CBR1

Last updated
CBR1
Protein CBR1 PDB 1wma.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases CBR1 , CBR, SDR21C1, hcarbonyl reductase 1, PG-9-KR
External IDs OMIM: 114830; MGI: 88284; HomoloGene: 37524; GeneCards: CBR1; OMA:CBR1 - orthologs
EC number 1.1.1.197
Orthologs
SpeciesHumanMouse
Entrez

873

12408

Ensembl

ENSG00000159228

ENSMUSG00000051483

UniProt

P16152

P48758

RefSeq (mRNA)

NM_001757
NM_001286789

NM_007620

RefSeq (protein)

NP_001273718
NP_001748

NP_031646

Location (UCSC) Chr 21: 36.07 – 36.07 Mb Chr 16: 93.4 – 93.41 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Carbonyl reductase 1, also known as CBR1, is an enzyme which in humans is encoded by the CBR1 gene. [5] [6] [7] 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. [5]

Contents

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. [5] CBR1 metabolizes many toxic environmental quinones and pharmacological relevant substrates such as the anticancer doxorubicin. [8] Several studies have shown that CBR1 plays a protective role in oxidative stress, neurodegeneration, and apoptosis. [9] 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. [10]

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. [11] Recent studies in human liver cytosols show that an untranslated polymorphism on the 3'UTR region of the CBR1 gene (rs9024) [12] is associated with higher levels of the cardiotoxic metabolite doxorubicinol. [13]

Structure

Gene

Human CBR1 gene includes 8 exons. [5]

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. [14] 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. [15]

Clinical significance

CBR1 has been reported to relate to tumor progression. [16] Suppression of CBR1 expression was associated with poor prognosis in uterine endometrial cancer and uterine cervical squamous cell carcinoma. [16] 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. [17]

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. [14]

In addition, CBR1 may play a critical role in prostaglandin F2α (PGF2α) synthesis in human amnion fibroblasts, and cortisol promotes the conversion of PGE2 into PGF2α 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 PGF2α in human amnion tissue with labor, and these findings may account for the increased production of PGF2α in the fetal membranes prior to the onset of labor. [18]

Interactions

CBR1 has been shown to interact with Cortisol, [18] C2 domain, [19] and Flavonoid. [20]

Related Research Articles

5α-Reductase Enzyme family

5α-Reductases, also known as 3-oxo-5α-steroid 4-dehydrogenases, are enzymes involved in steroid metabolism. They participate in three metabolic pathways: bile acid biosynthesis, androgen and estrogen metabolism. There are three isozymes of 5α-reductase encoded by the genes SRD5A1, SRD5A2, and SRD5A3.

<span class="mw-page-title-main">Flavin adenine dinucleotide</span> Redox-active coenzyme

In biochemistry, flavin adenine dinucleotide (FAD) is a redox-active coenzyme associated with various proteins, which is involved with several enzymatic reactions in metabolism. A flavoprotein is a protein that contains a flavin group, which may be in the form of FAD or flavin mononucleotide (FMN). Many flavoproteins are known: components of the succinate dehydrogenase complex, α-ketoglutarate dehydrogenase, and a component of the pyruvate dehydrogenase complex.

<span class="mw-page-title-main">Glutathione reductase</span> Enzyme

Glutathione reductase (GR) also known as glutathione-disulfide reductase (GSR) is an enzyme that in humans is encoded by the GSR gene. Glutathione reductase catalyzes the reduction of glutathione disulfide (GSSG) to the sulfhydryl form glutathione (GSH), which is a critical molecule in resisting oxidative stress and maintaining the reducing environment of the cell. Glutathione reductase functions as dimeric disulfide oxidoreductase and utilizes an FAD prosthetic group and NADPH to reduce one molar equivalent of GSSG to two molar equivalents of GSH:

<span class="mw-page-title-main">Glyceraldehyde 3-phosphate dehydrogenase</span> Enzyme of the glycolysis metabolic pathway

Glyceraldehyde 3-phosphate dehydrogenase is an enzyme of about 37kDa that catalyzes the sixth step of glycolysis and thus serves to break down glucose for energy and carbon molecules. In addition to this long established metabolic function, GAPDH has recently been implicated in several non-metabolic processes, including transcription activation, initiation of apoptosis, ER-to-Golgi vesicle shuttling, and fast axonal, or axoplasmic transport. In sperm, a testis-specific isoenzyme GAPDHS is expressed.

