.
- ^ a b Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: {603377}: {04/29/2015}: . World Wide Web URL: https://omim.org/
- ^ Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P (oktobar 2013). "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research. 113 (9): 1043–53. doi:10.1161/CIRCRESAHA.113.301151. PMC 4076475. PMID 23965338.
- ^ "SLC22A5 - Solute carrier family 22 member 5". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). Arhivirano s originala, 26. 7. 2018. Pristupljeno 20. 10. 2021.
- ^ Wu X, Prasad PD, Leibach FH, Ganapathy V (maj 1998). "cDNA sequence, transport function, and genomic organization of human OCTN2, a new member of the organic cation transporter family". Biochemical and Biophysical Research Communications. 246 (3): 589–95. doi:10.1006/bbrc.1998.8669. PMID 9618255.
- ^ a b "SLC22A5 - Solute carrier family 22 member 5 - Homo sapiens (Human) - SLC22A5 gene & protein". www.uniprot.org (jezik: engleski). Pristupljeno 25. 7. 2018.
- ^ Yilmaz TF, Atay M, Toprak H, Guler S, Aralasmak A, Alkan A (10. 3. 2014). "MRI findings in encephalopathy with primary carnitine deficiency: a case report". Journal of Neuroimaging. 25 (2): 325–328. doi:10.1111/jon.12102. PMID 24612242. S2CID 35640542.
- ^ Mazzini M, Tadros T, Siwik D, Joseph L, Bristow M, Qin F, Cohen R, Monahan K, Klein M, Colucci W (2011). "Primary carnitine deficiency and sudden death: in vivo evidence of myocardial lipid peroxidation and sulfonylation of sarcoendoplasmic reticulum calcium ATPase 2". Cardiology (jezik: engleski). 120 (1): 52–8. doi:10.1159/000333127. PMID 22116472. S2CID 207687571.
- ^ Yoon YA, Lee DH, Ki CS, Lee SY, Kim JW, Lee YW, Park HD (2012). "SLC22A5 mutations in a patient with systemic primary carnitine deficiency: the first Korean case confirmed by biochemical and molecular investigation". Annals of Clinical and Laboratory Science. 42 (4): 424–8. PMID 23090741.
- ^ Agnetti A, Bitton L, Tchana B, Raymond A, Carano N (januar 2013). "Primary carnitine deficiency dilated cardiomyopathy: 28 years follow-up". International Journal of Cardiology. 162 (2): e34–5. doi:10.1016/j.ijcard.2012.05.038. PMID 22658351.
- ^ Koizumi A, Nozaki J, Ohura T, Kayo T, Wada Y, Nezu J, Ohashi R, Tamai I, Shoji Y, Takada G, Kibira S, Matsuishi T, Tsuji A (novembar 1999). "Genetic epidemiology of the carnitine transporter OCTN2 gene in a Japanese population and phenotypic characterization in Japanese pedigrees with primary systemic carnitine deficiency". Human Molecular Genetics. 8 (12): 2247–54. doi:10.1093/hmg/8.12.2247. PMID 10545605.
Dopunska literatura
uredi- Ascunce RR, Nayar AC, Phoon CK, Srichai MB (2013). "Cardiac magnetic resonance findings in a case of carnitine deficiency". Texas Heart Institute Journal. 40 (1): 104–5. PMC 3568278. PMID 23468586.
- Erguven M, Yilmaz O, Koc S, Caki S, Ayhan Y, Donmez M, Dolunay G (2007). "A case of early diagnosed carnitine deficiency presenting with respiratory symptoms". Annals of Nutrition & Metabolism. 51 (4): 331–4. doi:10.1159/000107675. PMID 17726310. S2CID 40574037.
- Hwu WL, Chien YH, Tang NL, Law LK, Lin CY, Lee NC (oktobar 2007). "Deficiency of the carnitine transporter (OCTN2) with partial N-acetylglutamate synthase (NAGS) deficiency". Journal of Inherited Metabolic Disease. 30 (5): 816. doi:10.1007/s10545-007-0594-y. PMID 17703373. S2CID 2764651.
