Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.3.99.3 (acyl-CoA dehydrogenase)
 1,425 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To determine the importance of peroxisomes and mitochondria in hydroxyeicosatetraenoic acid (HETE) oxidation in vivo, urinary excretion of 12- and 15-HETE was measured in eight patients with a peroxisome deficiency disorder (Zellweger syndrome) showing normal mitochondrial beta-oxidation capacity, in three patients with a defect of mitochondrial long-chain fatty acid oxidation (long-chain acyl-CoA dehydrogenase deficiency), and in eight healthy subjects. 12- and 15-HETE were identified and quantified by gas chromatography/negative ion chemical ionization-mass spectrometry and specific RIA. The free compounds were found exclusively in the urine of peroxisome-deficient subjects (12-HETE: median 26 pg/mL, range 17-36 pg/mL; 15-HETE: median 40 pg/mL, range 29-61 pg/mL), whereas both compounds were below the detection limit (< 0.5 pg/mL) in the urine of patients with defective mitochondrial long-chain fatty acid oxidation and normal subjects (p < 0.002). These results implicate that peroxisomes are the main cellular organelle responsible for HETE oxidation in vivo. Analysis of HETE excretion in urine represents an additional new specific diagnostic tool in patients with Zellweger syndrome.
 ...
PMID:12- and 15-hydroxyeicosatetraenoic acid are excreted in the urine of peroxisome-deficient patients: evidence for peroxisomal metabolism in vivo. 882

Human skin fibroblasts convert [5,6,8,9,11,12,14,15-3H]arachidonic acid to two radiolabeled polar metabolites that accumulate in the culture medium. Previous studies identified the most abundant of these products as 4,7,10-hexadecatrienoic acid (16:3). We have now identified the second metabolite as 5,8-tetradecadienoic acid (14:2). Fibroblasts deficient in mitochondrial long-chain acyl coenzyme A dehydrogenase produce increased amounts of 14:2 from arachidonic acid. By contrast, Zellweger fibroblasts which are deficient in peroxisomal beta-oxidation do not convert arachidonic acid to either 14:2 or 16:3. These results demonstrate that 14:2 can be synthesized from arachidonic acid, that this oxidative process occurs in the peroxisomes, and that the pathway does not function in Zellweger's syndrome and similar diseases where there is a genetic deficiency in peroxisomal beta-oxidation.
 ...
PMID:Conversion of arachidonic acid to tetradecadienoic acid by peroxisomal oxidation. 925 Jun 15

Human skin fibroblasts can convert arachidonic acid to 14- and 16-carbon polyunsaturated fatty acid products by peroxisomal beta-oxidation. The purpose of this study was to determine whether similar products are formed from eicosapentaenoic acid (EPA) and whether EPA and arachidonic acid compete for utilization by this oxidative pathway. Three radiolabeled metabolites with shorter retention times than EPA on reverse-phase high-performance liquid chromatography accumulated in the medium during incubation of fibroblasts with [5,6,8,9,11,12,14,15,17,18-3H] EPA ([3H]EPA). These metabolites, which were not formed from [1-14C]EPA and were not detected in the cells, were identified as tetradecatrienoic acid (14:3n-3), hexadecatetraenoic acid (16:4n-3), and octadecatetraenoic acid (18:4n-3). The most abundant product under all of the conditions tested was 16:4n-3. [3H]EPA was converted to 16:4n-3 and 14:3n-3 by fibroblasts deficient in mitochondrial long-chain acyl CoA dehydrogenase, but not by Zellweger syndrome or acyl CoA oxidase mutants that are deficient in peroxisomal beta-oxidation. Competition studies indicated that 16:4n-3 formation from 5 microM [3H]EPA was reduced by 60% when 10 microM arachidonic acid was added, but the conversion of [3H]arachidonic acid to its chain-shortened products was not decreased by the addition of 10 microM EPA. These findings demonstrate that as in the case of arachidonic acid, chain-shortened polyunsaturated fatty acid products accumulate when EPA undergoes peroxisomal beta-oxidation. While EPA does not reduce arachidonic acid utilization by this pathway, it is possible that some biological actions of EPA may be mediated by the formation of the corresponding EPA products, 16:4n-3 and 14:3n-3.
 ...
PMID:Conversion of eicosapentaenoic acid to chain-shortened omega-3 fatty acid metabolites by peroxisomal oxidation. 961 Jul 64

The metabolic inactivation of leukotrienes proceeds by beta-oxidation from the omega-end. We investigated the importance of peroxisomes and mitochondria in LTB4 oxidation in vivo. LTB4 and its oxidation products were analysed after high-performance liquid chromatography separation by immunoassays and gas chromatography-mass spectrometry in the urine of patients with Zellweger syndrome, patients with long-chain acyl CoA dehydrogenase deficiency, and healthy controls. LTB4 (median 97; range 35-238 nmol/mol creatinine) and its omega-oxidation product omega-carboxy-LTB4 (median 898; range 267-4583 nmol/mol creatinine) were present and significantly increased in the urine of all patients with Zellweger syndrome compared to the controls (P <0.01). In contrast, LTB4 and omega-carboxy-LTB4 were below the detection limit (< 5 nmol/ mol creatinine) in patients with long-chain acyl CoA dehydrogenase deficiency and healthy controls. The beta-oxidation product omega-carboxy-tetranor-LTB3 was neither detectable in the urine of patients with Zellweger syndrome, patients with long-chain acyl CoA dehydrogenase deficiency nor in the controls (< 5 nmol/mol creatinine). Analysis of urinary leukotrienes represents an additional diagnostic tool in peroxisome deficiency disorders. Furthermore, these results clearly underline the essential role of peroxisomes in the oxidation of LTB4 in humans.
 ...
PMID:Increased urinary excretion of LTB4 and omega-carboxy-LTB4 in patients with Zellweger syndrome. 1034 Apr 43

