The hepoxilin connection in the epidermis

Brash, Alan R.; Yu, Zheyong; Boeglin, William E.; Schneider, Claus

doi:10.1111/j.1742-4658.2007.05909.x

Cited by 67 publications

(66 citation statements)

References 66 publications

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“…The concentration label in this study refers to the Sigma enzyme assuming 80% purity of the preparation. H 2 18 O (ϳ95%) was purchased 25 years ago from the Monsanto Research Corp. (Miamiburg, OH).…”

Section: Methodsmentioning

confidence: 99%

“…Widely expressed in animals and plants, and also in some bacteria and fungi, LOX enzymes participate in diverse physiological and pathological processes. Mammalian 12R-LOX and epidermal lipoxygenase-3 (eLOX3), for example, play an indispensable role in skin barrier formation (2,3), whereas plant LOX enzymes are involved in stress responses and development (4). A distinctive characteristic of LOX enzymes in general is that the resting enzyme requires activation before catalytic reactions with fatty acids and molecular oxygen can begin (5)(6)(7).…”

Section: Lipoxygenases (Lox)mentioning

confidence: 99%

“…The relative amounts of these HETE products (5-HETE ϩ 9-HETE Ͼ 15-HETE ϩ 11-HETE Ͼ 8-HETE ϩ 12-HETE) were consistent with the preference of this enzyme in hydrogen abstraction under aerobic conditions (H-7 Ͼ H-13 Ͼ H-10) (15), pointing to a similar hydrogen abstraction step during this anaerobic HETE synthesis. Incubations with 13S-[ 18 O]HPODE or in H 2 18 O followed by LC-MS analysis led to the unexpected finding that the hydroxyl of these HETE products was derived exclusively from water (Fig. 10).…”

Section: Effect Of O 2 Concentration or The A451g Mutation On The Ratmentioning

confidence: 99%

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On the Role of Molecular Oxygen in Lipoxygenase Activation

Zheng

Brash

2010

Journal of Biological Chemistry

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The oxygenation of polyunsaturated fatty acids by lipoxygenases (LOX) is associated with a lag phase during which the resting ferrous enzyme is converted to the active ferric form by reaction with fatty acid hydroperoxide. Epidermal lipoxygenase-3 (eLOX3) is atypical in displaying hydroperoxide isomerase activity with fatty acid hydroperoxides through cycling of the ferrous enzyme. Yet eLOX3 is capable of dioxygenase activity, albeit with a long lag phase and need for high concentrations of hydroperoxide activator. Here, we show that higher O 2 concentration shortens the lag phase in eLOX3, although it reduces the rate of hydroperoxide consumption, effects also associated with an A451G mutation known to affect the disposition of molecular oxygen in the LOX active site. These observations are consistent with a role of O 2 in interrupting hydroperoxide isomerase cycling. Activation of eLOX3, A451G eLOX3, and soybean LOX-1 with 13-hydroperoxy-linoleic acid forms oxygenated end products, which we identified as 9R-and 9S-hydroperoxy-12S,13S-trans-epoxyoctadec-10E-enoic acids. We deduce that activation partly depends on reaction of O 2 with the intermediate of hydroperoxide cleavage, the epoxyallylic radical, giving an epoxyallylic peroxyl radical that does not further react with Fe(III)-OH; instead, it dissociates and leaves the enzyme in the activated free ferric state. eLOX3 differs from soybean LOX-1 in more tightly binding the epoxyallylic radical and having limited access to O 2 within the active site, leading to a deficiency in activation and a dominant hydroperoxide isomerase activity.

