Prostaglandin catabolizing enzymes
Introduction
Prostaglandins are primarily metabolized by the initial oxidation of the 15(S)-hydroxyl group catalyzed by 15-hydroxyprostaglandin dehydrogenases (15-PGDHs). The significance of the dehydrogenases is attributed to the fact that 15-ketoprostaglandins possess greatly reduced biological activities [1]. Consequently, 15-PGDHs are considered to be the key enzymes responsible for the biological inactivation of prostaglandins and related eicosanoids. Two types of 15-PGDHs have been identified. Type I is NAD+-dependent and utilizes primarily prostaglandins and related eicosanoids as substrates [2], whereas Type II uses both NADP+ and NAD+ as cofactors and exhibits a much broader substrate specificity [3]. In fact, Type II has a 9-ketoprostaglandin reductase activity in addition to a 15-PGDH activity [4] and has been found to be identical to a general carbonyl reductase [5]. Because the Type II enzyme has much higher Km values for prostaglandins than the Type I enzyme, Type II does not appear to play an important role in catabolizing prostaglandins. It is generally believed that Type I, a NAD+-dependent and more prostaglandin and eicosanoid specific dehydrogenase, is the enzyme primarily involved in controlling the biological activities of prostaglandins and related eicosanoids. After the initial oxidation catalyzed by 15-PGDH, 15-ketoprostaglandins are further reduced to 15-keto-13,14-dihydroprostaglandins catalyzed by Δ13-15-ketoprostaglandin reductase (13-PGR) [6]. The enzyme catalyzes NADPH/NADH dependent reduction of Δ13 double bond. The products exhibit further reduced biological activities. Following the cloning of the cDNA of 13-PGR it was discovered that 13-PGR is identical to the previously described leukotriene B4 12-hydroxydehydrogenase (12-LTB4DH) in sequence [7]. It appears that the same enzyme protein exhibits both 13-PGR and 12-LTB4DH activities [8]. 12-LTB4DH appears to inactivate LTB4 since 12-keto-LTB4 exhibits minimal biological activity [7]. A separate catabolic pathway of thromboxane involves the oxidation of thromboxane B2 (TXB2) at C-11 catalyzed by NAD+-dependent 11-hydroxythromboxane B2 dehydrogenase (11-TXB2DH) [9]. The product of the reaction, 11-dehydro-TXB2, appears to be a more prominent metabolite than 2,3-dinor-TXB2, a metabolite of TXB2 through β-oxidation, in plasma and urine [10]. Quantitation of 11-dehydro-TXB2 in the blood has been considered a better index of assessing in vivo formation of thromboxane in view of the facile ex vivo synthesis of TXB2 by platelets [11], [12].
This review is an extension of a previous review [13] and focuses on recent developments in the biochemistry and molecular biology of Type I 15-PGDH, 13-PGR/12-LTB4DH, and 11-TXB2DH.
Section snippets
Enzymology
15-PGDH is ubiquitously present in mammalian tissues and has been purified to apparent homogeneity from several mammalian tissues. The enzyme is believed to be a dimer composed of identical subunits with a molecular weight of 29 kDa, although it has also been proposed that the monomeric enzyme might be active [14]. 15-PGDH can use a wide variety of prostaglandins as substrates with Km values in the μM range for PGE1, PGE2, PGF1α, PGF2α, PGI2, and 6-keto-PGF1α. PGB2, PGD2, and TXB2 are poor
Δ13-15-Ketoprostaglandin reductase/leukotriene B4 12-hydroxydehydrogenase
13-PGR catalyzes the NADH/NADPH dependent reduction of the Δ13 double bond of 15-ketoprostaglandins to yield 15-keto-13,14-dihydroprostaglandins and results in a further reduction of the biological activities of prostaglandins [6]. The same enzyme appears also to catalyze the NADP+-dependent oxidation of LTB4 to a much less active 12-keto-LTB4 [68]. 13-PGR has been purified from various mammalian tissues. Five different forms of the 13-PGR with different molecular weights and kinetic properties
11-Hydroxythromboxane B2 dehydrogenase
Metabolism of TXB2 appears to occur through two different pathways. One involves the β-oxidation of TXB2 resulting in the formation of 2,3-dinor-TXB2 [71], whereas the other is related to the dehydrogenation of the hemiacetal alcohol group at C-11 leading to the production of 11-dehydro-TXB2 [72]. Studies on the major plasma and urinary metabolites of infused or endogenous TXB2 have indicated that 11-dehydro-TXB2 is a more prominent product than 2,3-dinor-TXB2 [10]. In view of the facile ex
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