Hepoxilins: A review on their enzymatic formation, metabolism and chemical synthesis

Pace-Asciak, Cecil R.; Reynaud, Dénis; Demin, Peter

doi:10.1007/bf02538262

Cited by 55 publications

(29 citation statements)

References 55 publications

(33 reference statements)

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“…The term ''hepoxilin'' is generally used to refer to groups of 12-HPETE-derived epoxyalcohol fatty acids that have been detected in skin and other tissues (26). Hepoxilin A 3 is used for any stereoisomer with an 8-hydroxy-11,12-epoxy structure, whereas hepoxilin B 3 refers to the isomers with a 10-hydroxy-11,12-epoxyeicosatrienoic acid structure.…”

Section: Discussionmentioning

confidence: 99%

The lipoxygenase gene ALOXE3 implicated in skin differentiation encodes a hydroperoxide isomerase

Schneider

Boeglin

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

138

152

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Herein we identify a logical link of the biochemistry to the genetics. eLOX3 functions as a hydroperoxide isomerase (epoxyalcohol synthase) by using the product of 12R-LOX as the preferred substrate. 12R-Hydroperoxyeicosatetraenoic acid (12R-HPETE) is converted to 8R-hydroxy-11R,12R-epoxyeicosa-5Z,9E,14Z-trienoic acid, one of the isomers of hepoxilin A 3, and to 12-ketoeicosatetraenoic acid in a 2:1 ratio. Other hydroperoxides, including 8R-HPETE, 12S-HPETE, and 15S-HPETE, as well as the 13S-and 13R-hydroperoxides of linoleic acid are converted less efficiently. Mass spectrometric analysis of the epoxyalcohol formed from [ 18 O]15S-HPETE showed that both hydroperoxy oxygens are retained in the product. We propose that the ferrous form of eLOX3 initiates a redox cycle, unprecedented among LOX in being autocatalytic, in which the hydroperoxy substrate is isomerized to the epoxyalcohol or keto product. Our results provide strong biochemical evidence for a functional linkage of 12R-LOX and eLOX3 and clues into skin biochemistry and the etiology of ichthyosiform diseases in humans. L ipoxygenases (LOXs) are a family of nonheme ironcontaining enzymes that oxygenate unsaturated fatty acids such as arachidonic acid to specific hydroperoxide products (1). These may be metabolized further to various bioactive lipid mediators including leukotrienes, lipoxins, hydroxyeicosatetraenoic acids (HETEs), and hepoxilins (2). Although LOX enzymes are catalytically active with free fatty acid substrates, some will also oxygenate esterified substrates such as the phospholipid or cholesterol esters. LOX metabolites play important roles in cell signaling or modification of membrane structures (1, 3).There are five active LOXs found in human beings: 5-LOX, 12S-LOX, 12R-LOX, 15-LOX-1, and 15-LOX-2. A sixth gene family member, epidermal LOX type 3 (eLOX3, gene symbol ALOXE3) was described first in the mouse (4), and in humans in 2001 (5). The amino acid sequence of human eLOX3 shows the closest similarity to 12R-LOX (54% identity) and 15-LOX-2 (51%). It contains the characteristic well conserved amino acid residues found in all LOXs including the putative iron-binding ligands and additional structure-determining residues. These features clearly indicate that eLOX3 belongs to the LOX gene family. The question of the catalytic activity of eLOX3, nonetheless, has remained elusive. No enzymatic activity has been detected by using linoleic or arachidonic acids, the prototypical C18 and C20 LOX substrates, nor with methyl arachidonate or cholesteryl arachidonate (4). In the first section of Results we confirm and extend these findings.Studies in humans and the mouse indicate that eLOX3 has a limited scope of tissue expression, being mainly confined to keratinized epithelia such as skin. From PCR evidence it seems to be coexpressed in tissues that express the 12R-LOX (5). A functional relationship to skin pathophysiology is strongly suggested by a recent genetic study reporting that eLOX3 or 12R-LOX are mutated in six families affected by nonbul...

