CBR1
Karbonil-reduktaza 1, znana i kao CBR1, jest enzim koji je kod ljudi kodiran genom CBR1 sa hromosoma 21.[5][6][7] Protein kodiran ovim genom pripada porodici kratkolančanih dehidrogenaza/reduktaza (SDR), koje funkcionišu kao NADPH-zavisne oksidoreduktaze sa širokom specifičnosti za karbonil spojeve, kao što su kinonski, prostaglandini i različiti ksenobiotici. Za ovaj gen su pronađene alternativno prerađene varijante transkripta.[5]
Struktura
[uredi | uredi izvor]Aminokiselinska sekvenca
[uredi | uredi izvor]Dužina polipeptidnog lanca je 277 aminokiselina, a molekulska težina 30.375 Da.[5]
| 10 | 20 | 30 | 40 | 50 | ||||
|---|---|---|---|---|---|---|---|---|
| MSSGIHVALV | TGGNKGIGLA | IVRDLCRLFS | GDVVLTARDV | TRGQAAVQQL | ||||
| QAEGLSPRFH | QLDIDDLQSI | RALRDFLRKE | YGGLDVLVNN | AGIAFKVADP | ||||
| TPFHIQAEVT | MKTNFFGTRD | VCTELLPLIK | PQGRVVNVSS | IMSVRALKSC | ||||
| SPELQQKFRS | ETITEEELVG | LMNKFVEDTK | KGVHQKEGWP | SSAYGVTKIG | ||||
| VTVLSRIHAR | KLSEQRKGDK | ILLNACCPGW | VRTDMAGPKA | TKSPEEGAET | ||||
| PVYLALLPPD | AEGPHGQFVS | EKRVEQW |
Gen
[uredi | uredi izvor]Ljudski gen CBR1 sadrži osam egzona.[5]
Protein
[uredi | uredi izvor]Enzim se sastoji od 277 aminokiselinskih ostataka i široko je rasprostranjen u ljudskim tkivima kao što su organi: jetra, epiderma, želudac, tanko crijevo, bubreg, te neuronske ćelije i vlakna glatkih mišića.[8] Najbolji supstrati za CBR1 su kinoni, uključujući ubikinon-1 i tokoferolhinon (vitamin E). Ubikinoni (koenzim Q) su sastavni dijelovi respiratornog lanca, a tokoferolkinon štiti lipide bioloških membrana od lipidne peroksidacije, što ukazuje da CBR1 može imati važnu ulogu kao katalizator oksidacije–redukcije u biološkim procesima.[9]
Funkcija
[uredi | uredi izvor]Karbonil reduktaza je jedan od nekoliko monomernih, nikotinamid adenin-dinukleotid fosfat (NADPH) ovisnih oksidoreduktaza, koje imaju široku specifičnost za karbonilna spojeve. Ovaj enzim je široko rasprostranjen u ljudskim tkivima. Još jedan gen karbonil reduktaze, CBR3, nalazi se blizu ovog gena na hromosomskoj regiji 21q.[5] CBR1 metabolizira mnoge toksične okolišne kinone i farmakološki relevantne supstrate kao što je antikancerski doksorubicin.[10] Nekoliko studija je pokazalo da CBR1 i,a zaštitnu ulogu u oksidativnom stresu, neurodegeneracijama i apoptozama.[11] Osim toga, CBR1 inaktivira lipidne aldehide u ćelijama, tokom oksidativnog stresa. Stoga, CBR1 može imati korisnu ulogu u zaštiti od oštećenja ćelija koje su posljedica oksidativnog stresa.[12]
Polimorfizmi
[uredi | uredi izvor]Identificirana su dva nesinonimna polimorfizma na CBR1. Polimorfizam CBR1 V88I kodira supstituciju valina na izoleucinskoj poziciji 88 lanca aminokiselina. In vitro studije s rekombinantnim proteinima pokazuju da izoforma CBR1 V88 ima veći Vmax prema menadionskim supstratima (vitamin K3) i daunorubicin.[13] Nedavna istraživanja citosola ljudske jetre pokazuju da je neprevedeni polimorfizam na 3' UTR regiji gena "CBR1" (rs9024)[14] povezan s višim razinama kardiotoksičnog metabolita doksorubicinola.[15]
Klinički značaj
[uredi | uredi izvor]Prijavljeno je da je CBR1 vezan za progresiju tumora.[16] Supresija ekspresije CBR1 bila je povezana sa lošom prognozom kod maternićnog raka endometrija i cerviksa i karcinoma pločastih ćelija.[16] Prethodne studije pokazale su da je smanjena ekspresija CBR1 povezana s metastazama u limfnim čvorovima i lošom prognozom kod karcinoma jajnika, a indukcija ekspresije CBR1 u tumorima jajnika dovodi do spontanog smanjenja veličine tumora.[17]
