Murine 12(<i>R</i>)‐lipoxygenase: functional expression, genomic structure and chromosomal localization<sup>1</sup>

Krieg, Peter; Siebert, Malte; Kinzig, Andreas; Bettenhausen, Rainer; Marks, Friedrich; Fürstenberger, Gerhard

doi:10.1016/s0014-5793(99)00196-9

Cited by 44 publications

(41 citation statements)

References 34 publications

(53 reference statements)

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“…Murine (12R)-LOX strongly prefers methylated polyenoic fatty acids (22,27). Here, we confirmed these data with three different substrates: arachidonic acid, linoleic acid, and 20-HETE.…”

Section: Enzymesupporting

confidence: 83%

“…12 for review), but little is known about the corresponding mechanisms of the more recently discovered R-lipoxygenating enzyme species (21)(22)(23). However, during the preparation of this manuscript, a study that also included two R-LOXs was published (24).…”

Section: Lipoxygenases (Loxs)mentioning

confidence: 99%

“…For 11R-oxygenation, the L-hydrogen from C-13 is abstracted, and oxygen is inserted from the opposite direction (Scheme 2B). It has been suggested previously that, for murine (12R)-LOX, the substrate fatty acid may slide into the substrate-binding pocket with its carboxylate ahead (22,24,27). Introduction of small amino acids (Ala and Gly) at Val 631 may provide more space at the bottom of the active site so that the substrate fatty acid may slide deeper into the substratebinding cage.…”

Section: Composition Of the Reaction Products Formed From Fatty Acid mentioning

confidence: 99%

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Sequence Determinants for the Reaction Specificity of Murine (12R)-Lipoxygenase

Meruvu

Walther

Ivanov

et al. 2005

Journal of Biological Chemistry

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Mammalian lipoxygenases (LOXs) are categorized with respect to their positional specificity of arachidonic acid oxygenation. Sitedirected mutagenesis identified sequence determinants for the positional specificity of these enzymes, and a critical amino acid for the stereoselectivity was recently discovered. To search for sequence determinants of murine (12R Lipoxygenases (LOXs)2 form a heterogeneous family of lipid peroxidizing enzymes that catalyze dioxygenation of free and/or esterified polyunsaturated fatty acids to their corresponding hydroperoxy derivatives (1). They are involved in the biosynthesis of eicosanoids (2) such as the pro-inflammatory leukotrienes (3) and anti-inflammatory lipoxins (4), but have also been implicated in cell maturation (5), cancer (6), psoriasis (7), atherogenesis (8), and osteoporosis (9).Mechanistically, the LOX reaction consists of four elementary reactions, the stereochemistry of which is tightly controlled (see Scheme 1): (i) stereoselective hydrogen abstraction from a bisallylic methylene, forming a carbon-centered fatty acid radical; (ii) [ϩ2] or [Ϫ2] rearrangement of the fatty acid radical; (iii) stereospecific insertion of molecular dioxygen, forming an oxygen-centered hydroperoxy radical; and (iv) reduction of the hydroperoxy fatty acid radical to the corresponding anion. Our current understanding of how mammalian LOXs control the stereochemistry of the oxygenation reaction is derived from the x-ray structure of rabbit reticulocyte 15-LOX (10), from extensive mutagenesis studies on various LOX isoforms (11-15), and from experiments with chemically modified fatty acid substrates (16,17). The substrate-binding cleft of the rabbit enzyme is a U-shaped pocket, the bottom of which is defined by a triad of amino acids (Phe 353 , Ile 418 , and Ile 593 ). A simple model for substrate alignment at the active site of this enzyme suggests that polyenoic fatty acids may slide into the substratebinding pocket with their methyl end ahead (12). Molecular modeling (10, 18) and site-directed mutagenesis (12) suggest that the volume of the active site might be important for the positional specificity. This space-related hypothesis was initially opposed by the orientation-based model, which suggests the possibility of an inverse head-to-tail substrate alignment (19,20). However, more recent experimental data suggest that both hypotheses appear to be valid (12,17).Most of the mechanistic studies performed out in the past on the structural basis for the positional specificity of LOXs have been carried out on classical S-LOX isoforms (see Ref. 12 for review), but little is known about the corresponding mechanisms of the more recently discovered R-lipoxygenating enzyme species (21-23). However, during the preparation of this manuscript, a study that also included two R-LOXs was published (24). Multiple amino acid sequence alignments of R-and S-LOXs suggest that the R-lipoxygenating enzymes contain a conserved Gly in the central part of their primary structure. Mutation of Gly 427 to Ala in (...

