Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia.
Molecules. 2020 Dec 17;25(24):5980. doi: 10.3390/molecules25245980.
Serum paraoxonase-1 (PON1) is the most studied member of the group of paraoxonases (PONs). This enzyme possesses three enzymatic activities: lactonase, arylesterase, and paraoxonase activity. PON1 and its isoforms play an important role in drug metabolism as well as in the prevention of cardiovascular and neurodegenerative diseases. Although all three members of the PON family have the same origin and very similar amino acid sequences, they have different functions and are found in different locations. PONs exhibit substrate promiscuity, and their true physiological substrates are still not known. However, possible substrates include homocysteine thiolactone, an analogue of natural quorum-sensing molecules, and the recently discovered derivatives of arachidonic acid-bioactive δ-lactones. Directed evolution, site-directed mutagenesis, and kinetic studies provide comprehensive insights into the active site and catalytic mechanism of PON1. However, there is still a whole world of mystery waiting to be discovered, which would elucidate the substrate promiscuity of a group of enzymes that are so similar in their evolution and sequence yet so distinct in their function.
血清对氧磷酶 1（PON1）是对氧磷酶（PONs）家族中研究最多的成员。这种酶具有三种酶活性：内酯酶、芳基酯酶和对氧磷酶活性。PON1 及其同工酶在药物代谢以及预防心血管和神经退行性疾病中发挥重要作用。尽管 PON 家族的所有三个成员都有相同的起源和非常相似的氨基酸序列，但它们具有不同的功能，并且存在于不同的位置。PON 表现出底物的混杂性，其真正的生理底物仍不清楚。然而，可能的底物包括同型半胱氨酸硫内酯，一种天然群体感应分子的类似物，以及最近发现的花生四烯酸生物活性 δ-内酯衍生物。定向进化、定点突变和动力学研究为 PON1 的活性位点和催化机制提供了全面的见解。然而，仍有一个充满神秘的世界有待发现，这将阐明一组在进化和序列上如此相似但在功能上却截然不同的酶的底物混杂性。
