Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: CAS:75715-89-8 (LTE4)
 797 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chain shortening via beta-oxidation from the omega-end has been recognized as the major pathway for the degradation of cysteinyl leukotrienes as well as leukotriene B4 (LTB4). The metabolic compartmentation of this pathway was studied using peroxisomes purified from normal and clofibrate-treated rat liver. beta-Oxidation products of omega-carboxy-LTB4, including omega-carboxy-dinor-LTB4 identified by gas chromatography-mass spectrometry, were formed by the isolated peroxisomes. The reaction was dependent on CoA, ATP, and NAD and was stimulated by FAD. NADPH was necessary for the further metabolism of omega-carboxy-dinor-LTB4. Together with microsomes a degradation of omega-carboxy-LTB4 also proceeded in isolated mitochondria in the presence of CoA, ATP, and carnitine. beta-Oxidation of the cysteinyl leukotriene omega-carboxy-N-acetyl-leukotriene E4 was observed only with isolated peroxisomes in combination with lipid-depleted microsomes. Direct photoaffinity labeling using omega-carboxy-[3H] LTB4 and omega-carboxy-N-[3H]acetyl-LTE4 served to identify peroxisomal leukotriene-binding proteins. The bifunctional protein (EC 4.2.1.17 and 1.1.1.35) and 3-ketoacyl-CoA thiolase (EC 2.3.1.16) of the peroxisomal beta-oxidation system were the predominantly labeled polypeptides as revealed by precipitation with monospecific antibodies. In vivo studies with N-acetyl-[3H2]LTE4, N-acetyl-[3H8]LTE4, and N-[14C]acetyl-LTE4 after treatment with the peroxisome proliferator clofibrate indicated formation and biliary excretion of large amounts of metabolites more polar than omega-carboxy-tetranor-N-acetyl-LTE3 including omega-carboxy-tetranor-delta 13-N-acetyl-LTE4 and omega-carboxy-hexanor-N-acetyl-LTE3. Increased formation of beta-oxidized catabolites of N-acetyl-LTE4 and LTB4 was also observed in hepatocytes isolated after clofibrate treatment. Our results indicate that peroxisomes play a major role in the beta-oxidation of leukotrienes from the omega-end. Whereas omega-carboxy-LTB4 was beta-oxidized both in isolated peroxisomes and mitochondria, the cysteinyl leukotriene omega-carboxy-N-acetyl-LTE4 was exclusively degraded in peroxisomes.
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PMID:Peroxisomal degradation of leukotrienes by beta-oxidation from the omega-end. 176 71

Degradation of the cysteinyl leukotrienes LTE4 and N-acetyl-LTE4, and of LTB4 by beta-oxidation from the omega-end has been recognized as an important pathway in the inactivation of these mediators. The contribution of peroxisomes to leukotriene degradation and inactivation was studied in isolated hepatocytes, in isolated liver peroxisomes, and in patients with inherited peroxisome deficiency. (1) Isolated hepatocytes from rats pretreated with the peroxisome proliferator clofibrate produced highly increased amounts of beta-oxidation products derived from omega-carboxy-LTB4 and omega-carboxy-N-acetyl-LTE4 as compared to normal hepatocytes. (2) Isolated peroxisomes purified from normal and clofibrate-treated liver produced omega-carboxy-dinor-LTB4 and omega-carboxy-tetranor-LTB3 when nucleotide cofactors, including CoA, ATP, NAD+, FAD, and NADPH, were added. beta-Oxidation of the cysteinyl leukotriene omega-carboxy-N-acetyl-LTE4 was observed only with isolated peroxisomes together with a microsome fraction providing an acyl-CoA synthetase activity. (3) Peroxisomal leukotriene-binding proteins were identified by photo-affinity labeling with omega-carboxy-[3H]leukotrienes and precipitation of labeled polypeptides with antibodies against enzymes of the peroxisomal beta-oxidation system. (4) Peroxisomal degradation of leukotrienes in humans was studied by analyses of endogenous leukotrienes and their catabolites in urine from patients with an inherited peroxisomal deficiency disorder (Zellweger syndrome) and healthy infant controls. Urinary LTE4, relative to creatinine, was increased 10-fold in the patients, whereas the beta-oxidation product omega-carboxy-tetranor-LTE3 was only detectable in healthy infants. In addition, LTB4 was exclusively detected in the urine of patients with peroxisome deficiency. The increased levels of biologically active, proinflammatory mediators might be of pathophysiological significance. In addition, the altered pattern of leukotriene metabolites in urine may be of diagnostic value. The measurements in these patients underline the essential role of peroxisomes in the catabolism and inactivation of leukotrienes in humans.
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PMID:Peroxisomal leukotriene degradation: biochemical and clinical implications. 835 7