Niu Xiaodi, Zhang Ziji, Song Yangyang, Wang Hongsu
College of Food Science and Engineering, Jilin University, Changchun 130062, P.R. China.
J Agric Food Chem. 2025 Jul 9;73(27):16822-16832. doi: 10.1021/acs.jafc.5c05257. Epub 2025 Jun 27.
Most CYP51 inhibitors act competitively and are prone to resistance, whereas allosteric inhibitors hold promise but are difficult to develop. In this study, we employed the neural relational inference framework alongside the Gaussian network-based deep learning model CorrSite2.0 to proactively identify allosteric sites on CYP51. We confirmed celestolide as a natural allosteric inhibitor, targeting CYP51. Celestolide forms strong interactions with CYP51 at the identified allosteric site, inducing conformational changes in CYP51 that suppress its enzymatic activity. These findings were consistent with in vitro CYP51 inhibition assays, where celestolide exhibited an IC value of 133.28 μg/mL. Moreover, celestolide demonstrated potent antifungal activity against , increasing cell membrane permeability, causing membrane disruption, and ultimately leading to fungal cell death. In a gray mold infection model, celestolide effectively prevented fungal invasion of strawberries and significantly extended their shelf life by more than 1 week. These results highlight celestolide's potential as a natural preservative for postharvest fruit storage.
大多数细胞色素P450 51（CYP51）抑制剂具有竞争性作用且易于产生耐药性，而异构调节剂虽有前景但难以开发。在本研究中，我们采用神经关系推理框架以及基于高斯网络的深度学习模型CorrSite2.0来主动识别CYP51上的变构位点。我们证实了celestolide是一种靶向CYP51的天然变构抑制剂。Celestolide在已识别的变构位点与CYP51形成强烈相互作用，诱导CYP51的构象变化，从而抑制其酶活性。这些发现与体外CYP51抑制试验结果一致，在该试验中celestolide的半数抑制浓度（IC）值为133.28μg/mL。此外，celestolide对[具体真菌名称未给出]表现出强大的抗真菌活性，增加细胞膜通透性，导致膜破坏，最终导致真菌细胞死亡。在灰霉病感染模型中，celestolide有效防止了草莓受到真菌侵袭，并显著延长其货架期超过1周。这些结果凸显了celestolide作为采后果实储存天然防腐剂的潜力。