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“…Murine (12R)-LOX strongly prefers methylated polyenoic fatty acids (22,27). Here, we confirmed these data with three different substrates: arachidonic acid, linoleic acid, and 20-HETE.…”

Section: Enzymesupporting

confidence: 83%

Section: Lipoxygenases (Loxs)mentioning

confidence: 99%

Section: Composition Of the Reaction Products Formed From Fatty Acid mentioning

confidence: 99%

See 1 more Smart Citation

Sequence Determinants for the Reaction Specificity of Murine (12R)-Lipoxygenase

Meruvu

Walther

Ivanov

et al. 2005

Journal of Biological Chemistry

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“…In addition, some evidence suggests functions of LOX outside of the AA cascade, in that not only free PUFAs are a substrate for lipoxygenation reactions (6,(28)(29)(30). In addition, there are recent indications for functions of LOX that are independent of the enzymatic activity of individual LOXs (24,31).…”

Section: Discussionmentioning

confidence: 99%

Inducible expression of 15-lipoxygenase-2 and 8-lipoxygenase inhibits cell growth via common signaling pathways

Schweiger

Fürstenberger

Krieg

2007

Journal of Lipid Research

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Human 15-lipoxygenase (LOX)-2 and mouse 8-LOX represent orthologous members of the LOX family but display different positional specificities and tissue distribution. To study the functional role of 15-LOX-2 and 8-LOX in keratinocytes, an inducible Tet-On gene expression system was established in the premalignant mouse keratinocyte cell line 308. Doxycycline (dox)-induced expression of enzymatically active 15-LOX-2 and 8-LOX led to an inhibition of cell growth that was associated with an inhibition of DNA synthesis, as shown by a 15-46% reduction of 5-bromo-2-deoxy-uridine (BrdU) incorporation. The inhibitory effects were increased in the presence of exogenous arachidonic acid. In contrast, addition of linoleic acid or the LOX inhibitor baicalein reversed the growth-inhibitory effects. Treatment of the cells with 15-hydroxyeicosatetraenoic acid (HETE) or 8-HETE resulted in a similar inhibition of BrdU incorporation, whereas 13-hydroxyoctadecadienoic acid (HODE) and 9-HODE, in contrast, had no effects. Doxinduced keratinocytes showed increased levels of reactive oxygen species (ROS). The antioxidant N-acetyl-L-cysteine and a specific inhibitor of p38 mitogen-activated protein kinase, but not of extracellular signal-regulated kinase 1/2 or c-Jun N-terminal kinase/stress-activated kinases, completely abolished the LOX-induced growth inhibition, indicating a critical role of ROS and p38. Our data suggest that 15-LOX-2 and 8-LOX, although displaying different positional specificity, may use common signaling pathways to induce growth inhibition in premalignant epithelial cells.-Schweiger, D., G. Fü rstenberger, and P. Krieg. Inducible expression of 15-lipoxygenase-2 and 8-lipoxygenase inhibits cell growth via common signaling pathways. J. Lipid Res.

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“…ALOX12B was fi rst discovered in human ( 54 ) and mouse skin ( 55 ). Amino acid alignment of hALOX12B and nALOX12B indicated that from the 701 amino acids of hALOX12B, 524 (75%) were identifi ed in the Neandertal genome.…”

Section: Alox12b (12r-lox)mentioning

confidence: 99%

Lipoxygenase pathways in Homo neanderthalensis: functional comparison with Homo sapiens isoforms

Chaitidis

Adel

Anton

et al. 2013

Journal of Lipid Research

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Murine 12(R)‐lipoxygenase: functional expression, genomic structure and chromosomal localization¹

Cited by 44 publications

References 34 publications

Sequence Determinants for the Reaction Specificity of Murine (12R)-Lipoxygenase

Sequence Determinants for the Reaction Specificity of Murine (12R)-Lipoxygenase

Inducible expression of 15-lipoxygenase-2 and 8-lipoxygenase inhibits cell growth via common signaling pathways

Lipoxygenase pathways in Homo neanderthalensis: functional comparison with Homo sapiens isoforms

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Murine 12(R)‐lipoxygenase: functional expression, genomic structure and chromosomal localization1

Cited by 44 publications

References 34 publications

Sequence Determinants for the Reaction Specificity of Murine (12R)-Lipoxygenase

Sequence Determinants for the Reaction Specificity of Murine (12R)-Lipoxygenase

Inducible expression of 15-lipoxygenase-2 and 8-lipoxygenase inhibits cell growth via common signaling pathways

Lipoxygenase pathways in Homo neanderthalensis: functional comparison with Homo sapiens isoforms

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Murine 12(R)‐lipoxygenase: functional expression, genomic structure and chromosomal localization¹