Subcellular localization and physiological role of alpha-methylacyl-CoA racemase

alpha -Methylacyl-CoA racemase plays an important role in the beta -oxidati on of branched-chain fatty acids and fatty acid derivatives because it cata lyzes the conversion of several (2R)-methyl-branched-chain fatty acyl-CoAs to their (S)-stereoisomers. Only stereoisomers with the 2-methyl group in t he (S)-configuration can be degraded via beta -oxidation. Patients with a d eficiency of alpha -methylacyl-CoA racemase accumulate in their plasma pris tanic acid and the bile acid intermediates di- and trihydroxycholestanoic a cid, which are all substrates of the peroxisomal beta -oxidation system. Su bcellular fractionation experiments, however, revealed that both in humans and rats alpha -methylacyl-CoA racemase is bimodally distributed to both th e peroxisome and the mitochondrion. Our findings show that the peroxisomal and mitochondrial enzymes are produced from the same gene and that, as a co nsequence, the bimodal distribution pattern must be the result of different ial targeting of the same gene product. In addition, we investigated the ph ysiological role of the enzyme in the mitochondrion. Both in vitro studies with purified heterologously expressed protein and in vivo studies in fibro blasts of patients with an alpha -methylacyl-CoA racemase deficiency reveal ed that the mitochondrial enzyme plays a crucial role in the mitochondrial beta -oxidation of the breakdown products of pristanic acid by converting ( 2R,6)-dimethylheptanoyl-CoA to its (S)-stereoisomer.