Inhibition of rat brain prostaglandin D synthase by inorganic selenocompounds.
TL;DR: The inhibition by selenium required the preincubation of the metal with sulfhydryl compounds such as dithiothreitol (DTT), indicating that the formation of selenotrisulfide or some other adduct(s) is essential for the inhibition.
About: This article is published in Archives of Biochemistry and Biophysics.The article was published on 1991-08-15. It has received 74 citations till now. The article focuses on the topics: Selenium Compound & Prostaglandin-D synthase.
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TL;DR: A novel chemopreventive mechanism is proposed involving Se catalysis of reversible cysteine/disulfide transformations that occur in a number of redox-regulated proteins, including transcription factors, which would allow normalization of critical cellular processes in the early stages of transformation.
Abstract: Numerous studies in animal models and more recent studies in humans have demonstrated cancer chemopreventive effects with Se. There is extensive evidence that monomethylated forms of Se are critical metabolites for chemopreventive effects of Se. Induction of apoptosis in transformed cells is an important chemopreventive mechanism. Apoptosis can be triggered by micromolar levels of monomethylated forms of Se independent of DNA damage and in cells having a null p53 phenotype. Cell cycle protein kinase cdk2 and protein kinase C are strongly inhibited by various forms of Se. Inhibitory mechanisms involving modification of cysteine residues in proteins by Se have been proposed that involve formation of Se adducts of the selenotrisulfide (S-Se-S) or selenenylsulfide (S-Se) type or catalysis of disulfide formation. Selenium may facilitate reactions of protein cysteine residues by the transient formation of more reactive S-Se intermediates. A novel chemopreventive mechanism is proposed involving Se catalysis of reversible cysteine/disulfide transformations that occur in a number of redox-regulated proteins, including transcription factors. A time-limited activation mechanism for such proteins, with deactivation facilitated by Se, would allow normalization of critical cellular processes in the early stages of transformation. There is uncertainty at the present time regarding the role of selenoproteins in chemoprevention model systems where supranutritional levels of Se are employed. Mammalian thioredoxin reductase is one selenoprotein that shows increased activity with Se supplementation in the nutritional to supranutritional range. Enhanced thioredoxin reduction could have beneficial effects in oxidative stress, but possible adverse effects are considered. Other functions of thioredoxin reductase may be relevant to cell signaling pathways. The functional status of the thioredoxin/thioredoxin reductase system during in vivo chemoprevention with Se has not been established. Some in vitro studies have shown inhibitory effects of Se on the thioredoxin system correlated with growth inhibition by Se. A potential inactivating mechanism for thioredoxin reductase or other selenoenzymes involving formation of a stable diselenide form resistant to reduction is discussed. New aspects of Se biochemistry and possible functions of new selenoproteins in chemoprevention are described.
687 citations
TL;DR: This chapter reviews the biochemistry and the biochemical pharmacology of the enzymes involved in the formation of prostanoids and investigates the role of phospholipase A2 and PLA2 in regulating prostanoid biosynthesis.
Abstract: Prostanoids are cyclic, oxygenated products of ω3 and ω6 20- and 22-carbon essential fatty acids (FAs) that are formed enzymatically through “cyclooxygenases”. Prostaglandin endoperoxide synthases -1 and -2 (PGHS-1 and -2)a, which are also known as cyclooxygenases -1 and -2 (COX-1 and -2), catalyze the committed step in the biosynthesis of prostanoids (Figure 1). These compounds include what are sometimes referred to as the “classical” prostaglandins (PGs) PGD, PGE, and PGF as well as prostacyclins denoted as PGI's and the thromboxanes abbreviated Tx's; monohydroxy acids can also be formed via PGHSs, but information on the possible physiologic importance of such compounds is incomplete.1-3 The most abundant prostanoids are the “2-series” compounds (e.g. PGE2) that are formed from arachidonic acid (AA; 5Z, 8Z, 11Z, 14Z- eicosatetraenoic acid; 20:4 ω6; Figure 1). The “2” denotes the number of carbon-carbon double bonds in the product.
Figure 1
Biosynthetic pathway for the formation of prostanoids
PGHSs catalyze two distinct reactions that occur at physically distinct but functionally interacting sites. The cyclooxygenase (COX) reaction is a bis-oxygenation in which two O2 molecules are inserted into the carbon backbone of AA to yield PGG2 (Figure 1). The peroxidase (POX) reaction is a transformation in which the 15-hydroperoxyl group of PGG2 undergoes a net two electron reduction to PGH2 plus water. The POX reaction is important in the enzyme mechanism, but other peroxidases such as glutathione peroxidase may contribute importantly to the reduction of PGG2 to PGH2 in vivo.