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Section: Discussionmentioning

confidence: 99%

The lipoxygenase gene ALOXE3 implicated in skin differentiation encodes a hydroperoxide isomerase

Schneider

Boeglin

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

138

152

View full text Add to dashboard Cite

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“…Although heretofore only trans -epoxyalcohols have been reported from lipoxygenase catalysis (e.g., 23,28,[39][40][41], other enzymes can make the cis -epoxides. The majority of these are mechanistically quite distinct, however, because the epoxide is formed via oxygen transfer.…”

Section: Other Biosyntheses Of Cis-epoxyalcoholsmentioning

confidence: 99%

8R-Lipoxygenase-catalyzed synthesis of a prominent cis-epoxyalcohol from dihomo-γ-linolenic acid: a distinctive transformation compared with S-lipoxygenases

Jin

Boeglin

et al. 2012

Journal of Lipid Research

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This article is available online at http://www.jlr.org dins for research ( 3 ). Due to differences in the prostaglandin profi le from that typically seen in mammalian systems, for some time it was suspected that there existed a different prostaglandin biosynthetic pathway in coral ( 4,5 ). Although this putative noncyclooxygenase pathway of prostaglandin synthesis turned out to be a red herring and cyclooxygenase accounts for the biosynthesis ( 6, 7 ), research into polyunsaturated fatty acid metabolism in coral extracts uncovered other interesting biochemistry. Bundy and colleagues studied the related coral Pseudoplexaura porosa and uncovered 8 R -lipoxygenase activity, the fi rst known existence of an R -specifi c lipoxygenase ( 8 ). 8 R -LOX was subsequently found to be widespread in corals including in P. homomalla ( 5, 9 ) as well as in many marine invertebrates ( 10 ), and a 12 R -LOX is highly conserved and functionally essential in mammals ( 11,12 ). A second novel activity detected in coral extracts was allene oxide synthase ( 5, 13 ), which transforms the 8 R -LOX product, 8 R -hydroperoxy-eicosatetraenoic acid, to an allene epoxide ( 5 ), a proposed intermediate in biosynthesis of cyclopentenones such as the clavulones ( 14-16 ), and which hydrolyzes in vitro to an ␣ -ketol derivative ( 5 ).The work described in the present paper was initiated in the early 1990s, before the cloning of P. homomalla cyclooxygenases and lipoxygenases. It concerns an unexpected difference we observed in the metabolism of arachidonic acid (20:4 6) and dihomo-␥ -linolenic acid (20:3 6) in extracts of P. homomalla ; a prominent, relatively polar, product is formed specifi cally from 20:3 6. This difference had been noted before in work from the E. J. Corey laboratory ( 17 ).Abstract Conversion of fatty acid hydroperoxides to epoxyalcohols is a well known secondary reaction of lipoxygenases, described for S -specifi c lipoxygenases forming epoxyalcohols with a trans -epoxide confi guration. Here we report on R -specifi c lipoxygenase synthesis of a cis -epoxyalcohol. Although arachidonic and dihomo-␥ -linolenic acids are metabolized by extracts of the Caribbean coral Plexaura homomalla via 8 R -lipoxygenase and allene oxide synthase activities, 20:3 6 forms an additional prominent product, identifi ed using UV, GC-MS, and NMR in comparison to synthetic standards as 8 R ,9 S -cis -epoxy-10 S -erythro -hydroxy-eicosa-11 Z ,14 Zdienoic acid. Both oxygens of In the late 1960s and early 1970s, high concentrations of prostaglandin esters were identifi ed in the Caribbean sea whip coral Plexaura homomalla ( 1, 2 ), and for a few years this abundant octacoral served as a source of prostaglan-

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“…The hepoxilins (HXs) may be candidates for the control of lung fibrosis as they are formed through the 12-lipoxygenase pathway of metabolism of arachidonic acid (Pace-Asciak et al, 1983;Pace-Asciak, 1984;Pace-Asciak and Martin, 1984). These compounds have previously been shown to have significant biological actions (Pace-Asciak, 1984;Dho et al, 1990;Laneuville et al, 1992;Pace-Asciak et al, 1995;Reynaud et al, 1996Reynaud et al, , 1999Sutherland et al, 2000). HXs raise free intracellular calcium in human neutrophils ex vivo through the release from stores and vascular tissue in vitro and block the intracellular calcium rise evoked by inflammatory mediators (Laneuville et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

