NAD+-linked 15-hydroxyprostaglandin dehydrogenase (15-PGDH) catalyzes the oxidation of 15(S)-hydroxyl group of prostaglandin E2 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 prostaglandin E2, 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.