CBR1 explained

Carbonyl reductase 1, also known as CBR1, is an enzyme which in humans is encoded by the CBR1 gene.^{[1] [2] [3]} The protein encoded by this gene belongs to the short-chain dehydrogenases/reductases (SDR) family, which function as NADPH-dependent oxidoreductases having wide specificity for carbonyl compounds, such as quinones, prostaglandins, and various xenobiotics. Alternatively spliced transcript variants have been found for this gene.^[1]

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, CBR3, lies close to this gene on chromosome 21q22.12. CBR1 metabolizes many toxic environmental quinones and pharmacological relevant substrates such as the anticancer doxorubicin.^[4] Several studies have shown that CBR1 plays a protective role in oxidative stress, neurodegeneration, and apoptosis.^[5] In addition, CBR1 inactivates lipid aldehydes during oxidative stress in cells. Therefore, CBR1 may play a beneficial role in protecting against cellular damage resulting from oxidative stress.^[6]

Polymorphisms

Up-to-date two non-synonymous polymorphisms on CBR1 have been identified. The CBR1 V88I polymorphism encodes for a valine-to-isoleucine 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.^[7] Recent studies in human liver cytosols show that an untranslated polymorphism on the 3'UTR region of the CBR1 gene (rs9024)^[8] is associated with higher levels of the cardiotoxic metabolite doxorubicinol.^[9]

Structure

Gene

Human CBR1 gene includes 8 exons.^[1]

Protein

The enzyme consists of 277 amino acid residues and is widely distributed in human tissues such as liver, epidermis, stomach, small intestine, kidney, neuronal cells, and smooth muscle fibers.^[10] The best substrates of CBR1 are quinones, including ubiquinone-1 and tocopherolquinone (vitamin E). Ubiquinones (coenzyme Q) are constitutive parts of the respiratory chain, and tocopherolquinone protects lipids of biological membranes against lipid peroxidation, indicating that CBR1 may play an important role as an oxidation–reduction catalyst in biological processes.^[11]

Clinical significance

CBR1 has been reported to relate to tumor progression.^[12] Suppression of CBR1 expression was associated with poor prognosis in uterine endometrial cancer and uterine cervical squamous cell carcinoma.^[12] Previous studies showed that decreased CBR1 expression is associated with lymph node metastasis and poor prognosis in ovarian cancer, and induction of CBR1 expression in ovarian tumors leads to a spontaneous decrease in tumor size.^[13]

Recent study demonstrates that CBR1 attenuates apoptosis and promotes cell survival in pancreatic β cell lines under glucotoxic and glucolipotoxic conditions via reducing ROS generation. Their data demonstrates that CBR1 expression level and enzyme activity are decreased in pancreatic islets isolated from db/db mice, an animal model of type 2 diabetes. These results suggest that CBR1 may play a role in protecting pancreatic β-cells against oxidative stress under glucotoxic or glucolipotoxic conditions, and its reduced expression or activity may contribute to β-cell dysfunction in db/db mice or human type 2 diabetes.^[10]

In addition, CBR1 may play a critical role in prostaglandin F_2α (PGF_2α) synthesis in human amnion fibroblasts, and cortisol promotes the conversion of PGE2 into PGF_2α via glucocorticoid receptor (GR)-mediated induction of CBR1 in human amnion fibroblasts. This stimulatory effect of cortisol on CBR1 expression may partly explain the concurrent increases of cortisol and PGF_2α in human amnion tissue with labor, and these findings may account for the increased production of PGF_2α in the fetal membranes prior to the onset of labor.^[14]

Interactions

CBR1 has been shown to interact with Cortisol,^[14] C2 domain,^[15] and Flavonoid.^[16]