Human skin fibroblasts converted [5,6,8,9,11,12,14,15-3H]arachidonic acid ([3H]20:4) to eicosatrienoic acid (20:3), but appreciable amounts of radiolabeled 20:3 were not detected in corresponding incubations with [1-(14)C]20:4. This indicates that the main pathway for synthesizing 20:3 from arachidonic acid in the fibroblast involves oxidative removal of the carboxyl group of arachidonic acid. Fibroblasts deficient in long-chain acyl coenzyme A dehydrogenase (LCAD) converted [3H]20:4 to [3H]20:3. However, Zellweger fibroblasts that are deficient in peroxisomal fatty acid oxidation did not, indicating that the oxidative removal of the carboxyl group occurs in the peroxisomes. [3H]Hexadecatrienoic acid (16:3) was the main product that accumulated when [3H]20:4 was incubated with normal, LCAD deficient, and very long-chain acyl coenzyme A dehydrogenase (VLCAD) deficient fibroblasts, but Zellweger fibroblasts did not form this product. Normal fibroblasts converted [3H]16:3 to radiolabeled 20:3 and arachidonic acid. These findings suggest that some of the 16:3 produced from arachidonic acid by peroxisomal beta-oxidation can be recycled and that this recycling process constitutes a novel pathway for the conversion of arachidonic acid to 20:3 in human fibroblasts.
 ...
PMID:Role of peroxisomal oxidation in the conversion of arachidonic acid to eicosatrienoic acid in human skin fibroblasts. 1047 Nov 25

Epoxyeicosatrienoic acids (EETs), the eicosanoid biomediators synthesized from arachidonic acid by cytochrome P450 epoxygenases, are inactivated in many tissues by conversion to dihydroxyeicosatrienoic acids (DHETs). However, we find that human skin fibroblasts convert EETs mostly to chain-shortened epoxy-fatty acids and produce only small amounts of DHETs. Comparative studies with [5,6,8,9,11,12,14,15-(3)H]11,12-EET ([(3)H]11,12-EET) and [1-(14)C]11,12-EET demonstrated that chain-shortened metabolites are formed by removal of carbons from the carboxyl end of the EET. These metabolites accumulated primarily in the medium, but small amounts also were incorporated into the cell lipids. The most abundant 11, 12-EET product was 7,8-epoxyhexadecadienoic acid (7,8-epoxy-16:2), and two of the others that were identified are 9, 10-epoxyoctadecadienoic acid (9,10-epoxy-18:2) and 5, 6-epoxytetradecaenoic acid (5,6-epoxy-14:1). The main epoxy-fatty acid produced from 14,15-EET was 10,11-epoxyhexadecadienoic acid (10, 11-epoxy-16:2). [(3)H]8,9-EET was converted to a single metabolite with the chromatographic properties of a 16-carbon epoxy-fatty acid, but we were not able to identify this compound. Large amounts of the chain-shortened 11,12-EET metabolites were produced by long-chain acyl CoA dehydrogenase-deficient fibroblasts but not by Zellweger syndrome and acyl CoA oxidase-deficient fibroblasts. We conclude that the chain-shortened epoxy-fatty acids are produced primarily by peroxisomal beta-oxidation. This may serve as an alternate mechanism for EET inactivation and removal from the tissues. However, it is possible that the epoxy-fatty acid products may have metabolic or functional effects and that the purpose of the beta-oxidation pathway is to generate these products.
 ...
PMID:Conversion of epoxyeicosatrienoic acids (EETs) to chain-shortened epoxy fatty acids by human skin fibroblasts. 1062 3

Cysteinyl leukotrienes (LTs) are potent lipid mediators which are predominantly eliminated via bile. Their metabolic inactivation and degradation proceeds by beta-oxidation. However, although bile is the optimal material for analysis of LTs in man, only very sparse data on bile LT concentration under normal or pathophysiological conditions exist. The aim of the present study was to present for the first time a complete profile of endogenous LTs in human bile and to investigate the importance of bile LT analysis in peroxisomal and mitochondrial beta-oxidation deficiency. Cysteinyl LTs and their oxidation metabolites were analysed after HPLC separation by specific immunoassays or gas chromatography-mass spectrometry. Under physiological conditions, LTs are found in human bile (n = 8) in the nanomolar range with LTD4 predominating, whereas the other LTs were present in similar amounts. In bile of a patient with a peroxisome biogenesis disorder (Zellweger syndrome, ZS) LTE(4) was found to be slightly increased, whereas both omega-oxidation metabolites of LTE4, omega-hydroxy-LTE4 and omega-carboxy-LTE4, were highly increased (about 12-18 times). The beta-oxidation metabolite omega-carboxy-tetranor-LTE3 was below the detection limit (< 0.1 nmol/l; controls 1.4 +/- 1.2 nmol/l). This abnormal profile demonstrates an impaired degradation of LTs in ZS. In contrast, patients with X-linked adrenoleukodystrophy (X-ALD), medium-chain acyl CoA dehydrogenase deficiency (MCAD) as well as very long-chain acyl CoA dehydrogenase deficiency (VLCAD) did not show any differences in their biliary profile of LTs compared to controls. Increased levels of the biologically active cysteinyl LTs in the bile of patients with ZS might be of pathophysiological significance in the course of the disease, e.g. contributing to liver injury. In addition, our data confirm that the beta-oxidation of cysteinyl LTs in vivo occurs in peroxisomes and not in mitochondria.
 ...
PMID:Analysis of cysteinyl leukotrienes and their metabolites in bile of patients with peroxisomal or mitochondrial beta-oxidation defects. 1519 81