Research interests

In recent years, much progress has been made with respect to the unravelling of the functions of peroxisomes in metabolism, and it is now well established that peroxisomes are indispensable organelles, especially in higher eukaryotes. Peroxisomes catalyse a number of essential metabolic functions including fatty acid beta-oxidation, ether phospholipid biosynthesis, fatty acid a-oxidation and glyoxylate detoxification. The involvement of peroxisomes in these metabolic pathways necessitates the transport of metabolites in and out of peroxisomes. Recently, considerable progress has been made in the characterization of metabolite transport across the peroxisomal membrane. Peroxisomes posses several specialized transport systems to transport metabolites. This is exemplified by the identification of a specific transporter for adenine nucleotides and several half-ABC (ATP-binding cassette) transporters (ABCD1-3) which may be present as hetero- and homo-dimers. The importance to investigate permeability properties of the peroxisomal membrane is underlined by the existence of a number of different genetic diseases. One of these peroxisomal disorders is X-linked adrenoleukodystrophy (X-ALD). The gene mutated in X-linked adrenoleukodystrophy (X-ALD) codes for the HsABCD1 protein, a member of the superfamily of ATP-binding cassette (ABC) transporters and required for fatty acid transport across the peroxisomal membrane. Although defective HsABCD1 results in the accumulation of very long-chain fatty acids in plasma of X-ALD patients, there is still no direct biochemical evidence that HsABCD1 actually transports very long-chain fatty acids.

To study the transport of fatty acids across the peroxisomal membrane and their metabolism in vivo we have chosen Saccharomyces cerevisiae as a model system. An important advantage of studies in the yeast S. cerevisiae is that peroxisomes are the only organelles in which beta-oxidation of fatty acids takes place, in contrast to the situation in mammalian cells. In the latter case peroxisomes as well as mitochondria participate in fatty acid oxidation. Secondly, we study the mechanism of metabolic transport in vitro by  functional reconstitution of peroxisomal transporters into proteoliposomes. The resolution of the mechanism of these transporters is utmost significance for our thinking about peroxisomal disorders e.g. X-linked adrenoleukodystrophy and its pathophysiological mechanisms and future therapies.

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