Nedavna studija pokazuje da CBR1 slabi apoptoze i promovira preživljavanje ćelija u β ćelija pankreasa u glukotoksičnim i glukolipotoksičnim uslovima, smanjenjem proizvodnje reaktivnih vrsta kisika (ROS). Njihovi podaci pokazuju da su nivo ekspresije CBR1 i aktivnost enzima smanjeni u pankreasnim otočićima izoliranim od db/db miševa, životinjskog modela za dijabetes tipa 2. Ovi rezultati sugeriraju da CBR1 može imati ulogu u zaštiti β-ćelija pankreasa od oksidativnog stresa u glukotoksičnim ili glukolipotoksičnim uvjetima, a njegova smanjena ekspresija ili aktivnost može doprinijeti disfunkciji β-ćelija kod db/db miševa ili ljudskog dijabetesa tipa 2..[8]
Osim toga, CBR1 može imati kritičnu ulogu u sintezi PGF2α u ljudskim amnionskim fibroblastima, a kortizol promovira konverziju PGE2 u PGF2α, preko glukokortikoidnog receptora (GR) posredovane indukcije CBR1 u ljudskim amnionskim fibroblastima. Ovaj stimulativni učinak kortizola na ekspresiju CBR1 može dijelom objasniti istovremeni porast kortizola i PGF2α u ljudskom amnionskom tkivu s porođajem, a ovi nalazi mogu objasniti povećanu proizvodnju PGF2α u fetusnim membranama prije početka porođaja.[18]
Interakcije
[uredi | uredi izvor]Pokazalo se da CBR1 reaguje sa kortizolom,[18] domenom C2,[19] i flavonoidima.[20]
Reference
[uredi | uredi izvor]- ^ a b c GRCh38: Ensembl release 89: ENSG00000159228 - Ensembl, maj 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000051483 - 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 d e "Entrez Gene: CBR1 carbonyl reductase 1".
- ^ Lemieux N, Malfoy B, Forrest GL (Jan 1993). "Human carbonyl reductase (CBR) localized to band 21q22.1 by high-resolution fluorescence in situ hybridization displays gene dosage effects in trisomy 21 cells". Genomics. 15 (1): 169–72. doi:10.1006/geno.1993.1024. PMID 8432528.
- ^ Persson B, Kallberg Y, Bray JE, Bruford E, Dellaporta SL, Favia AD, Duarte RG, Jörnvall H, Kavanagh KL, Kedishvili N, Kisiela M, Maser E, Mindnich R, Orchard S, Penning TM, Thornton JM, Adamski J, Oppermann U (Mar 2009). "The SDR (short-chain dehydrogenase/reductase and related enzymes) nomenclature initiative". Chemico-Biological Interactions. 178 (1–3): 94–8. doi:10.1016/j.cbi.2008.10.040. PMC 2896744. PMID 19027726.
- ^ a b Rashid MA, Lee S, Tak E, Lee J, Choi TG, Lee JW, Kim JB, Youn JH, Kang I, Ha J, Kim SS (Nov 2010). "Carbonyl reductase 1 protects pancreatic β-cells against oxidative stress-induced apoptosis in glucotoxicity and glucolipotoxicity". Free Radical Biology & Medicine. 49 (10): 1522–33. doi:10.1016/j.freeradbiomed.2010.08.015. PMID 20728534.
- ^ Wermuth B (Feb 1981). "Purification and properties of an NADPH-dependent carbonyl reductase from human brain. Relationship to prostaglandin 9-ketoreductase and xenobiotic ketone reductase". The Journal of Biological Chemistry. 256 (3): 1206–13. doi:10.1016/S0021-9258(19)69950-3. PMID 7005231.
- ^ Wermuth B, Platts KL, Seidel A, Oesch F (Apr 1986). "Carbonyl reductase provides the enzymatic basis of quinone detoxication in man". Biochemical Pharmacology. 35 (8): 1277–82. doi:10.1016/0006-2952(86)90271-6. PMID 3083821.
- ^ Ismail E, Al-Mulla F, Tsuchida S, Suto K, Motley P, Harrison PR, Birnie GD (Mar 2000). "Carbonyl reductase: a novel metastasis-modulating function". Cancer Research. 60 (5): 1173–6. PMID 10728668.
