ACAT1
Mitohondrijska acetil-CoA acetiltransferaza, znana i kao acetoacetil-CoA tiolaza, je enzim koji je kod ljudi kodiran genom ACAT1 (eng skr. od Acetyl-Coenzyme A acetyltransferase 1).[5]
Acetil-koenzim A acetiltransferaza 1 je acetil-CoA C-acetiltransferazni enzim.
Aminokiselinska sekvenca
urediDužina polipeptidnog lanca je 427 aminokiselina, a molekulska težina 45.200 Da.[6]
10 | 20 | 30 | 40 | 50 | ||||
---|---|---|---|---|---|---|---|---|
MAVLAALLRS | GARSRSPLLR | RLVQEIRYVE | RSYVSKPTLK | EVVIVSATRT | ||||
PIGSFLGSLS | LLPATKLGSI | AIQGAIEKAG | IPKEEVKEAY | MGNVLQGGEG | ||||
QAPTRQAVLG | AGLPISTPCT | TINKVCASGM | KAIMMASQSL | MCGHQDVMVA | ||||
GGMESMSNVP | YVMNRGSTPY | GGVKLEDLIV | KDGLTDVYNK | IHMGSCAENT | ||||
AKKLNIARNE | QDAYAINSYT | RSKAAWEAGK | FGNEVIPVTV | TVKGQPDVVV | ||||
KEDEEYKRVD | FSKVPKLKTV | FQKENGTVTA | ANASTLNDGA | AALVLMTADA | ||||
AKRLNVTPLA | RIVAFADAAV | EPIDFPIAPV | YAASMVLKDV | GLKKEDIAMW | ||||
EVNEAFSLVV | LANIKMLEID | PQKVNINGGA | VSLGHPIGMS | GARIVGHLTH | ||||
ALKQGEYGLA | SICNGGGGAS | AMLIQKL |
Struktura
urediGen obuhvata oko 27 kb i sadrži dvanaest egzona prekinutih s jedanaest introna. Regiji koja se nalazi uz 5’ kraj gena nedostaje TATA okvir, ali sadrži mnogo parova G–C i također ima dvije CAAT kutije. Gen takođe može imati mjesto vezanja za faktor transkripcije Sp1 i ima sekvence koje podsećaju na mjesta vezivanja nekoliko drugih faktora transkripcije. Osim toga, postoji fragment DNK od po 101 bp, neposredno uzvodno od mjesta kapice koja ima aktivnost promotora.[7]
Ljudski gen ACAT1 proizvodi himernu iRNK putem trans-spajanja, procesa u kojem se odvojeni transkripti iz hromosoma 1 i 7 spajaju zajedno. Himerni iRNK transkript koristi dva odjeljka za pokretanje translacije: AUG (1397-1399) i GGC (1274-1276). Pokretanje prvog kodona (AUG) rezultira translacijom 50-kDa ACAT1, a iniciranje drugog (GGC) proizvodi još jednu enzimsku aktivnu 56-kDa izoformu; izoforma 56kDa prirodno je prisutna u ljudskim ćelijama, uključujući makrofage izvedene iz ljudskih monocita.[8]
Rezultirajući transkript kodira ACAT1, koji je protein od 45,1 kDa sastavljen od 427 aminokiselina.[9][10] To je također homotetramerni protein koji ima devet transmembranskih domena (TMD). Jedan aktivni ostatak je histidin na 460. poziciji, koji je na 7. TMD. ACAT1 ima sedam slobodnih ostataka cisteina, ali oni ne utiču na katalitsku aktivnost. Postoje dva funkcionalna dijela ovog proteina, TMD7 i TMD8; jedna strana je uključena u vezivanje supstrata i katalizu, dok je druga uključena u interakcije podjedinica i vezivanje.[11]
Funkcija
urediOvaj gen kodira mitohondrijski lokaliziran enzim koji katalizira reverzibilno stvaranje acetoacetil-CoA iz dvije molekule acetil-CoA.[5] Enzim ACAT1 ima nekoliko jedinstvenih svojstava. Prvo se aktivira vezivanjem kalijeve ione u blizini mjesta vezivanja CoA i katalitskog mjesta. Ovo vezivanje uzrokuje strukturnu promjenu u petlji aktivnog mjesta. Osim toga, ovaj enzim može koristiti 2-metil razgranati acetoacetil-CoA kao supstrat, što ga čini jedinstvenim među tiolazama.[12] ACAT1 is regulated at both transcriptional and translational levels. ACAT1 enzyme activity is enhanced ACAT1’s expression is promoted transcriptionally by leptin,[13] angiotensin II,[14] and insulin in human monocytes/macrophages.[15] Insulin-mediated regulation also involves ERK, p38MAPK, and JNK signaling pathways.[16]
Klinički značaj
urediNedostatak ketotiolaze
