NAD+-Linked 15-Hydroxyprostaglandin Dehydrogenase: Structure and Biological Functions

Abstract

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.

Talking to the Brain at the Blood-Brain Barrier through Inflammation-Induced Prostaglandin E2

“…Some examples are COX-2 (Cao et al, 1995;Engström et al, 2012; Inoue et al, 2002), mPGES-1 (Ek et al, 2001;, IL-1R1 Ek et al, 2001;Konsman et al, 2004;Matsuwaki et al, 2014), IkBα (Laflamme et al, 1999;Quan et al, 1997), and inducible lipocalin-2 (Hamzic et al, 2013a) in endothelial cells, and thromboxane-A synthases-1 (Tbxas1) in perivascular macrophages (Cyrus et al, 2010;Gabrielsen et al, 2010). Furthermore, functional coupling of increased production (COX-2, mPGES-1) and decreased degradation (15-PGDH) as revealed here was also previously reported to occur for PGE2 (Hahn et al, 1998;Tai et al, 2006). Thus, while providing a novel and comprehensive view of the inflammatory transcriptome in the BBB, our data corroborate several observations in earlier studies underlining the feasibility of the present method.…”

“…15-PGDH is an ubiquitous enzyme, but with its highest activity levels measured in the lungs (Piper et al, 1970). For the PGE2 metabolism, there are some reports showing a reciprocal regulation between COX-2 and 15-PGDH in inflammation with increased PGE2 production due to a coordinated up-regulation of COX-2 and down-regulation of 15-PGDH (Hahn et al, 1998;Ivanov et al, 2003;Tai et al, 2006).…”

COX2/mPGES1/PGE 2 pathway regulates PD-L1 expression in tumor-associated macrophages and myeloid-derived suppressor cells

“…It is well established that PGE 2 levels are regulated not only by its synthesis but also by its degradation (20). The key enzyme responsible for the biological inactivation of already formed prostaglandins is NAD + -linked 15-hydroxyprostaglandin dehydrogenase (15-PGDH).…”

Identification of Distinct Gene Expression Profiles between Esophageal Squamous Cell Carcinoma and Adjacent Normal Epithelial Tissues

“…We speculate that MAOA may also play an important role in inhibition of ESCC development. 15-Hydroxy prosta glandin dehydrogenase [NAD+] (HPGD) is a prostaglandinsynthesizing enzyme that physiologically antagonizes COX-2, and may play an important role in diverse physiological aspects ranging from inflammation to cancer (Tai et al 2006). A recent study has found that HPGD was downregulated in a majority of lung, colon, breast and bladder cancers (Mohamed et al 2011).…”