15-Hydroxyprostaglandin Dehydrogenase: A Key Metabolic Enzyme for Prostaglandins, 12-Hydroxyheptadecatrienoic Acid, and Resolvins.

The 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is a key prostaglandin catabolic enzyme. It is well known that 15-PGDH catalyzes the oxidation of prostaglandin E2 (PGE2) to form 15-oxo-PGE2 that is biologically inactive. The catalytic sites of 15-PGDH have been revealed using site-directed mutagenesis, homology modeling, molecular docking, and molecular dynamics simulation. 15-PGDH also catalyzes the oxidation of 12S-hydroxyheptadecatrienoic acid (12-HHT) to generate the 12-keto-heptadecatrienoic acid (12-KHT). Substrate specificity studies were carried out using a steady-state kinetic approach with highly purified 15-PGDH, and 12-HHT gave the highest affinity and efficiency among all 15-PGDH substrates including PGE2 and PGF2α. 12-HHT was shown to be a potent ligand for leukotriene B4 receptor 2 (BLT2), and the 12-HHT-BLT2 axis is likely to play an important role in wound healing and tissue regeneration. Unlike 15-oxo-PGE2, 12-KHT remains bioactive with an affinity to BLT2 comparable to that of 12-HHT. In addition to prostaglandins and 12-HHT, the pro-resolving mediators, including lipoxins and resolvins, are also sensitive to rapid inactivation via dehydrogenation by 15-PGDH. Screening of a list of natural products, anti-inflammatories and cardiovascular drugs, several 15-PGDH inhibitors have been identified, which have high potency in promoting wound healing and regeneration, likely via the preservation of the anti-inflammatory and pro-resolving substrates of 15-PGDH, including 12-HHT, lipoxins, and resolvins. The detailed studies on 15-PGDH substrate specificity provide molecular basis for designing longer-acting stable analogs of the substrates or high-affinity inhibitors that block 15-PGDH enzymatic activity. These stable analogs and inhibitors could have therapeutic potential in limiting inflammatory and neurodegenerative diseases, as well as stimulating wound healing and regeneration, leading to healthy aging.