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Section: Methodsmentioning

confidence: 99%

Section: Lipoxygenases (Lox)mentioning

confidence: 99%

Section: Effect Of O 2 Concentration or The A451g Mutation On The Ratmentioning

confidence: 99%

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On the Role of Molecular Oxygen in Lipoxygenase Activation

Zheng

Brash

2010

Journal of Biological Chemistry

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“…3). This is different in chemistry from synthesis of the group of epoxyhydroxy products that are often termed hepoxilins (28). Mechanistically, the epoxidation of the double bond could be accounted for by cross-molecular reaction of a peroxyl radical with a double bond (27).…”

Section: New Insights From Novel Products: Evidence For Intermoleculamentioning

confidence: 99%

Routes to 4-Hydroxynonenal: Fundamental Issues in the Mechanisms of Lipid Peroxidation

Schneider

Porter

Brash

2008

Journal of Biological Chemistry

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238

205

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Although investigation of the toxicological and physiological actions of ␣/␤-unsaturated 4-hydroxyalkenals has made great progress over the last 2 decades, understanding of the chemical mechanism of formation of 4-hydroxynonenal and related aldehydes has advanced much less. The aim of this review is to discuss mechanistic evidence for these non-enzymatic routes, especially of the underappreciated intermolecular pathways that involve dimerized and oligomerized fatty acid derivatives as key intermediates. These cross-molecular reactions of fatty acid peroxyls have also important implications for understanding of the basic initiation and propagation steps during lipid peroxidation and the nature of the products that arise.

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“…ALOX12B and ALOXE3 encode for arachidonate 12(R)-lipoxygenase and arachidonate lipoxygenase-3, respectively. The protein product of CYP4F22, a cytochrome P450 protein, and the two lipoxygenases arachidonate 12(R)-lipoxygenase and arachidonate lipoxygenase-3 are part of the lipid metabolism pathway involved in the formation of o-hydroxyceramides from arachidonic acid [Brash et al, 2007]. ABCA12 (MIM] 607800) missense mutations leading to defects in the ATP-binding cassette were reported in LI cases (type 2 LI [MIM] 601277]) [Lefèvre et al, 2003] and ABCA12 truncation mutations were reported underlying HI patients Kelsell et al, 2005].…”

Section: Introductionmentioning

confidence: 99%

ABCA12 mutations and autosomal recessive congenital ichthyosis: A review of genotype/phenotype correlations and of pathogenetic conceptsa

2010

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Mutations in ABCA12 have been described in autosomal recessive congenital ichthyoses (ARCI) including harlequin ichthyosis (HI), congenital ichthyosiform erythroderma (CIE), and lamellar ichthyosis (LI). HI shows the most severe phenotype. CIE and LI are clinically characterized by fine, whitish scales on a background of erythematous skin, and large, thick, dark scales over the entire body without serious background erythroderma, respectively. To date, a total of 56 ABCA12 mutations have been reported in 66 ARCI families including 48 HI, 10 LI, and 8 CIE families of African, European, Pakistani/Indian, and Japanese origin (online database: http://www.derm-hokudai.jp/ABCA12/). A total of 62.5% of reported ABCA12 mutations are expected to lead to truncated proteins. Most mutations in HI are truncation mutations and homozygous or compound heterozygous truncation mutations always results in HI phenotype. In CIE families, at least one mutation on each allele is typically a missense mutation. Combinations of missense mutations in the first ATPbinding cassette of ABCA12 underlie the LI phenotype. ABCA12 is a keratinocyte lipid transporter associated with lipid transport in lamellar granules, and loss of ABCA12 function leads to a defective lipid barrier in the stratum corneum, resulting in an ichthyotic phenotype. Recent work using mouse models confirmed ABCA12 roles in skin barrier formation.

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The hepoxilin connection in the epidermis

Cited by 67 publications

References 66 publications

On the Role of Molecular Oxygen in Lipoxygenase Activation

On the Role of Molecular Oxygen in Lipoxygenase Activation

Routes to 4-Hydroxynonenal: Fundamental Issues in the Mechanisms of Lipid Peroxidation

ABCA12 mutations and autosomal recessive congenital ichthyosis: A review of genotype/phenotype correlations and of pathogenetic conceptsa

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