PGH2 is thought not to accumulate in cells but rather to be converted quickly to what are considered the biologically relevant, downstream products. There are specific synthases involved in forming PGD2, PGE2, PGF2α, PGI2 and TxA2 from PGH2. Except for the case of PGF2α, which is formed by a two electron reduction of PGH2, these enzymes catalyze non-oxidative rearrangements. Finally, there is a PGH 19-hydoxylase that converts PGHs to their corresponding 19-hydroxy derivatives which themselves are substrates for PGE synthase(s). There are one or more specific G protein-linked receptors for each prostanoid, and in some cases prostanoids may also act through nuclear peroxisome proliferator activated receptors.
AA and other 20- and 22-carbon, highly unsaturated FAs are found esterified at the sn2 position of glycerophospholipids. Basal prostanoid formation generally occurs at a low rate relative to stimulated formation. A major factor limiting prostanoid formation is AA availability, which is controlled through the net rates of deacylation and reacylation of glycerophospholipids. Prostanoid formation is enhanced when phospholipase A2 (PLA2) activity is increased, and thus PLA2s play a substrate-limiting role in regulating prostanoid biosynthesis. Although reacylation may also be important, its possible role in regulating prostanoid biosynthesis is largely unexplored.
In this chapter we review the biochemistry and the biochemical pharmacology of the enzymes involved in converting AA to various prostanoid products. These enzymes include PGHS-1, PGHS-2, hematopoietic PGD synthase (H-PGDS), lipocalin-type PGD synthase (L-PGDS), microsomal PGE synthase-1 (mPGES-1), microsomal PGE synthase-2 (mPGES-2), cytosolic PGE synthase (cPGES), PGF synthase (PGFS), PGI synthase (PGIS) and TXA synthase (TXAS). The PLA2s involved in mobilizing AA and the receptors through which prostanoids function are surveyed in other chapters of this volume.
401 citations
TL;DR: X-ray crystallographic analyses revealed that PGDS possesses a beta-barrel structure with a hydrophobic pocket in which an active thiol, Cys(65), the active center for the catalytic reaction, was located facing to the inside of the pocket.
329 citations
TL;DR: Two distinct types of PGD synthase are purified; one is the lipocalin-type enzyme and the other is the hematopoietic enzyme, which acts as a PGD2-producing enzyme and also as a lipophilic ligand-binding protein, with high affinities.
Abstract: Prostaglandin (PG) D synthase catalyzes the isomerization of PGH2, a common precursor of various prostanoids, to produce PGD2 in the presence of sulfhydryl compounds PGD2 induces sleep, regulates nociception, inhibits platelet aggregation, acts as an allergic mediator, and is further converted to 9 alpha, 11 beta-PGF2 or the J series of prostanoids, such as PGJ2, delta 12-PGJ2, and 15-deoxy-delta 12,14-PGJ2 We have purified two distinct types of PGD synthase; one is the lipocalin-type enzyme and the other is the hematopoietic enzyme We isolated the cDNA and the gene for each enzyme and determined the tissue distribution profile and the cellular localization in several animal species Lipocalin-type PGD synthase is localized in the central nervous system and male genital organs of various mammals and the human heart and is secreted into cerebrospinal fluid, seminal plasma, and plasma, respectively The human enzyme was identified as beta-trace, which is a major protein in human cerebrospinal fluid This enzyme is considered to be a dual-function protein; it acts as a PGD2-producing enzyme and also as a lipophilic ligand-binding protein, because the enzyme binds retinoids, thyroids, and bile pigments, with high affinities Hematopoietic PGD synthase is widely distributed in the peripheral tissues and localized in the antigen-presenting cells, mast cells, and megakaryocytes The hematopoietic enzyme is the first recognized vertebrate homolog of the sigma class of glutathione S-transferase X-ray crystallographic analyses and generation of gene-knockout and transgenic mice for each enzyme have been performed
289 citations
TL;DR: Experimental evidence indicates that prostaglandins D2 and E2 are probably two of the major endogenous sleep‐regulating substances, one promoting sleep and the other wakefulness, in rats, dogs, rabbits, monkeys, and probably in humans as well.
Abstract: Although sleep-wake cycles are repeated every day and night and almost one-third of our lifetime is spent sleeping, the molecular mechanisms of sleep-wake regulation have remained little understood. Recent experimental evidence indicates that prostaglandins (PG) D2 and E2 are probably two of the major endogenous sleep-regulating substances, one promoting sleep and the other wakefulness, in rats, dogs, rabbits, monkeys, and probably in humans as well. Preliminary evidence indicates that the sites of action of PGD2 and E2 are located in the sleep and wake centers in or near the preoptic area and posterior hypothalamus, respectively.
238 citations
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TL;DR: The results suggest that the peroxidase with a broad substrate specificity is an integral part of prostaglandin endoperoxide synthetase which is responsible for the conversion of prostglandin G1 to H1.
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