<span class="mw-page-title-main">11β-Hydroxysteroid dehydrogenase type 1</span> Mammalian protein found in Homo sapiens

11β-Hydroxysteroid dehydrogenase type 1, also known as cortisone reductase, is an NADPH-dependent enzyme highly expressed in key metabolic tissues including liver, adipose tissue, and the central nervous system. In these tissues, HSD11B1 reduces cortisone to the active hormone cortisol that activates glucocorticoid receptors. It belongs to the family of short-chain dehydrogenases. It is encoded by the HSD11B1 gene.

<span class="mw-page-title-main">Cholesterol side-chain cleavage enzyme</span> Mammalian protein found in Homo sapiens

Cholesterol side-chain cleavage enzyme is commonly referred to as P450scc, where "scc" is an acronym for side-chain cleavage. P450scc is a mitochondrial enzyme that catalyzes conversion of cholesterol to pregnenolone. This is the first reaction in the process of steroidogenesis in all mammalian tissues that specialize in the production of various steroid hormones.

<span class="mw-page-title-main">Aldose reductase</span> Enzyme

In enzymology, aldose reductase is a cytosolic NADPH-dependent oxidoreductase that catalyzes the reduction of a variety of aldehydes and carbonyls, including monosaccharides. It is primarily known for catalyzing the reduction of glucose to sorbitol, the first step in polyol pathway of glucose metabolism.

<span class="mw-page-title-main">Carbonyl reductase (NADPH)</span> Class of enzymes

In enzymology, a carbonyl reductase (NADPH) (EC 1.1.1.184) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">NAD(P)H dehydrogenase (quinone 1)</span> Protein-coding gene in the species Homo sapiens

NAD(P)H dehydrogenase [quinone] 1 is an enzyme that in humans is encoded by the NQO1 gene. This protein-coding gene is a member of the NAD(P)H dehydrogenase (quinone) family and encodes a 2-electron reductase (enzyme). This FAD-binding protein forms homodimers and performs two-electron reduction of quinones to hydroquinones and of other redox dyes. It has a preference for short-chain acceptor quinones, such as ubiquinone, benzoquinone, juglone and duroquinone. This gene has an important paralog NQO2. This protein is located in the cytosol.

<span class="mw-page-title-main">AKR1B1</span> Protein-coding gene in the species Homo sapiens

Aldo-keto reductase family 1, member B1 (AKR1B1), also known as aldose reductase, is an enzyme that is encoded by the AKR1B1 gene in humans. It is a reduced nicotinamide-adenine dinucleotide phosphate (NADPH)-dependent enzyme catalyzing the reduction of various aldehydes and ketones to the corresponding alcohol. The involvement of AKR1B1 in oxidative stress diseases, cell signal transduction, and cell proliferation process endows AKR1B1 with potential as a therapeutic target.

<span class="mw-page-title-main">AKR1C3</span> Protein-coding gene in the species Homo sapiens

Aldo-keto reductase family 1 member C3 (AKR1C3), also known as 17β-hydroxysteroid dehydrogenase type 5 or 3α-hydroxysteroid dehydrogenase type 2 (3α-HSD2) is a steroidogenic enzyme that in humans is encoded by the AKR1C3 gene.

<span class="mw-page-title-main">AKR1C1</span> Protein-coding gene in the species Homo sapiens

Aldo-keto reductase family 1 member C1 also known as 20α-hydroxysteroid dehydrogenase, 3α-hydroxysteroid dehydrogenase, and dihydrodiol dehydrogenase 1/2 is an enzyme that in humans is encoded by the AKR1C1 gene.

