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Journal of Lipid Research, Vol. 42, 137-141, January 2001
Copyright © 2001 by Lipid Research, Inc.

Original Article

Plasma analysis of di- and trihydroxycholestanoic acid diastereoisomers in peroxisomal -methylacyl-CoA racemase deficiency

Correspondence to: Peter Vreken, at the University of Amsterdam Academic Medical Center, Laboratory of Genetic Metabolic Diseases, F0-224, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands., p.vreken{at}amc.uva.nl (E-mail)

We identified a new peroxisomal disorder caused by a deficiency of the enzyme -methylacyl-coenzyme A (CoA) racemase. Patients with this disorder show elevated plasma levels of pristanic acid and the bile acid intermediates di- and trihydroxycholestanoic acid (DHCA and THCA), which are all substrates for the peroxisomal ß-oxidation system. -Methylacyl-CoA racemase plays an important role in the ß-oxidation of branched-chain fatty acids and fatty acid derivatives because it catalyzes the conversion of several (2R)-methyl-branched-chain fatty acyl-CoAs to their (2S)-isomers. Only stereoisomers with the 2-methyl group in the (S)-configuration can be degraded via ß-oxidation. In this study we used liquid chromatography/tandem mass spectrometry (LC-MS/MS) to analyze the bile acid intermediates that accumulate in plasma from patients with a deficiency of -methylacyl-CoA racemase and, for comparison, in plasma from patients with Zellweger syndrome and patients with cholestatic liver disease.

We found that racemase-deficient patients accumulate exclusively the (R)-isomer of free and taurine-conjugated DHCA and THCA, whereas in plasma of patients with Zellweger syndrome and patients with cholestatic liver disease both isomers were present. On the basis of these results we describe an easy and reliable method for the diagnosis of -methylacyl-CoA racemase-deficient patients by plasma analysis. Our results also show that -methylacyl-CoA racemase plays a unique role in bile acid formation. — Ferdinandusse, S., H. Overmars, S. Denis, H. R. Waterham, R. J. A. Wanders, and P. Vreken. Plasma analysis of di- and trihydroxycholestanoic acid diastereoisomers in peroxisomal -methylacyl-CoA racemase deficiency. J. Lipid Res. 2001. 42: 137;–141.

Supplementary key words: bile acid intermediates, peroxisomal ß-oxidation, stereochemistry

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