Medium- and Long-Chain Dicarboxylic Aciduria in Patients with Zellweger Syndrome and Neonatal Adrenoleukodystrophy

Rocchiccioli, F.; Aubourg, Patrick; Bougnères, Pierre

doi:10.1203/00006450-198601000-00018

Cited by 62 publications

(28 citation statements)

References 14 publications

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“…Consistent with a previous report on the increased excretion of long-chain dicarboxylic acids, including C16, in patients with Zellweger syndrome and neonatal adrenoleukodystrophy (10), the mechanism behind the accumulation of dicarboxylic acylcarnitines is probably related to the microsomal generation of dicarboxylic acids. Under all conditions, there is some -oxidation of long-chain fatty acids, including C16:0 and C18:0, that produces the corresponding dicarboxylic acids, followed by activation by a microsomal dicarboxylyl-CoA synthetase (11).…”

Section: Discussionsupporting

confidence: 77%

Characteristic Acylcarnitine Profiles in Inherited Defects of Peroxisome Biogenesis: A Novel Tool for Screening Diagnosis Using Tandem Mass Spectrometry

et al. 2003

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Section: Discussionsupporting

confidence: 77%

Characteristic Acylcarnitine Profiles in Inherited Defects of Peroxisome Biogenesis: A Novel Tool for Screening Diagnosis Using Tandem Mass Spectrometry

et al. 2003

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“…In contrast, plasma levels of docosanoic acid (C22:0) are decreased in these patients (18). An excess of long-chain hydroxylated fatty acids and dicarboxylic acids was found in urine of patients with peroxisomal biogenesis disorders (19). Based on these data, we postulate that -oxidation of (very) long-chain fatty acids may provide an alternative route for fatty acid metabolism.…”

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confidence: 63%

Evidence for two enzymatic pathways for ω-oxidation of docosanoic acid in rat liver microsomes

Sanders

Ofman

Valianpour

et al. 2005

Journal of Lipid Research

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We studied the -oxidation of docosanoic acid (C22:0) in rat liver microsomes. C22:0 and 22-hydroxydocosanoic acid ( -hydroxy-C22:0) were used as substrates, and the reaction products were analyzed by electrospray ionization mass spectrometry. In the presence of NADPH, -oxidation of C22:0 produced not only the hydroxylated product, -hydroxy-C22:0, but also the dicarboxylic acid of C22:0, docosanedioic acid (C22:0-DCA). When rat liver microsomes were incubated with -hydroxy-C22:0 in the presence of either NAD ؉ or NADPH, C22:0-DCA was formed readily. Formation of C22:0-DCA from either C22:0 or -hydroxy-C22:0 with NADPH as cofactor was inhibited strongly by miconazole and disulfiram, whereas no inhibition was found with NAD ؉ as cofactor. Furthermore, -oxidation of C22:0 was reduced significantly when molecular oxygen was depleted. The high sensitivity toward the more specific cytochrome P450 inhibitors ketoconazole and 17-octadecynoic acid suggests that hydroxylation of C22:0 and -hydroxy-C22:0 may be catalyzed by one or more cytochrome P450 hydroxylases belonging to the CYP4A and/or CYP4F subfamily. This study demonstrates that C22:0 is a substrate for the -oxidation system in rat liver microsomes and that the product of the first hydroxylation step, -hydroxy-C22:0, may undergo further oxidation via two distinct pathways driven by NAD ؉ or NADPH. -Sanders, R-J., R. Ofman, F. Valianpour, S. Kemp, and R. J. A. Wanders. Evidence for two enzymatic pathways for -oxidation of docosanoic acid in rat liver microsomes. J. Lipid Res. 2005. 46: 1001-1008.

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“…decanedioyl-and octadecanedioyl-carnitine in plasma of PBD patients by tandem mass spectrometry (11) and the excretion of C16DCA in urine of PBD patients (9). The small residual activity found could be either mitochondrial or result from peroxisomal enzymes mislocalized in the cytosol.…”

Section: Downloaded Frommentioning

confidence: 99%

Identification of the peroxisomal β-oxidation enzymes involved in the degradation of long-chain dicarboxylic acids

Ferdinandusse

Denis

Roermund

et al. 2004

Journal of Lipid Research

127

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Dicarboxylic acids (DCAs) are -oxidation products of monocarboxylic acids. After activation by a dicarboxylyl-CoA synthetase, the dicarboxylyl-CoA esters are shortened via ␤ -oxidation. Although it has been studied extensively where this ␤ -oxidation process takes place, the intracellular site of DCA oxidation has remained controversial. Making use of fibroblasts from patients with defined mitochondrial and peroxisomal fatty acid oxidation defects, we show in this paper that peroxisomes, and not mitochondria, are involved in the ␤ -oxidation of C16DCA. Additional studies in fibroblasts from patients with X-linked adrenoleukodystrophy, straight-chain acyl-CoA oxidase (SCOX) deficiency, d -bifunctional protein (DBP) deficiency, and rhizomelic chondrodysplasia punctata type 1, together with direct enzyme measurements with human recombinant l -bifunctional protein (LBP) and DBP expressed in a fox2 deletion mutant of Saccharomyces cerevisiae , show that the main enzymes involved in ␤ -oxidation of C16DCA are SCOX, both LBP and DBP, and sterol carrier protein X, possibly together with the classic 3-ketoacyl-CoA thiolase. This is the first indication of a specific function for LBP, which has remained elusive until now. -Ferdinandusse, S., S. Denis, C. W. T. van Roermund, R. J. A. Wanders, and G. Dacremont. Identification of the peroxisomal ␤ -oxidation enzymes involved in the degradation of long-chain dicarboxylic acids.

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Medium- and Long-Chain Dicarboxylic Aciduria in Patients with Zellweger Syndrome and Neonatal Adrenoleukodystrophy

Cited by 62 publications

References 14 publications

Characteristic Acylcarnitine Profiles in Inherited Defects of Peroxisome Biogenesis: A Novel Tool for Screening Diagnosis Using Tandem Mass Spectrometry

Characteristic Acylcarnitine Profiles in Inherited Defects of Peroxisome Biogenesis: A Novel Tool for Screening Diagnosis Using Tandem Mass Spectrometry

Evidence for two enzymatic pathways for ω-oxidation of docosanoic acid in rat liver microsomes

Identification of the peroxisomal β-oxidation enzymes involved in the degradation of long-chain dicarboxylic acids

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