urediMutacije gena ACAT1 povezane su s nedostatkom u kodiranom proteinu, mitohondrijskoj acetoacetil-CoA tiolazi; ovo je takođe poznato kao nedostatak ketotiolaze. Mnoge su mutacije identificirane u određenim populacijama, a provedena su opsežna istraživanja kako bi se utvrdila alelna i genotipska učestalost defektnog gena.[17] Budući da je mitohondrijska acetoacetil-CoA tiolaza uključena u beta-oksidaciju, nedostatak ovog enzima obilježen je povećanom količinom spojeva holesterola. Osim toga, zahvaćen je i put aminokiseline izoleucina, tako da je zaustavljen pravilan metabolizam. Ovaj nedostatak spada u općenitiju klasu poremećaja poznatih kao organske kiseline, u kojoj disfunkcija određenog koraka katabolizma aminokiselina dovodi do izlučivanja neaminokiselina u urinu. Ovaj nedostatak posebno se eksprimira kao ketoza, acidoza, kao i hipoglikemija, ali postoje i druge kliničke manifestacije. Karakteristike poremećaja organske acidemije su povraćanje, loše hranjenje, neurvni simptomi, poput napada i abnormalnog tonusa te letargija koja napreduje u komu, što su sve manifestacije toksične encefalopatije. Klinički ishod dojenčadi s ovim poremećajima uveliko je određen vremenom postavljanja dijagnoze, a potencijalni ishod uveliko se poboljšava ako se bolest dijagnosticira u prvih deset dana života. Nedostatak ketotiolaza dijagnosticira se GC-MS-om i kvantitativnom analizom aminokiselina u urinu; dijagnostički markeri su 2-metil-3-hidroksi-maslačna kiselina, 2-metilacetoacetatna kiselina i tiglilglicin. Bolest se upravlja pokušavanjem obnavljanja biohemijske i fiziološke homeostaze; uobičajene terapije uključuju ograničavanje prehrane, kako bi se izbjegle prekursorske aminokiseline i upotreba spojeva za uklanjanje toksičnih metabolita ili povećanje aktivnosti enzima. Ova bolest se nasljeđuje na autosomno recesivan način, što znači da nositelji gena ne pokazuju simptome bolesti.[18]
Kancer
urediOsim toga, ekspresija ACAT1 povezana je s manifestacijama raka prostate, jer je ACAT1 značajnije eksprimiran u agresivnim uzorcima tkiva raka prostate u usporedbi s njegovom ekspresijom u benignim ćelijama.[19][20]
Reference
uredi- ^ a b c GRCh38: Ensembl release 89: ENSG00000075239 - Ensembl, maj 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000032047 - 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 "Entrez Gene: acetyl-Coenzyme A acetyltransferase 1".
- ^ "UniProt, P24752". Pristupljeno 15. 8. 2021.
- ^ Kano, M; Fukao, T; Yamaguchi, S; Orii, T; Osumi, T; Hashimoto, T (30. 12. 1991). "Structure and expression of the human mitochondrial acetoacetyl-CoA thiolase-encoding gene". Gene. 109 (2): 285–90. doi:10.1016/0378-1119(91)90623-j. PMID 1684944.
- ^ Chen, J; Zhao, XN; Yang, L; Hu, GJ; Lu, M; Xiong, Y; Yang, XY; Chang, CC; Song, BL; Chang, TY; Li, BL (septembar 2008). "RNA secondary structures located in the interchromosomal region of human ACAT1 chimeric mRNA are required to produce the 56-kDa isoform". Cell Research. 18 (9): 921–36. doi:10.1038/cr.2008.66. PMC 3086790. PMID 18542101.
- ^ 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 (Oct 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.
- ^ "Protein Information: P24752". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). Arhivirano s originala, 14. 8. 2016. Pristupljeno 23. 7. 2016.
- ^ Guo, ZY; Chang, CC; Chang, TY (4. 9. 2007). "Functionality of the seventh and eighth transmembrane domains of acyl-coenzyme A:cholesterol acyltransferase 1". Biochemistry. 46 (35): 10063–71. doi:10.1021/bi7011367. PMID 17691824.
- ^ Haapalainen, AM; Meriläinen, G; Pirilä, PL; Kondo, N; Fukao, T; Wierenga, RK (10. 4. 2007). "Crystallographic and kinetic studies of human mitochondrial acetoacetyl-CoA thiolase: the importance of potassium and chloride ions for its structure and function". Biochemistry. 46 (14): 4305–21. doi:10.1021/bi6026192. PMID 17371050. Referenca sadrži prazan nepoznati parametar:
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(pomoć) - ^ Hongo, S; Watanabe, T; Arita, S; Kanome, T; Kageyama, H; Shioda, S; Miyazaki, A (august 2009). "Leptin modulates ACAT1 expression and cholesterol efflux from human macrophages". American Journal of Physiology. Endocrinology and Metabolism. 297 (2): E474–82. doi:10.1152/ajpendo.90369.2008. PMID 19625677.
