The long term objectives of this research are to understand the biogenesis of peroxisomes in molecular detail and to identify and characterize human genes that cause fatal illness due to failure of peroxisome biogenesis. Peroxisomes are nearly ubiquitous in eukaryotic cells and have several essential functions, including fatty acid catabolism and the first steps in plasmalogen biosynthesis. Several fatal inherited disorders (including Zellweger syndrome and rhizomelic chondrodysplasia punctata (RCDP)) are causes by defects in peroxisome biogenesis. The accumulated evidence demonstrates a branched pathway of peroxisomal protein import, with each branch representing an import receptor specific for one of several types of peroxisome targeting sequences (PTS), followed by s shared membrane translocation process. Great progress has been made in identifying genes that are required for the biogenesis of peroxisomes; currently 17 are known in yeast. Studies of yeast as a model organism have proven to be valuable in identifying human disease genes. For example, we have cloned and characterized Pex7p, a yeast receptor for the type 2 peroxisomal targeting signal (PTS2). Phenotypic similarity between RCDP patients' fibroblasts and yeast pex7 mutants led us to clone the human PEX7 homolog, and show that defects in this gene cause RCDP. Transformation of wild type human PEX7 into patient fibroblasts cured the biochemical defects of these cells. We have obtained considerable evidence indicating (unexpectedly) that the PTS2 receptor functions within peroxisomes, and within peroxisomes, and have formulated several hypotheses for its mechanism of action; critical of these alternatives are planned. We have discovered two novel proteins that are essential for the import of PTS2- targeted proteins into peroxisomes, and have new data suggesting the existence of others. A human homolog of one of these novel proteins has also been identified, which is predicted to be another human disease gene. These discoveries form the basis for future work. The planned studies should provide fundamental new information about an intriguing problem in cell biology, peroxisome biogenesis, and may also lead to useful therapeutic applications to human diseases.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Molecular Cytology Study Section (CTY)
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Haft, Carol R
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Mount Sinai School of Medicine
Anatomy/Cell Biology
Schools of Medicine
New York
United States
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Nair, Devi M; Purdue, P Edward; Lazarow, Paul B (2004) Pex7p translocates in and out of peroxisomes in Saccharomyces cerevisiae. J Cell Biol 167:599-604
Lazarow, Paul B (2003) Peroxisome biogenesis: advances and conundrums. Curr Opin Cell Biol 15:489-97
Yang, X; Purdue, P E; Lazarow, P B (2001) Eci1p uses a PTS1 to enter peroxisomes: either its own or that of a partner, Dci1p. Eur J Cell Biol 80:126-38
Purdue, P E; Lazarow, P B (2001) Peroxisome biogenesis. Annu Rev Cell Dev Biol 17:701-52
Purdue, P E; Lazarow, P B (2001) Pex18p is constitutively degraded during peroxisome biogenesis. J Biol Chem 276:47684-9
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Purdue, P E; Skoneczny, M; Yang, X et al. (1999) Rhizomelic chondrodysplasia punctata, a peroxisomal biogenesis disorder caused by defects in Pex7p, a peroxisomal protein import receptor: a minireview. Neurochem Res 24:581-6
Purdue, P E; Yang, X; Lazarow, P B (1998) Pex18p and Pex21p, a novel pair of related peroxins essential for peroxisomal targeting by the PTS2 pathway. J Cell Biol 143:1859-69
Purdue, P E; Zhang, J W; Skoneczny, M et al. (1997) Rhizomelic chondrodysplasia punctata is caused by deficiency of human PEX7, a homologue of the yeast PTS2 receptor. Nat Genet 15:381-4
Zhang, J W; Lazarow, P B (1996) Peb1p (Pas7p) is an intraperoxisomal receptor for the NH2-terminal, type 2, peroxisomal targeting sequence of thiolase: Peb1p itself is targeted to peroxisomes by an NH2-terminal peptide. J Cell Biol 132:325-34

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