cDNA cloning of a 8-lipoxygenase and a novel epidermis-type lipoxygenase from phorbol ester-treated mouse skin

Krieg, Peter; Kinzig, Andreas; Heidt, Markus; Marks, Friedrich; Fürstenberger, Gerhard

doi:10.1016/s0005-2760(97)00214-2

Cited by 56 publications

(44 citation statements)

References 17 publications

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“…It is more distantly related to the 12S-and reticulocyte-type of 15S-lipoxygenase (38 and 35% similarity, respectively). This human sequence is closely related to a recently reported mouse lipoxygenase cDNA (Ϸ86% identity) (38) of which it appears to be a structural homologue.…”

Section: Investigation Of a Potential Isomerization Of 12s-to 12r-hetesupporting

confidence: 55%

A 12 R -lipoxygenase in human skin: Mechanistic evidence, molecular cloning, and expression

Boeglin

Kim

Brash

1998

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

159

138

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A recognized feature of psoriasis and other proliferative dermatoses is accumulation in the skin of the unusual arachidonic acid metabolite, 12R-hydroxyeicosatetraenoic acid (12R-HETE). This hydroxy fatty acid is opposite in chirality to the product of the well-known 12S-lipoxygenase and heretofore in mammals is known only as a product of cytochrome P450s. Here we provide mechanistic evidence for a lipoxygenase route to 12R-HETE in human psoriatic tissue and describe a 12R-lipoxygenase that can account for the biosynthesis. Initially we demonstrated retention of the C-12 deuterium of octadeuterated arachidonic acid in its conversion to 12R-HETE in incubations of psoriatic scales, indicating the end product is not formed by isomerization from 12S-H(P)ETE via the 12-keto derivative. Secondly, analysis of product formed from [10 R -3 H] and [10 S -3 H]-labeled arachidonic acids revealed that 12R-HETE synthesis is associated with stereospecific removal of the pro-R hydrogen from the 10-carbon of arachidonate. This result is compatible with 12R-lipoxygenase-catalyzed formation of 12R-HETE and not with a P450-catalyzed route to 12R-HETE in psoriatic scales. We cloned a lipoxygenase from human keratinocytes; the cDNA and deduced amino acid sequences share <50% identity to other human lipoxygenases. This enzyme, when expressed in Hela cells, oxygenates arachidonic acid to 12-HPETE, >98% 12R in configuration. The 12R-lipoxygenase cDNA is detectable by PCR in psoriatic scales and as a 2.5-kilobase mRNA by Northern analysis of keratinocytes. Identification of this enzyme extends the known distribution of R-lipoxygenases to humans and presents an additional target for potential therapeutic interventions in psoriasis.

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Section: Investigation Of a Potential Isomerization Of 12s-to 12r-hetesupporting

confidence: 55%

A 12 R -lipoxygenase in human skin: Mechanistic evidence, molecular cloning, and expression

Boeglin

Kim

Brash

1998

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

159

138

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“…In murine skin wounds, there are other lipoxygenases, including epidermis-type LOX3, 12R-LOX, and 8-LOX as well as 5-LOX from recruited leukocytes (26,30,31,50,(53)(54)(55)(56)(57)(58)(59). However, LOX3, 12R-LOX, 8-LOX, or 5-LOX is unlikely to catalyze DHA 14S-hydroxygenation in skin wounds based on the study conducted by other scientists (52) and ourselves.…”

Section: Discussionmentioning

confidence: 99%

14S,21R-Dihydroxydocosahexaenoic Acid Remedies Impaired Healing and Mesenchymal Stem Cell Functions in Diabetic Wounds