Hepoxilin Analogs Inhibit Bleomycin-Induced Pulmonary Fibrosis in the Mouse

Jankov

Li²,

Demin³

et al. 2002

J Pharmacol Exp Ther

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Bleomycin has been suggested to incite plasma extravasation and influx of inflammatory cells leading to pulmonary fibrosis. We hypothesized that stable analogs of the 12-lipoxygenase product, hepoxilin, may attenuate these effects. We initially investigated the effects of the four hepoxilin analogs (PBT-1 to -4) coadministered intradermally with bleomycin and found that PBT-1 and -2 significantly opposed the vascular permeability effects of bleomycin in rat skin. We subsequently tested the hepoxilin analogs for their actions in opposing the intratracheal bleomycin-evoked acute inflammatory phase of lung fibrosis in the mouse, characterized by a marked accumulation of macrophages and an increase in the rate of collagen synthesis and deposition. We found that the bleomycin-evoked effects on macrophage influx were inhibited by all the hepoxilin analogs (PBT-1, -3, and -4 Ͼ PBT-2) administered i.p. for 8 days. Increased total lung collagen was completely abrogated by PBT-1 and -2, whereas PBT-3 and -4 had little effect. A doseresponse study with PBT-1 indicated that the effective dose for inhibition of bleomycin-induced inflammatory and histological changes was below 10 g/day. These studies demonstrate an in vivo action of stable analogs of hepoxilin and support an effect on inflammation and vascular permeability from these novel compounds, especially for PBT-1.Idiopathic pulmonary fibrosis is a devastating disorder that is poorly understood and resistant to treatment (Cooper, 2000). The observation that the antibiotic bleomycin sulfate (BL), a potent cancer chemotherapeutic agent (Adamson, 1984;Nici et al., 1998), may cause interstitial lung fibrosis in humans (Yagoda et al., 1972) led to the development of animal models in which a single dose of BL administered intratracheally induced changes resembling human idiopathic pulmonary fibrosis histopathologically (Kelley et al., 1980). The acute phase of this response is characterized by a marked accumulation of inflammatory cells and an increase in the rate of collagen synthesis and deposition (Cooper et al., 1988;Gurujeyalakshmi and Giri, 1995;Giri and Hollinger, 1996).Previous animal studies have demonstrated that BLevoked lung fibrosis is exacerbated with nordihydroguaiaretic acid, a lipoxygenase inhibitor, suggesting that a lipoxygenase product may be involved in endogenous mechanisms controlling lung fibrosis (Giri and Hollinger, 1996). The hepoxilins (HXs) may be candidates for the control of lung fibrosis as they are formed through the 12-lipoxygenase pathway of metabolism of arachidonic acid (Pace-Asciak et al., 1983;Pace-Asciak, 1984;Pace-Asciak and Martin, 1984). These compounds have previously been shown to have significant biological actions (Pace-Asciak, 1984;Dho et al., 1990;Laneuville et al., 1992;Pace-Asciak et al., 1995;Reynaud et al., 1996Reynaud et al., , 1999Sutherland et al., 2000). HXs raise free intracellular calcium in human neutrophils ex vivo through the release from stores and vascular tissue in vitro and block the intracellular calc...

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Hepoxilins: A review on their enzymatic formation, metabolism and chemical synthesis

Abstract: This article reviews published evidence describing the enzymatic and nonenzymatic formation and the routes of metabolism of the hepoxilins. Also treated are the major approaches used for the chemical synthesis of these compounds and for some of their analogs.

Cited by 55 publications

References 55 publications

The lipoxygenase gene ALOXE3 implicated in skin differentiation encodes a hydroperoxide isomerase

The lipoxygenase gene ALOXE3 implicated in skin differentiation encodes a hydroperoxide isomerase

8R-Lipoxygenase-catalyzed synthesis of a prominent cis-epoxyalcohol from dihomo-γ-linolenic acid: a distinctive transformation compared with S-lipoxygenases

Hepoxilin Analogs Inhibit Bleomycin-Induced Pulmonary Fibrosis in the Mouse

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