<span class="mw-page-title-main">HPGD</span> Protein-coding gene in humans

Hydroxyprostaglandin dehydrogenase 15-(NAD), also called 15-hydroxyprostaglandin dehydrogenase [NAD+], is an enzyme that in humans is encoded by the HPGD gene.

<span class="mw-page-title-main">Aldo-keto reductase family 1, member A1</span> Mammalian protein found in Homo sapiens

Alcohol dehydrogenase [NADP+] also known as aldehyde reductase or aldo-keto reductase family 1 member A1 is an enzyme that in humans is encoded by the AKR1A1 gene. AKR1A1 belongs to the aldo-keto reductase (AKR) superfamily. It catalyzes the NADPH-dependent reduction of a variety of aromatic and aliphatic aldehydes to their corresponding alcohols and catalyzes the reduction of mevaldate to mevalonic acid and of glyceraldehyde to glycerol. Mutations in the AKR1A1 gene has been found associated with non-Hodgkin's lymphoma.

<span class="mw-page-title-main">CRYZ</span> Protein-coding gene in the species Homo sapiens

Quinone oxidoreductase is an enzyme that in humans is encoded by the CRYZ gene.

<span class="mw-page-title-main">CBR3</span> Protein-coding gene in the species Homo sapiens

Carbonyl reductase [NADPH] 3 is an enzyme that in humans is encoded by the CBR3 gene.

<span class="mw-page-title-main">RDH13</span> Protein-coding gene in humans

Retinol dehydrogenase 13 (all-trans/9-cis) is a protein that in humans is encoded by the RDH13 gene. This gene encodes a mitochondrial short-chain dehydrogenase/reductase, which catalyzes the reduction and oxidation of retinoids. The encoded enzyme may function in retinoic acid production and may also protect the mitochondria against oxidative stress. Alternatively spliced transcript variants have been described.

<span class="mw-page-title-main">AKR1C2</span> Protein-coding gene in the species Homo sapiens

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In enzymology, a prostaglandin-F synthase (PGFS; EC 1.1.1.188) is an enzyme that catalyzes the chemical reaction:

3α-Hydroxysteroid dehydrogenase (3α-HSD) is an enzyme (1.1.1.50) that plays a role in the metabolism of steroids and non-steroidal compounds in humans and other species, such as bacteria, fungi, plants, and so on. This enzyme catalyzes the chemical reaction of conversion of 3-ketosteroids into 3α-hydroxysteroids. The enzyme has various protein isoforms (isozymes).

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000159228 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000051483 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 3 4 "Entrez Gene: CBR1 carbonyl reductase 1".
  6. ↑ 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.
  7. ↑ 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. Bibcode:2009CBI...178...94P. doi:10.1016/j.cbi.2008.10.040. PMC   2896744 . PMID   19027726.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ "Reference SNP Cluster Report: rs9024". Entrez SNP. National Center for Biotechnology Information/National Institutes of Health.
  13. ↑ 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.
  14. 1 2 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. (Erratum:  doi:10.1016/j.freeradbiomed.2018.07.011, PMID   30076001,  Retraction Watch)
  15. ↑ 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.
  16. 1 2 Murakami A, Yakabe K, Yoshidomi K, Sueoka K, Nawata S, Yokoyama Y, Tsuchida S, Al-Mulla F, Sugino N (1 October 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.
  17. ↑ Osawa Y, Yokoyama Y, Shigeto T, Futagami M, Mizunuma H (March 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 . hdl: 10129/5591 . PMID   25572536.
  18. 1 2 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.
  19. ↑ Yagi H, Conroy PJ, Leung EW, Law RH, Trapani JA, Voskoboinik I, Whisstock JC, Norton RS (16 October 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.
  20. ↑ 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.

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