A Kinetic Model for the Interaction of Nitric Oxide with a Mammalian Lipoxygenase

Holzhütter, Hermann‐Georg; Wiesner, Rainer; Rathmann, Jörg; Stößer, Reinhard; Kühn, Hartmut

doi:10.1111/j.1432-1033.1997.00608.x

Cited by 42 publications

(25 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our work extends the observation that endogenous NO inhibits lipoxygenase metabolism (47). Although the above studies suggest that NO may inhibit lipoxygenase metabolism, other investigators have noted that NO up-regulates the activity of lipoxygenases (48,49), including 5-LO (50), in different models.…”

Section: Discussionsupporting

confidence: 83%

Prolonged Exposure to Lipopolysaccharide Inhibits Macrophage 5-Lipoxygenase Metabolism Via Induction of Nitric Oxide Synthesis

Coffey

Phare

Peters‐Golden

2000

The Journal of Immunology

View full text Add to dashboard Cite

LPS from bacteria can result in the development of sepsis syndrome and acute lung injury. Although acute exposure to endotoxin primes leukocytes for enhanced synthesis of leukotrienes (LT), little is known about the effect of chronic exposure. Therefore, we determined the effect of prolonged LPS treatment on 5-lipoxygenase (5-LO) metabolism of arachidonic acid in alveolar macrophages (AM) and in peripheral blood monocytes. Pretreatment of AM with LPS caused time- and dose-dependent suppression of LT synthetic capacity. LPS pretreatment failed to inhibit arachidonic acid (AA) release. The fact that LPS inhibited LT synthesis from endogenous AA more than from exogenous AA suggested an effect on 5-LO-activating protein (FLAP). In addition, an inhibitory effect of LPS treatment on AM 5-LO activity was suggested by cell-free 5-LO enzyme assay. No effect on the expression of either 5-LO or FLAP proteins was observed. New protein synthesis was necessary for LPS-induced reduction of 5-LO metabolism in AM, and immunoblotting demonstrated marked induction of NO synthase (NOS). Inhibition by LPS was reproduced by an NO donor and was abrogated by inhibitors of constitutive and inducible NOS. Compared with AM, peripheral blood monocytes exhibited no suppression by LPS of 5-LO metabolism and no induction of inducible NOS. We conclude that prolonged exposure to LPS impairs AM 5-LO metabolism by NO-mediated suppression of both 5-LO and FLAP function. Because LT contribute to antimicrobial defense, this down-regulation of 5-LO metabolism may contribute to the increased susceptibility to pneumonia in patients following sepsis.

show abstract

Section: Discussionsupporting

confidence: 83%

Prolonged Exposure to Lipopolysaccharide Inhibits Macrophage 5-Lipoxygenase Metabolism Via Induction of Nitric Oxide Synthesis

Coffey

Phare

Peters‐Golden

2000

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…Among the biological targets of NO, low molecular weight reduced thiols, protein sulfhydryls (12)(13)(14), and heme and nonheme iron can be nitrosated (15)(16)(17). S-Nitrosothiols exhibit characteristic electronic maxima in the regions 330 -350 and 530 -550 nm (12), whereas heme-nitrosyl complexes can be readily detected directly by low temperature EPR spectroscopy (18,19).…”