- ^ Maser E (Feb 2006). "Neuroprotective role for carbonyl reductase?". Biochemical and Biophysical Research Communications. 340 (4): 1019–22. doi:10.1016/j.bbrc.2005.12.113. PMID 16406002.
- ^ Gonzalez-Covarrubias V, Ghosh D, Lakhman SS, Pendyala L, Blanco JG (Jun 2007). "A functional genetic polymorphism on human carbonyl reductase 1 (CBR1 V88I) impacts on catalytic activity and NADPH binding affinity". Drug Metabolism and Disposition. 35 (6): 973–80. doi:10.1124/dmd.107.014779. PMC 2442771. PMID 17344335.
- ^ "Reference SNP Cluster Report: rs9024". Entrez SNP. National Center for Biotechnology Information/National Institutes of Health.
- ^ Gonzalez-Covarrubias V, Zhang J, Kalabus JL, Relling MV, Blanco JG (Feb 2009). "Pharmacogenetics of human carbonyl reductase 1 (CBR1) in livers from black and white donors". Drug Metabolism and Disposition. 37 (2): 400–7. doi:10.1124/dmd.108.024547. PMC 2680526. PMID 19022938.
- ^ a b Murakami, A; Yakabe, K; Yoshidomi, K; Sueoka, K; Nawata, S; Yokoyama, Y; Tsuchida, S; Al-Mulla, F; Sugino, N (1. 10. 2012). "Decreased carbonyl reductase 1 expression promotes malignant behaviours by induction of epithelial mesenchymal transition and its clinical significance". Cancer Letters. 323 (1): 69–76. doi:10.1016/j.canlet.2012.03.035. PMID 22542806.
- ^ Osawa, Y; Yokoyama, Y; Shigeto, T; Futagami, M; Mizunuma, H (mart 2015). "Decreased expression of carbonyl reductase 1 promotes ovarian cancer growth and proliferation". International Journal of Oncology. 46 (3): 1252–8. doi:10.3892/ijo.2014.2810. PMID 25572536.
- ^ a b Guo, C; Wang, W; Liu, C; Myatt, L; Sun, K (august 2014). "Induction of PGF2α synthesis by cortisol through GR dependent induction of CBR1 in human amnion fibroblasts". Endocrinology. 155 (8): 3017–24. doi:10.1210/en.2013-1848. PMC 4098009. PMID 24654784.
- ^ Yagi, H; Conroy, PJ; Leung, EW; Law, RH; Trapani, JA; Voskoboinik, I; Whisstock, JC; Norton, RS (16. 10. 2015). "Structural Basis for Ca2 -mediated Interaction of the Perforin C2 Domain with Lipid Membranes". The Journal of Biological Chemistry. 290 (42): 25213–26. doi:10.1074/jbc.m115.668384. PMC 4646173. PMID 26306037.
- ^ Nelson, SH; Grunebaum, H (april 1971). "A follow-up study of wrist slashers". The American Journal of Psychiatry. 127 (10): 1345–9. doi:10.1176/ajp.127.10.1345. PMID 5549925.
Dopunska literatura
[uredi | uredi izvor]- Wirth H, Wermuth B (Dec 1992). "Immunohistochemical localization of carbonyl reductase in human tissues". The Journal of Histochemistry and Cytochemistry. 40 (12): 1857–63. doi:10.1177/40.12.1453004. PMID 1453004.
- Inazu N, Ruepp B, Wirth H, Wermuth B (Mar 1992). "Carbonyl reductase from human testis: purification and comparison with carbonyl reductase from human brain and rat testis". Biochimica et Biophysica Acta (BBA) - General Subjects. 1116 (1): 50–6. doi:10.1016/0304-4165(92)90127-g. PMID 1540623.
- Forrest GL, Akman S, Doroshow J, Rivera H, Kaplan WD (Oct 1991). "Genomic sequence and expression of a cloned human carbonyl reductase gene with daunorubicin reductase activity". Molecular Pharmacology. 40 (4): 502–7. PMID 1921984.
- Forrest GL, Akman S, Krutzik S, Paxton RJ, Sparkes RS, Doroshow J, Felsted RL, Glover CJ, Mohandas T, Bachur NR (Apr 1990). "Induction of a human carbonyl reductase gene located on chromosome 21". Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression. 1048 (2–3): 149–55. doi:10.1016/0167-4781(90)90050-c. PMID 2182121.
- Wermuth B, Platts KL, Seidel A, Oesch F (Apr 1986). "Carbonyl reductase provides the enzymatic basis of quinone detoxication in man". Biochemical Pharmacology. 35 (8): 1277–82. doi:10.1016/0006-2952(86)90271-6. PMID 3083821.
