PXA1, A POSSIBLE SACCHAROMYCES-CEREVISIAE ORTHOLOG OF THE HUMAN ADRENOLEUKODYSTROPHY GENE

The adrenoleukodystrophy protein (ALDp) is an ATP binding cassette (AB C) transporter in the human peroxisome membrane. It is defective in X chromosome-linked adrenoleukodystrophy (ALD), a neurodegenerative diso rder with impaired peroxisomal oxidation of very long chain fatty acid s. We report cloning and characterization of PXA1, a yeast gene encodi ng a protein (Pxa1p) exhibiting high similarity to ALDp. Disruption of PXA1 results in impaired growth on oleic acid and reduced ability to oxidize oleate. Pxa1p is peroxisome associated; however, in the PXA1 m utant yeast, as in ALD cells, peroxisomes are morphologically intact. Disruption of a second yeast gene, YKL741, which encodes a more distan tly related ALDp homolog (Yk174p), in either wild-type or PXA1 mutant yeast, results in a growth phenotype identical to that of the PXA1 mut ant. This result suggests that Yk1741p and Pxa1p may be subunits of th e same transporter. Sequence analysis of Pxa1p, ALDp, and related ABC transporters reveals a possible fatty acid binding domain and a 14-ami no acid EAA-like motif, previously described only in prokaryotes. Beca use of the similarities in sequence and function, we propose that Pxa1 p is the Saccharomyces cerevisiae ortholog of ALDp.