Human and Mouse ELOX3 Have Distinct Substrate Specificities: Implications for Their Linkage with Lipoxygenases in Skin

Overview

Journal Arch Biochem Biophys

Publisher Elsevier

Specialties Biochemistry
Biophysics

Date 2006 Oct 19

PMID 17045234

Citations 20

Authors

Zheyong Yu

Claus Schneider

William E Boeglin

Alan R Brash

Affiliations

Soon will be listed here.

Abstract

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; LOX-derived 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 s(-1); at 30 microM substrate), mouse eLOX3 shows the highest turnover with 8R-HPETE (2.9 s(-1)) followed by 8S-HPETE (1.3 s(-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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References

Hughes M, Brash A . Investigation of the mechanism of biosynthesis of 8-hydroxyeicosatetraenoic acid in mouse skin. Biochim Biophys Acta. 1991; 1081(3):347-54. DOI: 10.1016/0005-2760(91)90292-p. View

Baer A, Costello P, Green F . Stereospecificity of the products of the fatty acid oxygenases derived from psoriatic scales. J Lipid Res. 1991; 32(2):341-7. View

Furstenberger G, Hagedorn H, Jacobi T, Besemfelder E, Stephan M, Lehmann W . Characterization of an 8-lipoxygenase activity induced by the phorbol ester tumor promoter 12-O-tetradecanoylphorbol-13-acetate in mouse skin in vivo. J Biol Chem. 1991; 266(24):15738-45. View

Pace-Asciak C, Reynaud D, Demin P . Hepoxilins: a review on their enzymatic formation, metabolism and chemical synthesis. Lipids. 1995; 30(2):107-14. DOI: 10.1007/BF02538262. View

Jisaka M, Kim R, Boeglin W, Nanney L, Brash A . Molecular cloning and functional expression of a phorbol ester-inducible 8S-lipoxygenase from mouse skin. J Biol Chem. 1997; 272(39):24410-6. DOI: 10.1074/jbc.272.39.24410. View

Krieg P, Kinzig A, Heidt M, Marks F, Furstenberger G . cDNA cloning of a 8-lipoxygenase and a novel epidermis-type lipoxygenase from phorbol ester-treated mouse skin. Biochim Biophys Acta. 1998; 1391(1):7-12. DOI: 10.1016/s0005-2760(97)00214-2. View

Boeglin W, Kim R, Brash A . A 12R-lipoxygenase in human skin: mechanistic evidence, molecular cloning, and expression. Proc Natl Acad Sci U S A. 1998; 95(12):6744-9. PMC: 22619. DOI: 10.1073/pnas.95.12.6744. View

Burger F, Krieg P, Kinzig A, Schurich B, Marks F, Furstenberger G . Constitutive expression of 8-lipoxygenase in papillomas and clastogenic effects of lipoxygenase-derived arachidonic acid metabolites in keratinocytes. Mol Carcinog. 1999; 24(2):108-17. DOI: 10.1002/(sici)1098-2744(199902)24:2<108::aid-mc5>3.0.co;2-r. View

Krieg P, Siebert M, Kinzig A, Bettenhausen R, Marks F, Furstenberger G . Murine 12(R)-lipoxygenase: functional expression, genomic structure and chromosomal localization. FEBS Lett. 1999; 446(1):142-8. DOI: 10.1016/s0014-5793(99)00196-9. View

10.

Kinzig A, Heidt M, Furstenberger G, Marks F, Krieg P . cDNA cloning, genomic structure, and chromosomal localization of a novel murine epidermis-type lipoxygenase. Genomics. 1999; 58(2):158-64. DOI: 10.1006/geno.1999.5816. View

11.

Brash A . Lipoxygenases: occurrence, functions, catalysis, and acquisition of substrate. J Biol Chem. 1999; 274(34):23679-82. DOI: 10.1074/jbc.274.34.23679. View

12.

Yu Z, Schneider C, Boeglin W, Brash A . Mutations associated with a congenital form of ichthyosis (NCIE) inactivate the epidermal lipoxygenases 12R-LOX and eLOX3. Biochim Biophys Acta. 2005; 1686(3):238-47. DOI: 10.1016/j.bbalip.2004.10.007. View

13.

Flores A, Li L, McHugh N, Aneskievich B . Enzyme association with PPARgamma: evidence of a new role for 15-lipoxygenase type 2. Chem Biol Interact. 2005; 151(2):121-32. DOI: 10.1016/j.cbi.2004.11.001. View

14.

Kim E, Rundhaug J, Benavides F, Yang P, Newman R, Fischer S . An antitumorigenic role for murine 8S-lipoxygenase in skin carcinogenesis. Oncogene. 2004; 24(7):1174-87. DOI: 10.1038/sj.onc.1208269. View

15.

Muga S, Thuillier P, Pavone A, Rundhaug J, Boeglin W, Jisaka M . 8S-lipoxygenase products activate peroxisome proliferator-activated receptor alpha and induce differentiation in murine keratinocytes. Cell Growth Differ. 2000; 11(8):447-54. View

16.

Anton R, Vila L . Stereoselective biosynthesis of hepoxilin B3 in human epidermis. J Invest Dermatol. 2000; 114(3):554-9. DOI: 10.1046/j.1523-1747.2000.00903.x. View

17.

Eckl K, Krieg P, Kuster W, Traupe H, Andre F, Wittstruck N . Mutation spectrum and functional analysis of epidermis-type lipoxygenases in patients with autosomal recessive congenital ichthyosis. Hum Mutat. 2005; 26(4):351-61. DOI: 10.1002/humu.20236. View

18.

Jobard F, Lefevre C, Karaduman A, Blanchet-Bardon C, Emre S, Weissenbach J . Lipoxygenase-3 (ALOXE3) and 12(R)-lipoxygenase (ALOX12B) are mutated in non-bullous congenital ichthyosiform erythroderma (NCIE) linked to chromosome 17p13.1. Hum Mol Genet. 2002; 11(1):107-13. DOI: 10.1093/hmg/11.1.107. View

19.

Schneider C, Brash A . Lipoxygenase-catalyzed formation of R-configuration hydroperoxides. Prostaglandins Other Lipid Mediat. 2002; 68-69:291-301. DOI: 10.1016/s0090-6980(02)00041-2. View

20.

Funk C, Chen X, Johnson E, Zhao L . Lipoxygenase genes and their targeted disruption. Prostaglandins Other Lipid Mediat. 2002; 68-69:303-12. DOI: 10.1016/s0090-6980(02)00036-9. View