Department of Biotechnology and Life Science, Faculty of Engineering, Tokyo University of Agriculture and Technology, 2-24-16 Naka-cho, Koganei 184-8588, Japan.
Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Imizu 939-0398, Japan.
Biomolecules. 2023 Jun 24;13(7):1036. doi: 10.3390/biom13071036.
Vitamin D () is metabolized by various cytochrome P450 (CYP) enzymes, resulting in the formation of diverse metabolites. Among them, 4α,25-dihydroxyvitamin D () and 4β,25-dihydroxyvitamin D () are both produced from 25-hydroxyvitamin D () by CYP3A4. However, is detectable in serum, whereas is not. We hypothesized that the reason for this is a difference in the susceptibility of and to CYP24A1-mediated metabolism. Here, we synthesized and , and confirmed that has greater metabolic stability than . We also identified 4α,24,25- and 4β,24,25-trihydroxyvitamin D ( and ) as metabolites of and , respectively, by HPLC comparison with synthesized authentic samples. Docking studies suggest that the β-hydroxy group at C4 contributes to the greater metabolic stability of by blocking a crucial hydrogen-bonding interaction between the C25 hydroxy group and Leu325 of CYP24A1.
维生素 D () 可被多种细胞色素 P450 (CYP) 酶代谢，形成多种代谢物。其中，4α,25-二羟维生素 D () 和 4β,25-二羟维生素 D () 均可由 25-羟维生素 D () 通过 CYP3A4 生成。然而，血清中可检测到 ，而不能检测到 。我们假设原因在于 CYP24A1 介导的代谢对 和 的敏感性不同。在此，我们合成了 和 ，并证实 比 具有更高的代谢稳定性。我们还通过与合成的标准样品进行 HPLC 比较，分别鉴定了 4α,24,25-和 4β,24,25-三羟维生素 D ( 和 ) 为 和 的代谢物。对接研究表明，C4 位的 β-羟基基团通过阻断 CYP24A1 中 C25 羟基和 Leu325 之间的关键氢键相互作用，有助于 具有更高的代谢稳定性。