Further reading

• Wirth H, Wermuth B . Immunohistochemical localization of carbonyl reductase in human tissues . The Journal of Histochemistry and Cytochemistry . 40 . 12 . 1857–63 . Dec 1992 . 1453004 . 10.1177/40.12.1453004 . free .
• Inazu N, Ruepp B, Wirth H, Wermuth B . 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 . Mar 1992 . 1540623 . 10.1016/0304-4165(92)90127-g .
• Forrest GL, Akman S, Doroshow J, Rivera H, Kaplan WD . Genomic sequence and expression of a cloned human carbonyl reductase gene with daunorubicin reductase activity . Molecular Pharmacology . 40 . 4 . 502–7 . Oct 1991 . 1921984 .
• Forrest GL, Akman S, Krutzik S, Paxton RJ, Sparkes RS, Doroshow J, Felsted RL, Glover CJ, Mohandas T, Bachur NR . 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 . Apr 1990 . 2182121 . 10.1016/0167-4781(90)90050-c .
• Wermuth B, Platts KL, Seidel A, Oesch F . Carbonyl reductase provides the enzymatic basis of quinone detoxication in man . Biochemical Pharmacology . 35 . 8 . 1277–82 . Apr 1986 . 3083821 . 10.1016/0006-2952(86)90271-6 .
• Wermuth B, Bohren KM, Heinemann G, von Wartburg JP, Gabbay KH . 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 . Nov 1988 . 10.1016/S0021-9258(18)37576-8 . 3141401 . free .
• Bohren KM, von Wartburg JP, Wermuth B . Kinetics of carbonyl reductase from human brain . The Biochemical Journal . 244 . 1 . 165–71 . May 1987 . 3311025 . 1147968 . 10.1042/bj2440165.
• Wermuth B . 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 . Feb 1981 . 10.1016/S0021-9258(19)69950-3 . 7005231 . free .
• Wermuth B, Mäder-Heinemann G, Ernst E . Cloning and expression of carbonyl reductase from rat testis . European Journal of Biochemistry . 228 . 2 . 473–9 . Mar 1995 . 7705364 . 10.1111/j.1432-1033.1995.tb20286.x .
• Krook M, Ghosh D, Strömberg R, Carlquist M, Jörnvall H . 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 . Jan 1993 . 8421682 . 45691 . 10.1073/pnas.90.2.502 . 1993PNAS...90..502K . free .
• Lemieux N, Malfoy B, Forrest GL . 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 . Jan 1993 . 8432528 . 10.1006/geno.1993.1024 .
• Watanabe K, Sugawara C, Ono A, Fukuzumi Y, Itakura S, Yamazaki M, Tashiro H, Osoegawa K, Soeda E, Nomura T . Mapping of a novel human carbonyl reductase, CBR3, and ribosomal pseudogenes to human chromosome 21q22.2 . Genomics . 52 . 1 . 95–100 . Aug 1998 . 9740676 . 10.1006/geno.1998.5380 .
• Tinguely JN, Wermuth B . Identification of the reactive cysteine residue (Cys227) in human carbonyl reductase . European Journal of Biochemistry . 260 . 1 . 9–14 . Feb 1999 . 10091578 . 10.1046/j.1432-1327.1999.00089.x .
• Finckh C, Atalla A, Nagel G, Stinner B, Maser E . 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 . Jan 2001 . 11306092 . 10.1016/S0009-2797(00)00306-9 . 2001CBI...130..761F .
• Book: Balcz B, Kirchner L, Cairns N, Fountoulakis M, Lubec G . Increased brain protein levels of carbonyl reductase and alcohol dehydrogenase in Down Syndrome and Alzheimer's disease . Protein Expression in Down Syndrome Brain . Journal of Neural Transmission. Supplementum . 61 . 193–201 . 2002 . 11771743 . 10.1007/978-3-7091-6262-0_15 . 978-3-211-83704-7 .
• Skálová L, Nobilis M, Szotáková B, Kondrová E, Savlík M, Wsól V, Pichard-Garcia L, Maser E . Carbonyl reduction of the potential cytostatic drugs benfluron and 3,9-dimethoxybenfluron in human in vitro . Biochemical Pharmacology . 64 . 2 . 297–305 . Jul 2002 . 12123751 . 10.1016/S0006-2952(02)01068-7 .
• Cheon MS, Shim KS, Kim SH, Hara A, Lubec G . 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 . Jul 2003 . 12836057 . 10.1007/s00726-003-0009-9 . 52799223 .

