Tai H-H, Cho H, Tong M, Ding Y
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, 40536-0082, USA.
Curr Pharm Des. 2006;12(8):955-62. doi: 10.2174/138161206776055958.
NAD(+)-linked 15-hydroxyprostaglandin dehydrogenase (15-PGDH) catalyzes the oxidation of 15(S)-hydroxyl group of prostaglandins and lipoxins resulting in the formation of 15-keto metabolites which exhibit greatly reduced biological activities. Therefore, this enzyme has been considered the key enzyme responsible for the inactivation of prostaglandins and lipoxins. Both the cDNA and the genomic DNA of the 15-PGDH gene have been cloned. Structural characterization, transcriptional regulation and biological functions of this enzyme have been investigated. Molecular modeling corroborated with site-directed mutagenesis has identified key residues and domains involved in coenzyme and substrate binding. Catalytic mechanism has been proposed. Studies on the regulation of enzyme expression and activity by physiological and pharmacological agents have begun to uncover its significant roles in cancer, inflammation and reproduction. Apparently, 15-PGDH works with cyclooxygenase-2 to control the cellular levels of prostaglandins. Their reciprocal regulation within the same cells appears to determine the fate of the cells. Because of its ability to inactivate both prostaglandins and lipoxins of two opposite biological activities, the roles of 15-PGDH in cancer and inflammation are particularly intriguing and challenging. Future investigations in these areas are warranted.
烟酰胺腺嘌呤二核苷酸（NAD⁺）依赖性15-羟基前列腺素脱氢酶（15-PGDH）催化前列腺素和脂氧素15（S）-羟基的氧化，生成生物活性大大降低的15-酮代谢物。因此，该酶被认为是负责前列腺素和脂氧素失活的关键酶。15-PGDH基因的cDNA和基因组DNA均已被克隆。人们对该酶的结构特征、转录调控及生物学功能进行了研究。分子建模与定点诱变相结合，已确定了参与辅酶和底物结合的关键残基和结构域，并提出了催化机制。关于生理和药理试剂对该酶表达和活性的调控研究已开始揭示其在癌症、炎症和生殖中的重要作用。显然，15-PGDH与环氧化酶-2共同作用来控制细胞内前列腺素的水平。它们在同一细胞内的相互调控似乎决定了细胞的命运。由于15-PGDH能够使具有两种相反生物活性的前列腺素和脂氧素均失活，其在癌症和炎症中的作用尤其引人关注且具有挑战性。有必要对这些领域进行进一步研究。
