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Journal of Lipid Research, Vol. 41, 1752-1759, November 2000
Copyright © 2000 by Lipid Research, Inc.

Original Article

Mitochondrial and peroxisomal targeting of 2-methylacyl-CoA racemase in humans

Correspondence to: Paul P. Van Veldhoven

2-Methylacyl-CoA racemase is an auxiliary enzyme required for the peroxisomal ß-oxidative breakdown of (2R)-pristanic acid and the (25R)-isomer of C₂₇ bile acid intermediates. The enzyme activity is found not only in peroxisomes but also is present in mitochondria of human liver and fibroblasts. The C terminus of the human racemase, a protein of 382 amino acids with a molecular mass of 43,304 daltons as deduced from its cloned cDNA, consists of KASL. Hitherto this sequence has not been recognized as a peroxisomal targeting signal (PTS1). From the in vitro interaction between recombinant racemase and recombinant human PTS1 receptor (Pex5p), and the peroxisomal localization of green fluorescent protein (GFP) fused to the N terminus of full-length racemase or its last six amino acids in tranfected Chinese hamster ovary (CHO) cells, we concluded that ASL is a new PTS1 variant. To be recognized by Pex5p, however, the preceding lysine residue is critical. As shown in another series of transfection experiments with GFP fused to the C terminus of the full-length racemase or racemase with deletions of the N terminus, mitochondrial targeting information is localized between amino acids 22 and 85.

Hence, our data show that a single transcript gives rise to a racemase protein containing two topogenic signals, explaining the dual cellular localization of the activity. — Amery, L., M. Fransen, K. De Nys, G. P. Mannaerts, and P. P. Van Veldhoven. Mitochondrial and peroxisomal targeting of 2-methylacyl-CoA racemase in humans. J. Lipid Res. 2000. 41: 1752;–1759.

Supplementary key words: cholestanoic acid, pristanic acid, ß-oxidation, peroxins, bile acids, epimerase

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