| 1. |
- Elmabsout, Ali Ateia, et al.
(författare)
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Cloning and Functional Studies of a Splice Variant of CYP26B1 Expressed in Vascular Cells
- 2012
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Ingår i: Plos One. - San Francisco, USA : Public Library of Science (PLoS). - 1932-6203. ; 7:5
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Tidskriftsartikel (refereegranskat)abstract
- Background: All-trans retinoic acid (atRA) plays an essential role in the regulation of gene expression, cell growth and differentiation and is also important for normal cardiovascular development but may in turn be involved in cardiovascular diseases, i.e. atherosclerosis and restenosis. The cellular atRA levels are under strict control involving several cytochromes P450 isoforms (CYPs). CYP26 may be the most important regulator of atRA catabolism in vascular cells. The present study describes the molecular cloning, characterization and function of atRA-induced expression of a spliced variant of the CYP26B1 gene. Methodology/Principal Findings: The coding region of the spliced CYP26B1 lacking exon 2 was amplified from cDNA synthesized from atRA-treated human aortic smooth muscle cells and sequenced. Both the spliced variant and full length CYP26B1 was found to be expressed in cultured human endothelial and smooth muscle cells, and in normal and atherosclerotic vessel. atRA induced both variants of CYP26B1 in cultured vascular cells. Furthermore, the levels of spliced mRNA transcript were 4.5 times higher in the atherosclerotic lesion compared to normal arteries and the expression in the lesions was increased 20-fold upon atRA treatment. The spliced CYP26B1 still has the capability to degrade atRA, but at an initial rate one-third that of the corresponding full length enzyme. Transfection of COS-1 and THP-1 cells with the CYP26B1 spliced variant indicated either an increase or a decrease in the catabolism of atRA, probably depending on the expression of other atRA catabolizing enzymes in the cells. Conclusions/Significance: Vascular cells express the spliced variant of CYP26B1 lacking exon 2 and it is also increased in atherosclerotic lesions. The spliced variant displays a slower and reduced degradation of atRA as compared to the full-length enzyme. Further studies are needed, however, to clarify the substrate specificity and role of the CYP26B1 splice variant in health and disease.
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| 2. |
- Elmabsout, Ali, et al.
(författare)
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Cloning and functional studies of a splice variant of CYP26B1 : a cellular storage protein for all-trans retinoic acid
- 2010
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Ingår i: In Vivo. - 0258-851X .- 1791-7549. ; 24:3, s. 345-346
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundAll-trans retinoic acid (atRA) plays an essential role in the regulation of gene expression, cell growth and differentiation and is also important for normal cardiovascular development but may in turn be involved in cardiovascular diseases, i.e. atherosclerosis and restenosis. The cellular atRA levels are under strict control involving several cytochromes P450 isoforms (CYPs). CYP26 may be the most important regulator of atRA catabolism in vascular cells. The present study describes the molecular cloning, characterization and function of atRA-induced expression of a spliced variant of the CYP26B1 gene.Methodology/Principal FindingsThe coding region of the spliced CYP26B1 lacking exon 2 was amplified from cDNA synthesized from atRA-treated human aortic smooth muscle cells and sequenced. Both the spliced variant and full length CYP26B1 was found to be expressed in cultured human endothelial and smooth muscle cells, and in normal and atherosclerotic vessel. atRA induced both variants of CYP26B1 in cultured vascular cells. Furthermore, the levels of spliced mRNA transcript were 4.5 times higher in the atherosclerotic lesion compared to normal arteries and the expression in the lesions was increased 20-fold upon atRA treatment. The spliced CYP26B1 still has the capability to degrade atRA, but at an initial rate one-third that of the corresponding full length enzyme. Transfection of COS-1 and THP-1 cells with the CYP26B1 spliced variant indicated either an increase or a decrease in the catabolism of atRA, probably depending on the expression of other atRA catabolizing enzymes in the cells.Conclusions/SignificanceVascular cells express the spliced variant of CYP26B1 lacking exon 2 and it is also increased in atherosclerotic lesions. The spliced variant displays a slower and reduced degradation of atRA as compared to the full-length enzyme. Further studies are needed, however, to clarify the substrate specificity and role of the CYP26B1 splice variant in health and disease.
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| 3. |
- Eriksson, Leif A., 1964-, et al.
(författare)
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Tetrazole derivatives as cytochrome p450 inhibitors
- 2019
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Patent (populärvet., debatt m.m.)abstract
- According to the invention there is provided a compound of formula I, wherein R1 and R2 have meanings given in the description, which compounds are useful in the treatment of skin disorders and other diseases.
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| 4. |
- Karlsson, Magnus, et al.
(författare)
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Homology Models and Molecular Modeling of Human Retinoic Acid Metabolizing Enzymes Cytochrome P450 26A1 (CYP26A1) and P450 26B1 (CYP26B1)
- 2008
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Ingår i: Journal of Chemical Theory and Computation. - Columbus, Ohio : American Chemical Society. - 1549-9618 .- 1549-9626. ; 4:6, s. 1021-1027
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Tidskriftsartikel (refereegranskat)abstract
- Homology models of cytochrome P450 26A1 and cytochrome P450 26B1 were constructed using the crystal structures of human, CYP2C8, CYP2C9, and CYP3A4 as templates for the model building. The homology models generated were investigated for their docking capacities against the natural substrate all-trans-retinoic acid (atRA), five different tetralone-derived retinoic acid metabolizing blocking agents (RAMBAs), and R115866. Interaction energies (IE) and linear interaction energies (LIE) were calculated for all inhibitors in both homology models after molecular dynamics (MD) simulation of the enzyme-ligand complexes. The results revealed that the homologues had the capacity to distinguish between strong and weak inhibitors. Important residues in the active site were identified from the CYP26A1/B1-atRA complexes. Residues involved in hydrophobic interactions with atRA were Pro113, Phe222, Phe299, Val370, Pro371, and Phe374 in CYP26A1 and Leu88, Pro118, Phe222, Phe295, Ile368, and Tyr272 in CYP26B1. Hydrogen bonding interactions were observed between the atRA carboxylate group and Arg 90 in CYP26A1 and with Arg76, Arg95, and Ser369 in CYP26B1.
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| 5. |
- Saenz Mendez, Patricia, et al.
(författare)
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Homology models of human all-trans retinoic acid metabolizing enzymes CYP26B1 and CYP26B1 spliced-variant.
- 2012
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Ingår i: Journal of Chemical Information and Modeling. - Washington, USA : American Chemical Society (ACS). - 1549-9596 .- 1549-960X. ; 52:10, s. 2631-2637
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Tidskriftsartikel (refereegranskat)abstract
- Homology models of CYP26B1 (cytochrome P450RAI2) and CYP26B1 spliced variant were derived using the crystal structure of cyanobacterial CYP120A1 as template for the model building. The quality of the homology models generated were carefully evaluated, and the natural substrate all-trans-retinoic acid (atRA), several tetralone-derived retinoic acid metabolizing blocking agents (RAMBAs), and a well-known potent inhibitor of CYP26B1 (R115866) were docked into the homology model of full-length cytochrome P450 26B1. The results show that in the model of the full-length CYP26B1, the protein is capable of distinguishing between the natural substrate (atRA), R115866, and the tetralone derivatives. The spliced variant of CYP26B1 model displays a reduced affinity for atRA compared to the full-length enzyme, in accordance with recently described experimental information.
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