- Makhseed N, Vallance HD, Potter M, Waters PJ, Wong LT, Lillquist Y, Pasquali M, Amat di San Filippo C, Longo N (2004). "Carnitine transporter defect due to a novel mutation in the SLC22A5 gene presenting with peripheral neuropathy". Journal of Inherited Metabolic Disease. 27 (6): 778–80. doi:10.1023/B:BOLI.0000045837.23328.f4. PMID 15617188. S2CID 24144621.
- 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.
- 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.
- Wu X, Prasad PD, Leibach FH, Ganapathy V (maj 1998). "cDNA sequence, transport function, and genomic organization of human OCTN2, a new member of the organic cation transporter family". Biochemical and Biophysical Research Communications. 246 (3): 589–95. doi:10.1006/bbrc.1998.8669. PMID 9618255.
- Shoji Y, Koizumi A, Kayo T, Ohata T, Takahashi T, Harada K, Takada G (juli 1998). "Evidence for linkage of human primary systemic carnitine deficiency with D5S436: a novel gene locus on chromosome 5q". American Journal of Human Genetics. 63 (1): 101–8. doi:10.1086/301911. PMC 1377235. PMID 9634512.
- 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.
- Burwinkel B, Kreuder J, Schweitzer S, Vorgerd M, Gempel K, Gerbitz KD, Kilimann MW (august 1999). "Carnitine transporter OCTN2 mutations in systemic primary carnitine deficiency: a novel Arg169Gln mutation and a recurrent Arg282ter mutation associated with an unconventional splicing abnormality". Biochemical and Biophysical Research Communications. 261 (2): 484–7. doi:10.1006/bbrc.1999.1060. PMID 10425211.
- 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.
- Vaz FM, Scholte HR, Ruiter J, Hussaarts-Odijk LM, Pereira RR, Schweitzer S, de Klerk JB, Waterham HR, Wanders RJ (1999). "Identification of two novel mutations in OCTN2 of three patients with systemic carnitine deficiency". Human Genetics. 105 (1–2): 157–61. doi:10.1007/s004390051079. PMID 10480371.
- Koizumi A, Nozaki J, Ohura T, Kayo T, Wada Y, Nezu J, Ohashi R, Tamai I, Shoji Y, Takada G, Kibira S, Matsuishi T, Tsuji A (novembar 1999). "Genetic epidemiology of the carnitine transporter OCTN2 gene in a Japanese population and phenotypic characterization in Japanese pedigrees with primary systemic carnitine deficiency". Human Molecular Genetics. 8 (12): 2247–54. doi:10.1093/hmg/8.12.2247. PMID 10545605.
- 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.
- Wang Y, Kelly MA, Cowan TM, Longo N (2000). "A missense mutation in the OCTN2 gene associated with residual carnitine transport activity". Human Mutation. 15 (3): 238–45. doi:10.1002/(SICI)1098-1004(200003)15:3<238::AID-HUMU4>3.0.CO;2-3. PMID 10679939.
- 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.
- Karlic H, Lohninger A, Laschan C, Lapin A, Böhmer F, Huemer M, Guthann E, Rappold E, Pfeilstöcker M (juli 2003). "Downregulation of carnitine acyltransferases and organic cation transporter OCTN2 in mononuclear cells in healthy elderly and patients with myelodysplastic syndromes". Journal of Molecular Medicine. 81 (7): 435–42. doi:10.1007/s00109-003-0447-6. PMID 12802501. S2CID 10992930.
- Amat di San Filippo C, Wang Y, Longo N (novembar 2003). "Functional domains in the carnitine transporter OCTN2, defective in primary carnitine deficiency". The Journal of Biological Chemistry. 278 (48): 47776–84. doi:10.1074/jbc.M307911200. PMID 14506273.
Vanjski linkovi
uredi- 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.