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New insights in peroxisomal beta-oxidation
Ferdinandusse, S.
Publication date
2002
Link to publication
Citation for published version (APA):
Ferdinandusse, S. (2002). New insights in peroxisomal beta-oxidation.
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ChapterChapter 1
Introduction n
Peroxisomess play a major role in whole cell fatty acid P-oxidation by catalyzing the oxidativee chain-shortening of a range of fatty acids and fatty acid derivatives, which cannot bee broken down by mitochondria. Substrates of the peroxisomal P-oxidation system includee both straight-chain fatty acids, like the very long-chain fatty acids C26:0 and C24:0,, and 2-methyl-branched-chain fatty acids, like pristanic acid and the bile acid intermediatess di- and trihydroxycholestanoic acid (DHCA and THCA). The importance off the peroxisomal pi-oxidation system is stressed by the existence of a variety of different diseasess in which peroxisomal p-oxidation is impaired. Extensive research has been performedd on the peroxisomal p-oxidation system and in the past years the knowledge has expandedd rapidly, especially with the discovery of a second set of peroxisomal p-oxidation enzymess and the identification of patients with a deficiency of one of these enzymes, D-bifunctionall protein. Many questions remained, however, and the purpose of the studiess described in this thesis was to resolve at least some of these questions.
Thee main focus of this thesis is on the p-oxidation of branched-chain fatty acids and thee bile acid intermediates and on patients in whom p-oxidation of these substrates is affected.. In chapter two a short review of the current knowledge of the peroxisomal p-oxidationn system is given. Chapter three describes the molecular cloning and expression off human carnitine octanoyltransferase (COT) and evidence is presented which shows that COTT is involved in the peroxisomal p-oxidation of branched-chain fatty acids. In chapter fourr patients discribed in literature with an unresolved defect in peroxisomal p-oxidation aree investigated for a deficiency of sterol carrier protein X (SCPx), one of the peroxisomal thiolases,, using a newly developed method to measure SCPx activity. In chapter five the onlyy patient ever reported with peroxisomal 3-ketoacyl-CoA thiolase deficiency is reinvestigated.. Chapter six describes the identification of patients with a deficiency of a-methylacyl-CoAA racemase and in chapter seven the physiological role and the subcellularr localization of this enzyme is further investigated. In chapter eight and nine thee stereochemistry of the peroxisomal fatty acid oxidation systems is studied and in particularr the role of a-methylacyl-CoA racemase therein. In plasma from patients with differentt peroxisomal fatty acid oxidation disorders the diastereomers of DHCA, THCA andd of phytanic acid, pristanic acid and the metabolites of pristanic acid were analyzed. In chapterr ten, cell lines of many different patients with an established deficiency of mitochondriall or peroxisomal fatty acid oxidation are used to investigate the subcellular localizationn of the last step of the biosynthesis of docosahexaenoic acid (DHA), an importantt polyunsaturated fatty acid. In addition, it is studied which of the peroxisomal P-oxidationn enzymes are involved in this process.
