CBR1
Carbonyl reductase 1, also known as CBR1, is an enzyme which in humans is encoded by the CBR1 gene.[1][2][3]
Function
Carbonyl reductase is one of several monomeric, NADPH-dependent oxidoreductases having wide specificity for carbonyl compounds. This enzyme is widely distributed in human tissues. Another carbonyl reductase gene, CRB3, lies close to this gene on chromosome 21q.[1] CBR1 metabolizes many toxic environmental quinones and pharmacological relevant substrates such as the anticancer doxorubicin.[4]
Polymorphisms
Up-to-date two non-synonymous polymorphisms on CBR1 have been identified. The CBR1 V88I polymorphism encodes for a valine-to-isoleucin substitution at position 88 of the aminoacid chain. In vitro studies with recombinant proteins indicate that the CBR1 V88 isoform has a higher Vmax towards the substrates menadione (vitamin K3) and daunorubicin.[5] Recent studies in human liver cytosols show that an untranslated polymorphism on the 3'UTR region of the CBR1 gene (rs9024)[6] is associated with higher levels of the cardiotoxic metabolite doxorubicinol.[7]
References
- ^ a b "Entrez Gene: CBR1 carbonyl reductase 1". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=873.
- ^ Lemieux N, Malfoy B, Forrest GL (January 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): 169–172. 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 (March 2009). "The SDR (short-chain dehydrogenase/reductase and related enzymes) nomenclature initiative". Chem. Biol. Interact. 178 (1–3): 94–98. doi:10.1016/j.cbi.2008.10.040. PMC 2896744. PMID 19027726. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2896744.
- ^ Wermuth B, Platts KL, Seidel A, Oesch F (April 1986). "Carbonyl reductase provides the enzymatic basis of quinone detoxication in man". Biochem. Pharmacol. 35 (8): 1277–1282. doi:10.1016/0006-2952(86)90271-6. PMID 3083821.
- ^ Gonzalez-Covarrubias V, Ghosh D, Lakhman SS, Pendyala L, Blanco JG (June 2007). "A functional genetic polymorphism on human carbonyl reductase 1 (CBR1 V88I) impacts on catalytic activity and NADPH binding affinity". Drug Metab. Dispos. 35 (6): 973–980. doi:10.1124/dmd.107.014779. PMC 2442771. PMID 17344335. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2442771.
- ^ "Reference SNP Cluster Report: rs9024". Entrez SNP. National Center for Biotechnology Information/National Institutes of Health. http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?rs=9024.
- ^ Gonzalez-Covarrubias V, Zhang J, Kalabus JL, Relling MV, Blanco JG (February 2009). "Pharmacogenetics of human carbonyl reductase 1 (CBR1) in livers from black and white donors". Drug Metab. Dispos. 37 (2): 400–407. doi:10.1124/dmd.108.024547. PMC 2680526. PMID 19022938. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2680526.
Further reading
- Wirth H, Wermuth B (1992). "Immunohistochemical localization of carbonyl reductase in human tissues". J. Histochem. Cytochem. 40 (12): 1857–63. doi:10.1177/40.12.1453004. PMID 1453004.
- Inazu N, Ruepp B, Wirth H, Wermuth B (1992). "Carbonyl reductase from human testis: purification and comparison with carbonyl reductase from human brain and rat testis". Biochim. Biophys. Acta 1116 (1): 50–6. PMID 1540623.
- Forrest GL, Akman S, Doroshow J et al. (1991). "Genomic sequence and expression of a cloned human carbonyl reductase gene with daunorubicin reductase activity". Mol. Pharmacol. 40 (4): 502–7. PMID 1921984.
- Forrest GL, Akman S, Krutzik S et al. (1990). "Induction of a human carbonyl reductase gene located on chromosome 21". Biochim. Biophys. Acta 1048 (2–3): 149–55. PMID 2182121.
- Wermuth B, Platts KL, Seidel A, Oesch F (1986). "Carbonyl reductase provides the enzymatic basis of quinone detoxication in man". Biochem. Pharmacol. 35 (8): 1277–1282. doi:10.1016/0006-2952(86)90271-6. PMID 3083821.
- Wermuth B, Bohren KM, Heinemann G et al. (1988). "Human carbonyl reductase. Nucleotide sequence analysis of a cDNA and amino acid sequence of the encoded protein". J. Biol. Chem. 263 (31): 16185–8. PMID 3141401.
- Bohren KM, von Wartburg JP, Wermuth B (1987). "Kinetics of carbonyl reductase from human brain". Biochem. J. 244 (1): 165–71. PMC 1147968. PMID 3311025. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1147968.
- Wermuth B (1981). "Purification and properties of an NADPH-dependent carbonyl reductase from human brain. Relationship to prostaglandin 9-ketoreductase and xenobiotic ketone reductase". J. Biol. Chem. 256 (3): 1206–13. PMID 7005231.
- Wermuth B, Mäder-Heinemann G, Ernst E (1995). "Cloning and expression of carbonyl reductase from rat testis". Eur. J. Biochem. 228 (2): 473–479. doi:10.1111/j.1432-1033.1995.tb20286.x. PMID 7705364.
- Krook M, Ghosh D, Strömberg R et al. (1993). "Carboxyethyllysine in a protein: native carbonyl reductase/NADP(+)-dependent prostaglandin dehydrogenase". Proc. Natl. Acad. Sci. U.S.A. 90 (2): 502–506. doi:10.1073/pnas.90.2.502. PMC 45691. PMID 8421682. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=45691.
- Lemieux N, Malfoy B, Forrest GL (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): 169–172. doi:10.1006/geno.1993.1024. PMID 8432528.
- Watanabe K, Sugawara C, Ono A et al. (1999). "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 (1999). "Identification of the reactive cysteine residue (Cys227) in human carbonyl reductase". Eur. J. Biochem. 260 (1): 9–14. doi:10.1046/j.1432-1327.1999.00089.x. PMID 10091578.
- Hattori M, Fujiyama A, Taylor TD et al. (2000). "The DNA sequence of human chromosome 21". Nature 405 (6784): 311–319. doi:10.1038/35012518. PMID 10830953.
- Finckh C, Atalla A, Nagel G et al. (2001). "Expression and NNK reducing activities of carbonyl reductase and 11beta-hydroxysteroid dehydrogenase type 1 in human lung". Chem. Biol. Interact. 130-132 (1–3): 761–773. doi:10.1016/S0009-2797(00)00306-9. PMID 11306092.
- Balcz B, Kirchner L, Cairns N et al. (2002). "Increased brain protein levels of carbonyl reductase and alcohol dehydrogenase in Down syndrome and Alzheimer's disease". J. Neural Transm. Suppl. (61): 193–201. PMID 11771743.
- Skálová L, Nobilis M, Szotáková B et al. (2002). "Carbonyl reduction of the potential cytostatic drugs benfluron and 3,9-dimethoxybenfluron in human in vitro". Biochem. Pharmacol. 64 (2): 297–305. doi:10.1016/S0006-2952(02)01068-7. PMID 12123751.
- Strausberg RL, Feingold EA, Grouse LH et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–16903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=139241.
- Cheon MS, Shim KS, Kim SH et al. (2004). "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.
- Gerhard DS, Wagner L, Feingold EA et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–2127. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=528928.
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PDB gallery
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1wma: Crystal structure of human CBR1 in complex with Hydroxy-PP
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