Cytochrome P450 (CYP) epoxygenases are a special subset of heme-containing CYP enzymes capable of performing the epoxidation of polyunsaturated fatty acids (PUFA) and the metabolism of xenobiotics. This dual functionality positions epoxygenases along a metabolic crossroad. Therefore, structure-function studies are critical for understanding their role in bioactive oxy-lipid synthesis, drug-PUFA interactions, and for designing therapeutics that directly target the epoxygenases. To better exploit CYP epoxygenases as therapeutic targets, there is a need for improved understanding of epoxygenase structure-function. Of the characterized epoxygenases, human CYP2J2 stands out as a potential target because of its role in cardiovascular physiology. In this review, the early research on the discovery and activity of epoxygenases is contextualized to more recent advances in CYP epoxygenase enzymology with respect to PUFA and drug metabolism. Additionally, this review employs CYP2J2 epoxygenase as a model system to highlight both the seminal works and recent advances in epoxygenase enzymology. Herein we cover CYP2J2’s interactions with PUFAs and xenobiotics, its tissue-specific physiological roles in diseased states, and its structural features that enable epoxygenase function. Additionally, the enumeration of research on CYP2J2 identifies the future needs for the molecular characterization of CYP2J2 to enable a new axis of therapeutic design.

细胞色素 P450 (CYP) 环氧化酶是含血红素 CYP 酶的特殊子集，能够进行多不饱和脂肪酸 (PUFA) 的环氧化和异生物质的代谢。这种双重功能将环氧化酶置于代谢十字路口。因此，结构功能研究对于了解它们在生物活性氧脂合成、药物-PUFA相互作用中的作用以及设计直接靶向环氧化酶的疗法至关重要。为了更好地利用 CYP 环氧化酶作为治疗靶点，需要加深对环氧化酶结构功能的了解。在已表征的环氧化酶中，人类 CYP2J2 由于其在心血管生理学中的作用而成为潜在靶点。在这篇综述中，关于环氧化酶的发现和活性的早期研究与 CYP 环氧化酶酶学在 PUFA 和药物代谢方面的最新进展相关。此外，本综述采用 CYP2J2 环氧化酶作为模型系统，以强调环氧化酶酶学的开创性工作和最新进展。在此，我们介绍了 CYP2J2 与 PUFA 和异生素的相互作用、其在疾病状态下的组织特异性生理作用以及其实现环氧化酶功能的结构特征。此外，对 CYP2J2 的研究列举确定了未来对 CYP2J2 分子表征的需求，以实现治疗设计的新轴。