- ^ Kanome, T; Watanabe, T; Nishio, K; Takahashi, K; Hongo, S; Miyazaki, A (septembar 2008). "Angiotensin II upregulates acyl-CoA:cholesterol acyltransferase-1 via the angiotensin II Type 1 receptor in human monocyte-macrophages". Hypertension Research. 31 (9): 1801–10. doi:10.1291/hypres.31.1801. PMID 18971559.
- ^ Ge, J; Zhai, W; Cheng, B; He, P; Qi, B; Lu, H; Zeng, Y; Chen, X (septembar 2013). "Insulin induces human acyl-coenzyme A: cholesterol acyltransferase1 gene expression via MAP kinases and CCAAT/enhancer-binding protein α.". Journal of Cellular Biochemistry. 114 (9): 2188–98. doi:10.1002/jcb.24568. PMID 23564383. S2CID 22816300.
- ^ Xin, C; Yan-Fu, W; Ping, H; Jing, G; Jing-Jing, W; Chun-Li, M; Wei, L; Bei, C (maj 2009). "Study of the insulin signaling pathways in the regulation of ACAT1 expression in cultured macrophages". Cell Biology International. 33 (5): 602–6. doi:10.1016/j.cellbi.2009.02.011. PMID 19269342. S2CID 13605913.
- ^ Francis, T; Wartofsky, L (1. 9. 1992). "Common thyroid disorders in the elderly". Postgraduate Medicine. 92 (3): 225–30, 233–6. doi:10.1080/00325481.1992.11701452. PMID 1518756.
- ^ Seashore, MR; Pagon, RA; Adam, MP; Ardinger, HH; Bird, TD; Dolan, CR; Fong, CT; Smith, RJH; Stephens, K (1993). "The Organic Acidemias: An Overview". Gene Reviews (R) Seattle (WA): University of Washington, Seattle; 1993-2015. journal zahtijeva
|journal=
(pomoć) - ^ Saraon, P; Trudel, D; Kron, K; Dmitromanolakis, A; Trachtenberg, J; Bapat, B; van der Kwast, T; Jarvi, KA; Diamandis, EP (april 2014). "Evaluation and prognostic significance of ACAT1 as a marker of prostate cancer progression". The Prostate. 74 (4): 372–80. doi:10.1002/pros.22758. PMID 24311408. S2CID 2169465.
- ^ Saraon, P; Cretu, D; Musrap, N; Karagiannis, GS; Batruch, I; Drabovich, AP; van der Kwast, T; Mizokami, A; Morrissey, C; Jarvi, K; Diamandis, EP (juni 2013). "Quantitative proteomics reveals that enzymes of the ketogenic pathway are associated with prostate cancer progression". Molecular & Cellular Proteomics. 12 (6): 1589–601. doi:10.1074/mcp.m112.023887. PMC 3675816. PMID 23443136.
Dopunska literatura
uredi- Locke JA, Wasan KM, Nelson CC, et al. (2008). "Androgen-mediated cholesterol metabolism in LNCaP and PC-3 cell lines is regulated through two different isoforms of acyl-coenzyme A:Cholesterol Acyltransferase (ACAT)". Prostate. 68 (1): 20–33. doi:10.1002/pros.20674. PMID 18000807. S2CID 40860952.
- Fukao T, Boneh A, Aoki Y, Kondo N (2008). "A novel single-base substitution (c.1124A>G) that activates a 5-base upstream cryptic splice donor site within exon 11 in the human mitochondrial acetoacetyl-CoA thiolase gene". Mol. Genet. Metab. 94 (4): 417–21. doi:10.1016/j.ymgme.2008.04.014. PMID 18511318.
- Reynolds CA, Hong MG, Eriksson UK, et al. (2010). "Analysis of lipid pathway genes indicates association of sequence variation near SREBF1/TOM1L2/ATPAF2 with dementia risk". Hum. Mol. Genet. 19 (10): 2068–78. doi:10.1093/hmg/ddq079. PMC 2860895. PMID 20167577.
- Haapalainen AM, Meriläinen G, Pirilä PL, et al. (2007). "Crystallographic and kinetic studies of human mitochondrial acetoacetyl-CoA thiolase: the importance of potassium and chloride ions for its structure and function". Biochemistry. 46 (14): 4305–21. doi:10.1021/bi6026192. PMID 17371050.