mentioning

confidence: 99%

Reaction of Human Myoglobin and Nitric Oxide

Witting¹,

Douglas²,

Mauk³

2001

Journal of Biological Chemistry

View full text Add to dashboard Cite

The amino acid sequence of human myoglobin (Mb) is similar to other mammalian Mb except for a unique cysteine residue at position 110 (Cys 110 ). Anaerobic treatment of ferrous forms of wild-type human Mb, the C110A variant of human Mb or horse heart Mb, with either authentic NO or chemically derived NO in vitro yields heme-NO complexes as detected by electron paramagnetic resonance spectroscopy (EPR). By contrast, no EPR-detectable heme-NO complex was observed from the aerobic reactions of NO and either the ferric or oxy-Mb forms of wild-type human or horse heart myoglobins. Mass analyses of wild-type human Mb treated aerobically with NO indicated a mass increase of ϳ30 atomic mass units (i.e., NO/Mb ‫؍‬ 1 mol/mol). Mass analyses of the corresponding apoprotein after heme removal showed that NO was associated with the apoprotein fraction. New electronic maxima were detected at A 333 nm (⑀ ‫؍‬ 3665 ؎ 90 mol ؊1 cm ؊1 ; mean ؎ S.D.) and A 545 nm (⑀ ‫؍‬ 44 ؎ 3 mol ؊1 cm ؊1 ) in solutions of S-nitrosated wild-type human Mb (similar to S-nitrosoglutathione). Importantly, the sulfhydryl S-H stretch vibration for Cys 110 measured by Fourier transform infrared ( ϳ 2552 cm ؊1 ) was absent for both holo-and apo-forms of the wild-type human protein after aerobic treatment of the protein with NO. Together, these data indicate that the reaction of wild-type human Mb and NO yields either heme-NO or a novel S-nitrosated protein dependent on the oxidation state of the heme iron and the presence or absence of dioxygen.

show abstract

“…Inhibition of both plant and mammalian 15-LOX-dependent lipid oxidation by high concentrations of nitric oxide ( ⅐ NO) was ascribed to formation of an enzyme-nitrosyl complex (25)(26)(27). Nitric oxide can form a nitrosyl complex with the active site of 15-LOX, a single six-coordinate ferrous iron liganded to nitrogen and/or oxygen atoms (28), that is detectable by electron paramagnetic resonance spectroscopy (EPR).…”

mentioning

confidence: 99%

15-Lipoxygenase Catalytically Consumes Nitric Oxide and Impairs Activation of Guanylate Cyclase

O'Donnell

Taylor²,

Parthasarathy

et al. 1999

Journal of Biological Chemistry

View full text Add to dashboard Cite

Reactivation of E red , considerably slower than dioxygenase activity, is then required to complete the catalytic cycle and leads to a net inhibition of rates of (13S)-HPODE formation. This reaction of ⅐ NO with 15-LOX inhibited ⅐ NO-dependent activation of soluble guanylate cyclase and consequent cGMP production. Since accelerated ⅐ NO production, enhanced 15-LOX gene expression, and 15-LOX product formation occurs in diverse inflammatory conditions, these observations indicate that reactions of ⅐ NO with lipoxygenase peroxyl radical intermediates will result in modulation of both ⅐ NO bioavailability and rates of production of lipid signaling mediators.Lipoxygenases are a family of ubiquitously expressed nonheme iron-containing enzymes that oxidize the unsaturated fatty acids arachidonate and linoleate to bioactive hydroperoxides and other metabolites (Scheme 1). For example, 5-LOX 1 generates precursors for leukotrienes, products involved in inflammation and allergic responses (1). 12-Lipoxygenases, present in vascular endothelium, smooth muscle cells, platelets, and leukocytes (2, 3), contribute to vascular cell hypertrophy, proliferation, and hypertensive actions, while 15-LOX is involved in cell development and differentiation, particularly in reticulocytes where 15-LOX oxidation of mitochondrial phospholipids is a trigger for their degradation (2,4,5).A central pathogenic role for 15-LOX in atherosclerosis comes from multiple lines of evidence, in particular the colocalization of 15-LOX mRNA, enzymatic activity, and the relatively specific pattern of isomeric 15-LOX oxygenation products that have been detected in early human and rabbit lesions (6 -9). The accumulation and oxidation of low density lipoprotein (LDL) lipids by monocytes and the subsequent accumulation of oxidized lipids and foam cells in the vascular intima is a hallmark of early atherogenesis. In vitro studies have shown

show abstract

A Kinetic Model for the Interaction of Nitric Oxide with a Mammalian Lipoxygenase

Cited by 42 publications

References 39 publications

Prolonged Exposure to Lipopolysaccharide Inhibits Macrophage 5-Lipoxygenase Metabolism Via Induction of Nitric Oxide Synthesis

Prolonged Exposure to Lipopolysaccharide Inhibits Macrophage 5-Lipoxygenase Metabolism Via Induction of Nitric Oxide Synthesis

Reaction of Human Myoglobin and Nitric Oxide

15-Lipoxygenase Catalytically Consumes Nitric Oxide and Impairs Activation of Guanylate Cyclase

Contact Info

Product

Resources

About