Notes and References

1. Web site: Entrez Gene: CBR1 carbonyl reductase 1.
2. Lemieux N, Malfoy B, Forrest GL . 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 . Jan 1993 . 8432528 . 10.1006/geno.1993.1024 .
3. 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 . The SDR (short-chain dehydrogenase/reductase and related enzymes) nomenclature initiative . Chemico-Biological Interactions . 178 . 1–3 . 94–8 . Mar 2009 . 19027726 . 2896744 . 10.1016/j.cbi.2008.10.040 . 2009CBI...178...94P .
4. Wermuth B, Platts KL, Seidel A, Oesch F . Carbonyl reductase provides the enzymatic basis of quinone detoxication in man . Biochemical Pharmacology . 35 . 8 . 1277–82 . Apr 1986 . 3083821 . 10.1016/0006-2952(86)90271-6 .
5. Ismail E, Al-Mulla F, Tsuchida S, Suto K, Motley P, Harrison PR, Birnie GD . Carbonyl reductase: a novel metastasis-modulating function . Cancer Research . 60 . 5 . 1173–6 . Mar 2000 . 10728668 .
6. Maser E . Neuroprotective role for carbonyl reductase? . Biochemical and Biophysical Research Communications . 340 . 4 . 1019–22 . Feb 2006 . 16406002 . 10.1016/j.bbrc.2005.12.113 .
7. Gonzalez-Covarrubias V, Ghosh D, Lakhman SS, Pendyala L, Blanco JG . 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 . Jun 2007 . 17344335 . 2442771 . 10.1124/dmd.107.014779 .
8. Web site: Reference SNP Cluster Report: rs9024 . Entrez SNP . National Center for Biotechnology Information/National Institutes of Health.
9. Gonzalez-Covarrubias V, Zhang J, Kalabus JL, Relling MV, Blanco JG . Pharmacogenetics of human carbonyl reductase 1 (CBR1) in livers from black and white donors . Drug Metabolism and Disposition . 37 . 2 . 400–7 . Feb 2009 . 19022938 . 2680526 . 10.1124/dmd.108.024547 .
10. Rashid MA, Lee S, Tak E, Lee J, Choi TG, Lee JW, Kim JB, Youn JH, Kang I, Ha J, Kim SS . Carbonyl reductase 1 protects pancreatic β-cells against oxidative stress-induced apoptosis in glucotoxicity and glucolipotoxicity . Free Radical Biology & Medicine . 49 . 10 . 1522–33 . Nov 2010 . 20728534 . 10.1016/j.freeradbiomed.2010.08.015 .
11. Wermuth B . 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 . Feb 1981 . 10.1016/S0021-9258(19)69950-3 . 7005231 . free .
12. Murakami. A. Yakabe. K. Yoshidomi. K. Sueoka. K. Nawata. S. Yokoyama. Y. Tsuchida. S. Al-Mulla. F. Sugino. N. Decreased carbonyl reductase 1 expression promotes malignant behaviours by induction of epithelial mesenchymal transition and its clinical significance.. Cancer Letters. 1 October 2012. 323. 1. 69–76. 22542806. 10.1016/j.canlet.2012.03.035.
13. Osawa. Y. Yokoyama. Y. Shigeto. T. Futagami. M. Mizunuma. H. Decreased expression of carbonyl reductase 1 promotes ovarian cancer growth and proliferation.. International Journal of Oncology. March 2015. 46. 3. 1252–8. 25572536. 10.3892/ijo.2014.2810. free. 10129/5591. free.
14. Guo. C. Wang. W. Liu. C. Myatt. L. Sun. K. Induction of PGF2α synthesis by cortisol through GR dependent induction of CBR1 in human amnion fibroblasts.. Endocrinology. August 2014. 155. 8. 3017–24. 24654784. 10.1210/en.2013-1848. 4098009.
15. Yagi. H. Conroy. PJ. Leung. EW. Law. RH. Trapani. JA. Voskoboinik. I. Whisstock. JC. Norton. RS. Structural Basis for Ca2+-mediated Interaction of the Perforin C2 Domain with Lipid Membranes.. The Journal of Biological Chemistry. 16 October 2015. 290. 42. 25213–26. 26306037. 10.1074/jbc.m115.668384. 4646173. free.
16. Nelson. SH. Grunebaum. H. A follow-up study of wrist slashers.. The American Journal of Psychiatry. April 1971. 127. 10. 1345–9. 5549925. 10.1176/ajp.127.10.1345.