- Chen J, Zhao XN, Yang L, et al. (2008). "RNA secondary structures located in the interchromosomal region of human ACAT1 chimeric mRNA are required to produce the 56-kDa isoform". Cell Res. 18 (9): 921–36. doi:10.1038/cr.2008.66. PMC 3086790. PMID 18542101.
- Raman J, Fritz TA, Gerken TA, et al. (2008). "The catalytic and lectin domains of UDP-GalNAc:polypeptide alpha-N-Acetylgalactosaminyltransferase function in concert to direct glycosylation site selection". J. Biol. Chem. 283 (34): 22942–51. doi:10.1074/jbc.M803387200. PMC 2517002. PMID 18562306.
- Xin C, Yan-Fu W, Ping H, et al. (2009). "Study of the insulin signaling pathways in the regulation of ACAT1 expression in cultured macrophages". Cell Biol. Int. 33 (5): 602–6. doi:10.1016/j.cellbi.2009.02.011. PMID 19269342. S2CID 13605913.
- Li Q, Bai H, Fan P (2008). "[Analysis of acyl-coenzyme A: cholesterol acyltransferase 1 polymorphism in patients with endogenous hypertriglyceridemia in Chinese population]". Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 25 (2): 206–10. PMID 18393248.
- Guo ZY, Chang CC, Chang TY (2007). "Functionality of the seventh and eighth transmembrane domains of acyl-coenzyme A:cholesterol acyltransferase 1". Biochemistry. 46 (35): 10063–71. doi:10.1021/bi7011367. PMID 17691824.
- Fukao T, Yamaguchi S, Orii T, Hashimoto T (1995). "Molecular basis of beta-ketothiolase deficiency: mutations and polymorphisms in the human mitochondrial acetoacetyl-coenzyme A thiolase gene". Hum. Mutat. 5 (2): 113–20. doi:10.1002/humu.1380050203. PMID 7749408. S2CID 36280301.
- Barbe L, Lundberg E, Oksvold P, et al. (2008). "Toward a confocal subcellular atlas of the human proteome". Mol. Cell. Proteomics. 7 (3): 499–508. doi:10.1074/mcp.M700325-MCP200. PMID 18029348.
- Fukao T, Nguyen HT, Nguyen NT, et al. (2010). "A common mutation, R208X, identified in Vietnamese patients with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency". Mol. Genet. Metab. 100 (1): 37–41. doi:10.1016/j.ymgme.2010.01.007. PMID 20156697.
- Hongo S, Watanabe T, Arita S, et al. (2009). "Leptin modulates ACAT1 expression and cholesterol efflux from human macrophages". Am. J. Physiol. Endocrinol. Metab. 297 (2): E474–82. doi:10.1152/ajpendo.90369.2008. PMID 19625677.
- Antalis CJ, Arnold T, Lee B, et al. (2009). "Docosahexaenoic acid is a substrate for ACAT1 and inhibits cholesteryl ester formation from oleic acid in MCF-10A cells". Prostaglandins Leukot. Essent. Fatty Acids. 80 (2–3): 165–71. doi:10.1016/j.plefa.2009.01.001. PMID 19217763.
- Bzoma B; Debska-Slizieñ A; Dudziak M; et al. (2008). "[Genetic predisposition to systemic complications of arterial hypertension in maintenance haemodialysis patients]". Pol. Merkur. Lekarski. 25 (147): 209–16. PMID 19112833.
- Kanome T, Watanabe T, Nishio K, et al. (2008). "Angiotensin II upregulates acyl-CoA:cholesterol acyltransferase-1 via the angiotensin II Type 1 receptor in human monocyte-macrophages". Hypertens. Res. 31 (9): 1801–10. doi:10.1291/hypres.31.1801. PMID 18971559.
- Ruaño G, Bernene J, Windemuth A, et al. (2009). "Physiogenomic comparison of edema and BMI in patients receiving rosiglitazone or pioglitazone". Clin. Chim. Acta. 400 (1–2): 48–55. doi:10.1016/j.cca.2008.10.009. PMID 18996102.
- Thümmler S, Dupont D, Acquaviva C, et al. (2010). "Different clinical presentation in siblings with mitochondrial acetoacetyl-CoA thiolase deficiency and identification of two novel mutations". Tohoku J. Exp. Med. 220 (1): 27–31. doi:10.1620/tjem.220.27. PMID 20046049.
- An S, Jang YS, Park JS, et al. (2008). "Inhibition of acyl-coenzyme A:cholesterol acyltransferase stimulates cholesterol efflux from macrophages and stimulates farnesoid X receptor in hepatocytes". Exp. Mol. Med. 40 (4): 407–17. doi:10.3858/emm.2008.40.4.407. PMC 2679275. PMID 18779653.
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Vanjski linkovi
uredi- Lokacija ljudskog genoma ACAT1 i stranica sa detaljima o genu ACAT1 u UCSC Genome Browseru.