Tian

Lü

Shah

et al. 2011

Journal of Biological Chemistry

104

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Treatment of diabetes-impaired wound healing remains a major unresolved medical challenge. Here, we identified suppressed formation of a novel reparative lipid mediator 14S,21R-dihydroxydocosa-4Z,7Z,10Z,12E,16Z,19Z-hexaenoic acid (14S,21R-diHDHA) in cutaneous wounds of diabetic db/db mice. These results indicate that diabetes impedes the biosynthetic pathways of 14S,21R-diHDHA in skin wounds. Administration of exogenous 14S,21R-diHDHA to wounds in diabetic animals rescued healing and angiogenesis. When db/db mesenchymal stem cells (MSCs) were administered together with 14S,21R-diHDHA to wounds in diabetic animals, they coacted to accelerate wound re-epithelialization, granulation tissue formation, and synergistically improved vascularization. In the pivotal cellular processes of angiogenesis, 14S,21R-diHDHA enhanced VEGF release, vasculature formation, and migration of db/db dermal microvascular endothelial cells (DMVECs), as well as remedied paracrine angiogenic functions of db/db MSCs, including VEGF secretion and the promotion of DMVEC migration and vasculature formation. Our results show that 14S,21R-diHDHA activates the p38 MAPK pathway in wounds, db/db MSCs, and DMVECs. Overall, the impeded formation of 14S,21R-diHDHA described in this study suggests that diabetes could affect the generation of pro-healing lipid mediators in wound healing. By restoring wound healing and MSC functions, 14S,21R-diHDHA is a new lead for the development of better therapeutics used in treating wounds of diabetics.

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“…Several orthologs have altered catalytic activities across the two species. For example, the ortholog of human 15-LOX-2 has 8-LOX activity in the mouse [8,9]. And of particular relevance here, there are differences between mouse and human 12R-LOX.…”

Section: Introductionmentioning

confidence: 92%

Human and mouse eLOX3 have distinct substrate specificities: Implications for their linkage with lipoxygenases in skin

Schneider

Boeglin

et al. 2006

Archives of Biochemistry and Biophysics

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Genetic and biochemical evidence suggests a functional link between human 12R-lipoxygenase (12R-LOX) and epidermal lipoxygenase-3 (eLOX3) in normal differentiation of the epidermis; LOXderived fatty acid hydroperoxide is isomerized by the atypical eLOX3 into a specific epoxyalcohol that is a potential mediator in the pathway. Mouse epidermis expresses a different complement of LOX enzymes, and therefore this metabolic linkage could differ. To test this concept, we compared the substrate specificities of recombinant mouse and human eLOX3 toward sixteen hydroperoxy stereoisomers of arachidonic and linoleic acids. Both enzymes metabolized R-hydroperoxides 2-3 times faster than the corresponding S enantiomers. Whereas 12R-hydroperoxyeicosatetraenoic acid (12R-HPETE) is the best substrate for human eLOX3 (2.4 sec −1 ; at 30 µM substrate), mouse eLOX3 shows the highest turnover with 8R-HPETE (2.9 sec −1 ) followed by 8S-HPETE (1.3 sec −1 ). Novel product structures were characterized from reactions of mouse eLOX3 with 5S-, 8R-, and 8S-HPETEs. 8S-HPETE is converted specifically to a single epoxyalcohol, identified as 10R-hydroxy-8S,9S-epoxyeicosa-5Z,11Z,14Z-trienoic acid. The substrate preference of mouse eLOX3 and the unique occurrence of an 8S-LOX enzyme in mouse skin point to a potential LOX pathway for the production of epoxyalcohol in murine epidermal differentiation.

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cDNA cloning of a 8-lipoxygenase and a novel epidermis-type lipoxygenase from phorbol ester-treated mouse skin

Cited by 56 publications

References 17 publications

A 12 R -lipoxygenase in human skin: Mechanistic evidence, molecular cloning, and expression

A 12 R -lipoxygenase in human skin: Mechanistic evidence, molecular cloning, and expression

14S,21R-Dihydroxydocosahexaenoic Acid Remedies Impaired Healing and Mesenchymal Stem Cell Functions in Diabetic Wounds

Human and mouse eLOX3 have distinct substrate specificities: Implications for their linkage with lipoxygenases in skin

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