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

Sacha Ferdinandusse,Simone Denis,Carlo W.T Van Roermund,Ronald J.A Wanders,Georges Dacremont

doi:10.1194/jlr.m300512-jlr200

Sacha Ferdinandusse, Simone Denis + Show 3 more

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https://doi.org/10.1194/jlr.m300512-jlr200

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Abstract

Dicarboxylic acids (DCAs) are omega-oxidation products of monocarboxylic acids. After activation by a dicarboxylyl-CoA synthetase, the dicarboxylyl-CoA esters are shortened via beta-oxidation. Although it has been studied extensively where this beta-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 beta-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 beta-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.

Highlights

Dicarboxylic acids (DCAs) are ␻-oxidation products of monocarboxylic acids
Fibroblasts from patients with a mitochondrial fatty acid oxidation defect revealed normal ␤-oxidation activities compared with the activity measured in control fibroblasts
We studied the involvement of different peroxisomal ␤-oxidation enzymes in the oxidation of [1614C]16DCA and found normal activities in fibroblasts from patients suffering from X-linked adrenoleukodystrophy (XALD), rhizomelic chondrodysplasia punctata (RCDP) type 1, and d-bifunctional protein (DBP) deficiency but strongly reduced oxidation activities in fibroblasts from patients with straight-chain acyl-CoA oxidase (SCOX) deficiency (Table 1)

Summary

Introduction

Dicarboxylic acids (DCAs) are ␻-oxidation products of monocarboxylic acids. After activation by a dicarboxylyl-CoA synthetase, the dicarboxylyl-CoA esters are shortened via ␤-oxidation. 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 fox 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. Fatty acids are first converted into ␻-hydroxymonocarboxylic acids by a microsomal cytochrome P450 and further oxidized to ␻-ketomonocarboxylic acids and DCAs through the sequential action of cytosolic long-chain alcohol and aldehyde dehy-

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