期刊
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
卷 173, 期 -, 页码 42-56出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jsbmb.2016.09.024
关键词
Hydroxyvitamin D; CYP11A1; ROR alpha; ROR gamma; VDR; 1,25D3-MARRS
资金
- NIH [R21AR066505, 1R01AR056666, 2R01AR052190, 1R21AR063242, 1S100D010678, RR-026377]
- University of Western Australia
- NIEHS, NIH [Z01-ES-101586]
The classical pathway of vitamin D activation follows the sequence D3 -> 25(OH)D3 -> 1,25(OH)(2)D3 with the final product acting on the receptor for vitamin D (VDR). An alternative pathway can be started by the action of CYP11A1 on the side chain of D3, primarily producing 20(OH)D3, 22(OH)D3, 20,23(OH)(2)D3, 20,22(OH)(2)D3 and 17,20,23(OH)(3)D3. Some of these metabolites are hydroxylated by CYP27B1 at C1 alpha, by CYP24A1 at C24 and C25, and by CYP27A1 at C25 and C26. The products of these pathways are biologically active. In the epidermis and/or serum or adrenals we detected 20(OH)D3, 22(OH)D3, 20,22(OH)(2)D3, 20,23(OH)(2)D3, 17,20,23(OH)(3)D3, 1,20(OH)(2)D3, 1,20,23(OH)(3)D3, 1,20,22(OH)(3)D3, 20,24(OH)(2)D3, 1,20,24 (OH)(3)D3, 20,25(OH)(2)D3, 1,20,25(OH)(3)D3, 20,26(OH)(2)D3 and 1,20,26(OH)(3)D3. 20(OH)D3 and 20,23 (OH)(2)D3 are non-calcemic, while the addition of an OH at Cl a confers some calcemic activity. Molecular modeling and functional assays show that the major products of the pathway can act as biased agonists for the VDR with high docking scores to the ligand binding domain (LBD), but lower than that of 1,25 (OH)(2)D3. Importantly, cell based functional receptor studies and molecular modeling have identified the novel secosteroids as inverse agonists of both ROR alpha and ROR gamma receptors. Specifically, they have high docking scores using crystal structures of ROR alpha and ROR gamma LBDs. Furthermore, 20(OH)D3 and 20,23 (OH)(2)D3 have been tested in a cell model that expresses a Tet-on ROR alpha or ROR gamma vector and a RORE-LUC reporter (ROR-responsive element), and in a mammalian 2-hybrid model that test interactions between an LBD-interacting LXXLL-peptide and the LBD of ROR alpha/gamma. These assays demonstrated that the novel secosteroids have ROR-antagonist activities that were further confirmed by the inhibition of IL17 promoter activity in cells overexpressing ROR alpha/gamma. In conclusion, endogenously produced novel D3 hydroxy-derivatives can act both as biased agonists of the VDR and/or inverse agonists of ROR alpha/gamma. We suggest that the identification of large number of endogenously produced alternative hydroxymetabolites of D3 that are biologically active, and of possible alternative receptors, may offer an explanation for the pleiotropic and diverse activities of vitamin D, previously assigned solely to 1,25 (OH)(2)D3 and VDR. Published by Elsevier Ltd.
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