Xyloketal B, a marine compound, acts on a network of molecular proteins and regulates the activity and expression of rat cytochrome P450 3a: a bioinformatic and animal study

Su, Junhui; Chang, Cui; Xiang, Qi; Zhou, Zhi-Wei; Luo, Rong; Yang, Lun; He, Zhi-Xu; Yang, Hongtu; Li, Jianan; Bei, Yu; Xu, Jinmei; Zhang, Minjing; Zhang, Qihao; Su, Zhijian; Huang, Yadong; Pang, Jiyan; Zhou, Shu-Feng

In order to characterize the role of XKB in the regulation of CYPs, we next performed a homology modeling experiment to examine the interactions between XKB and rat Cyp3a2. The rat Cyp3a2 homology model was built based on human CYP3A4 (PDB ID 4K9W). Our data show that the rat Cyp3a2 homology model shared 83.3% sequence similarity and 68.4% identity with human CYP3A4. It has been reported that rat Cyp3a2 exhibits a 73% homology amino acid sequence to human CYP3A4. 48 This difference may affect the interaction between XKB and rat Cyp3a2. Indeed, our findings show that XKB interacted with the rat Cyp3a2 homology model via hydrogen bond formation at Ala482 located in the active site of the enzyme. However, there was no interaction between XKB and human CYP3A4 Ala482 located in the active site, but Gly481. Collectively, our modeling study shows that XKB can act as a substrate and/or inhibitor for both rat Cyp3a2 and human CYP3A4. However, when we extrapolate these results to humans, we should bear in mind that Cyp3a2 and CYP3A4 share a certain degree of sequence similarity identity, so functional validation is always needed.