Non-cyclooxygenase-derived prostanoids (F2-isoprostanes) are formed in situ on phospholipids.

Morrow, Jason D.; Awad, Joseph; Boss, H J; Blair, Ian A.; Roberts, nd L J

doi:10.1073/pnas.89.22.10721

Cited by 669 publications

(408 citation statements)

References 28 publications

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“…Analysis of IsoK protein adducts involves quantification of IsoK-lysyl adducts following enzymatic digestion of proteins to individual amino acids. A unique aspect of isoprostane and, thus also, IsoK formation is that they are initially formed in situ esterified to phospholipids followed by phospholipase release (13). Because of their high FIG.…”

Section: Resultsmentioning

confidence: 99%

Modification of Proteins by Isoketal-containing Oxidized Phospholipids

Brame¹,

Boutaud

Davies

et al. 2004

Journal of Biological Chemistry

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Oxidative stress frequently leads to altered function of membrane proteins. Isoketals are highly reactive products of the isoprostane pathway of free radical-induced lipid peroxidation that rapidly form covalent protein adducts and exhibit a remarkable proclivity to form protein cross links in vitro. Examination of isoketal adducts from an animal model of oxidative injury revealed that initial adducts were formed by isoketals esterified in phospholipids, representing a novel oxidative injuryassociated modification of proteins by phospholipids. Maturation of adducts involved cleavage from phospholipids and conversion of adducts to a more stable chemical form that can be detected for extended periods. Because initial adducts were formed by phospholipidesterified isoketals, the functional consequence of isoketal adduction was examined using a model membrane protein (a cardiac K ؉ channel). These studies revealed that isoketal adduction profoundly altered protein function, inhibiting potassium current in a dosedependent manner. These findings indicate that phospholipid-esterified isoketals rapidly adduct membrane proteins and that such modification can alter protein function, suggesting a generalized cellular mechanism for alteration of membrane function as a consequence of oxidative stress.Oxidative stress from the generation of free radicals has been implicated in the pathogenesis of a wide variety of human diseases including atherosclerosis, cancer, and neurodegenerative diseases (1-3). Fatty acids esterified in membrane phospholipids are a major target of attack by free radicals (4 -6). We have described previously the formation of a series of highly electrophilic ␥-ketoaldehyde isomers in vitro, which we term isoketals (IsoKs) 1 (7), by rearrangement of endoperoxide intermediates in the isoprostane pathway of free radical-induced peroxidation of phospholipid-esterified arachidonic acid (8). Incorporation of oxygen at different sites of arachidonyl radical formation results in the formation of 8 structural isomers, each of which is composed of 4 racemic diastereoisomers (see Fig. 1A). Analogous molecules, termed neuroketals, are formed from the free radical-catalyzed oxidation of docosahexanoic acid and form protein adducts analogous to those described below for IsoKs (9).IsoKs adduct covalently with the ⑀-amino group of lysine residues in vitro within seconds, which is orders of magnitude faster than has been reported for other products of lipid peroxidation, including 4-hydroxynonenal (7). This remarkable reactivity has precluded the detection of free IsoKs in vivo because of their sequestration as adducts. Therefore, we elucidated the nature of IsoK protein adducts in vitro as an initial step toward identifying the formation of IsoK adducts in vivo (7, 10). IsoKs initially form reversible Schiff base adducts which irreversibly cyclize to pyrroles. The pyrroles then undergo facile autoxidation to stable lactam and hydroxylactam adducts (see Fig. 1B) (7, 10). Consistent with this process, Schiff base adducts f...

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Section: Resultsmentioning

confidence: 99%

Modification of Proteins by Isoketal-containing Oxidized Phospholipids

Brame¹,

Boutaud

Davies

et al. 2004

Journal of Biological Chemistry

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“…These isoprostanes are potent vasoconstrictors that limit blood flow to the kidney, inducing ischaemia, acidosis and hence contribute to renal dysfunction. Isoprostanes have been found esterified to the tissue lipids which suggest they are formed in situ and released by phospholipases (20). In about 30% of patients diagnosed with rhabdomyolysis acute renal failure occurs, accounting for *7% of renal failure cases (21,22).…”

