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Identification of the pathway of α-oxidation of cerebronic acid in peroxisomes

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Lipids

Abstract

Cerebronic acid (2-hydroxytetracosanoic acid), an α-hydroxy very long-chain fatty acid (VLCFA) and a component of cerebrosides and sulfatides, is unique to nervous tissues. Studies were carried out to identify the pathway and the subcellular site involved in the oxidation of cerebronic acid. The results from these studies revealed that cerebronic acid was catabolized by α-oxidation to CO2 and tricosanoic acid (23:0). Studies with subcellular fractions indicated that cerebronic acid was α-oxidized in fractions having particulate bound catalase and enzyme systems for the β-oxidation of VLCFA (e.g., lignoceric acid), suggesting peroxisomes as the subcellular organelle responsible for α-oxidation of cerebronic acid. Etomoxir, an inhibitor of mitochondrial fatty acid oxidation, had no effect on cerebronic acid α-oxidation. Further, cerebronic acid oxidation was found to be dependent on the presence of NAD+ but not FAD, NADPH, ATP, Mg2+, or CoASH. Intraorganellar localization studies indicated that the enzyme system for the α-oxidation of cerebronic acid was associated with the peroxisomal limiting membranes. Studies on cultured fibroblasts from normal subjects and patients with peroxisomal disorders indicated an impairment of α-oxidation of cerebronic acid in cell lines that lack peroxisomes [e.g., Zellweger syndrome (ZS)]. On the other hand, α-oxidation of cerebronic acid was found to be normal in cell lines from X-linked adrenoleukodystrophy, adult Refsum disease, and rhizomelic chondrodysplasia punctata. Our results clearly demonstrate that α-oxidation of α-hydroxy VLCFA (cerebronic acid) is a peroxisomal function and that this oxidation is impaired in ZS. Furthermore, this α-oxidation enzyme system is distinct from the one for the α-oxidation of β-carbon branched-chain fatty acids (e.g., phytanic acid).

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Abbreviations

DMEM:

Dulbecco's modified Eagle's minimum essential medium

BCS:

bovine calf serum

MOPS:

3-(N-morpholino)propanesulfonic acid

PBr3 :

phosphorus tribromide

PMSF:

phenylmethylsulfonyl fluoride

RCDP:

rhizomelic chondrodysplasia punctata

RD:

Refsum disease

VLCFA:

very long-chain fatty acid

X-ALD:

X-linked adrenoleukodystrophy

ZS:

Zellweger syndrome

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Authors and Affiliations

  1. Department of Pediatrics, Medical University of South Carolina, 171 Ashley Ave., 29425, Charleston, SC

    Rajat Sandhir, Mushfiquddin Khan & Inderjit Singh

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  1. Rajat Sandhir
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  2. Mushfiquddin Khan
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  3. Inderjit Singh
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Correspondence to Inderjit Singh.

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Sandhir, R., Khan, M. & Singh, I. Identification of the pathway of α-oxidation of cerebronic acid in peroxisomes. Lipids 35, 1127–1133 (2000). https://doi.org/10.1007/s11745-000-0628-5

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  • DOI: https://doi.org/10.1007/s11745-000-0628-5

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