- Wermuth B, Bohren KM, Heinemann G, von Wartburg JP, Gabbay KH (Nov 1988). "Human carbonyl reductase. Nucleotide sequence analysis of a cDNA and amino acid sequence of the encoded protein". The Journal of Biological Chemistry. 263 (31): 16185–8. doi:10.1016/S0021-9258(18)37576-8. PMID 3141401.
- Bohren KM, von Wartburg JP, Wermuth B (maj 1987). "Kinetics of carbonyl reductase from human brain". The Biochemical Journal. 244 (1): 165–71. doi:10.1042/bj2440165. PMC 1147968. PMID 3311025.
- Wermuth B (Feb 1981). "Purification and properties of an NADPH-dependent carbonyl reductase from human brain. Relationship to prostaglandin 9-ketoreductase and xenobiotic ketone reductase". The Journal of Biological Chemistry. 256 (3): 1206–13. doi:10.1016/S0021-9258(19)69950-3. PMID 7005231.
- Wermuth B, Mäder-Heinemann G, Ernst E (Mar 1995). "Cloning and expression of carbonyl reductase from rat testis". European Journal of Biochemistry. 228 (2): 473–9. doi:10.1111/j.1432-1033.1995.tb20286.x. PMID 7705364.
- Krook M, Ghosh D, Strömberg R, Carlquist M, Jörnvall H (Jan 1993). "Carboxyethyllysine in a protein: native carbonyl reductase/NADP( )-dependent prostaglandin dehydrogenase". Proceedings of the National Academy of Sciences of the United States of America. 90 (2): 502–6. Bibcode:1993PNAS...90..502K. doi:10.1073/pnas.90.2.502. PMC 45691. PMID 8421682.
- Lemieux N, Malfoy B, Forrest GL (Jan 1993). "Human carbonyl reductase (CBR) localized to band 21q22.1 by high-resolution fluorescence in situ hybridization displays gene dosage effects in trisomy 21 cells". Genomics. 15 (1): 169–72. doi:10.1006/geno.1993.1024. PMID 8432528.
- Watanabe K, Sugawara C, Ono A, Fukuzumi Y, Itakura S, Yamazaki M, Tashiro H, Osoegawa K, Soeda E, Nomura T (Aug 1998). "Mapping of a novel human carbonyl reductase, CBR3, and ribosomal pseudogenes to human chromosome 21q22.2". Genomics. 52 (1): 95–100. doi:10.1006/geno.1998.5380. PMID 9740676.
- Tinguely JN, Wermuth B (Feb 1999). "Identification of the reactive cysteine residue (Cys227) in human carbonyl reductase". European Journal of Biochemistry. 260 (1): 9–14. doi:10.1046/j.1432-1327.1999.00089.x. PMID 10091578.
- Finckh C, Atalla A, Nagel G, Stinner B, Maser E (Jan 2001). "Expression and NNK reducing activities of carbonyl reductase and 11beta-hydroxysteroid dehydrogenase type 1 in human lung". Chemico-Biological Interactions. 130–132 (1–3): 761–73. doi:10.1016/S0009-2797(00)00306-9. PMID 11306092.
- Balcz B, Kirchner L, Cairns N, Fountoulakis M, Lubec G (2002). "Increased brain protein levels of carbonyl reductase and alcohol dehydrogenase in Down syndrome and Alzheimer's disease". Journal of Neural Transmission. Supplementum (61): 193–201. doi:10.1007/978-3-7091-6262-0_15. ISBN 978-3-211-83704-7. PMID 11771743.
- Skálová L, Nobilis M, Szotáková B, Kondrová E, Savlík M, Wsól V, Pichard-Garcia L, Maser E (Jul 2002). "Carbonyl reduction of the potential cytostatic drugs benfluron and 3,9-dimethoxybenfluron in human in vitro". Biochemical Pharmacology. 64 (2): 297–305. doi:10.1016/S0006-2952(02)01068-7. PMID 12123751.
- Cheon MS, Shim KS, Kim SH, Hara A, Lubec G (Jul 2003). "Protein levels of genes encoded on chromosome 21 in fetal Down syndrome brain: Challenging the gene dosage effect hypothesis (Part IV)". Amino Acids. 25 (1): 41–7. doi:10.1007/s00726-003-0009-9. PMID 12836057. S2CID 52799223.
Vanjski linkovi
[uredi | uredi izvor]- Lokacija ljudskog genoma CBR1 i stranica sa detaljima o genu CBR1 u UCSC Genome Browseru.
- {{PDBe-KB2|P16152|Carbonyl reductase [NADPH]