Section: Introductionmentioning

confidence: 99%

Histidine and not tyrosine is required for the Peroxide‐induced formation of haem to protein cross‐linked myoglobin

et al. 2007

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SummaryPeroxide-induced oxidative modifications of haem proteins such as myoglobin and haemoglobin can lead to the formation of a covalent bond between the haem and globin. These haem to protein cross-linked forms of myoglobin and haemoglobin are cytotoxic and have been identified in pathological conditions in vivo. An understanding of the mechanism of haem to protein cross-link formation could provide important information on the mechanisms of the oxidative processes that lead to pathological complications associated with the formation of these altered myoglobins and haemoglobins. We have re-examined the mechanism of the formation of haem to protein cross-link to test the previously reported hypothesis that the haem forms a covalent bond to the protein via the tyrosine 103 residue (Catalano, C. E., Choe, Y. S., Ortiz de Montellano, P. R., J. Biol. Chem. 1989, 10534 -10541).Comparison of native horse myoglobin, recombinant sperm whale myoglobin and Tyr 103 ! Phe sperm whale mutant shows that, contrary to the previously proposed mechanism of haem to protein cross-link formation, the absence of tyrosine 103 has no impact on the formation of haem to protein cross-links. In contrast, we have found that engineered myoglobins that lack the distal histidine residue either cannot generate haem to protein cross-links or show greatly suppressed levels of modified protein. Moreover, addition of a distal histidine to myoglobin from Aplysia limacina, that naturally lacks this histidine, restores the haem protein's capacity to generate haem to protein cross-links. The distal histidine is, therefore, vital for the formation of haem to protein cross-link and we explore this outcome. IUBMB Life, 59: 477-489, 2007

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“…11 Despite the many studies carried out on oxidative stress, there has not been a reliable and noninvasive method to monitor lipid peroxidation in vivo, as with the use of blood and urine. Some years ago, however, the group of Morrow et al 12 demonstrated the production of a series of prostaglandin F 2 -like compounds, named F 2 -isoprostanes, which are formed in vivo and in vitro by free radical-catalyzed peroxidation of phospholipid-bound arachidonic acid, 13 a pathway that is independent of the cyclooxygenase pathway. F 2 -isoprostanes might therefore be considered a reliable marker of oxidative stress (lipid peroxidation) 14 and thus be used to evaluate the oxidative status in a number of human pathologies, such as alcoholic liver disease and diabetes.…”

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confidence: 99%

F2-isoprostanes stimulate collagen synthesis in activated hepatic stellate cells: a link with liver fibrosis?

Comporti

Arezzini

Signorini

et al. 2005

Laboratory Investigation

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Carbon tetrachloride (CCl 4 )-induced hepatic fibrosis has been considered to be linked to oxidative stress and mediated by aldehydic lipid peroxidation products. In the present study, we investigated whether collagen synthesis is induced by F 2 -isoprostanes, the most proximal products of lipid peroxidation and known mediators of important biological effects. By contrast with aldehydes, F 2 -isoprostanes act through receptors able to elicit definite signal transduction pathways. In a rat model of CCl 4 -induced hepatic fibrosis, plasma F 2 -isoprostanes were markedly elevated for the entire experimental period; hepatic collagen content also increased. When hepatic stellate cells (HSCs) from normal liver were cultured with F 2 -isoprostanes in the concentration range found in the in vivo studies (10 À9 -10 À8 M), a striking increase in DNA synthesis (reversed by the thromboxane A 2 antagonist SQ 29 548), in cell proliferation and in collagen synthesis was observed. Total collagen content was similarly increased. Moreover, F 2 -isoprostanes markedly increased the production of transforming growth factor-b1 by U937 cells, considered a model of liver macrophages. The data provide evidence for the possibility that F 2 -isoprostanes generated by lipid peroxidation in hepatocytes mediate HSC proliferation and collagen production seen in hepatic fibrosis.

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Non-cyclooxygenase-derived prostanoids (F2-isoprostanes) are formed in situ on phospholipids.

Cited by 669 publications

References 28 publications

Modification of Proteins by Isoketal-containing Oxidized Phospholipids

Modification of Proteins by Isoketal-containing Oxidized Phospholipids

Histidine and not tyrosine is required for the Peroxide‐induced formation of haem to protein cross‐linked myoglobin

F2-isoprostanes stimulate collagen synthesis in activated hepatic stellate cells: a link with liver fibrosis?

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