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The pfr1 gene from the human pathogenic fungus Paracoccidioides brasiliensis encodes a half-ABC transporter that is transcribed in response to treatment with fluconazole.
Gray, Christopher H; Ines Borges-Walmsley, M; Evans, Gareth J; Walmsley, Adrian R.
Afiliação
  • Gray CH; Centre for Infectious Diseases, Wolfson Research Institute, University of Durham, Queen's Campus, Stockton-on-Tees TS17 6BH, UK.
Yeast ; 20(10): 865-80, 2003 Jul 30.
Article em En | MEDLINE | ID: mdl-12868056
We have isolated a gene that encodes a half-ABC-transporter, designated Pfr1, from the dimorphic human pathogenic fungus Paracoccidioides brasiliensis, which has high identity with members of the ABC-superfamily involved in multidrug resistance. The pfr1 gene is predicted to encode a 827 amino acid protein that, in common with mammalian Mdr1, has a TM-NBD topology. The transcription of the pfr1 gene is induced by the triazole drug fluconazole but not by amphotericin B, suggesting a role in transport-mediated azole resistance. However, Pfr1 has greatest identity to the mitochondrial ABC transporters Mdl1 and Mdl2 from Saccharomyces cerevisiae and mammalian ABC-me, with identities of 47.2%, 40.6% and 39.5%, respectively, over the length of these proteins. Furthermore, the N-terminus of Pfr1 is rich in positively charged residues, a feature of mitochondrial targeting sequences. Considering these features, it seems likely that Pfr1 is a mitochondrial protein. Previous studies have revealed that the acquisition of azole resistance in S. cerevisiae is linked to mitochondrial loss and, conversely, that mitochondrial dysfunction can lead to the upregulation of PDR transporters mediated by the transcription factor Pdr3. Our studies suggest that a mitochondrial ABC transporter is induced as part of the cellular response to drug treatment. The promoter region of pfr1 contains a PDRE-like consensus sequence to which Pdr3 binds, which may be the element responsible for the upregulation of Pfr1 in response to fluconazole. The nucleotide binding domain of Pfr1 was expressed and purified from Escherichia coli and shown to retain ATPase activity, consistent with Pfr1 functioning as a homodimeric transport ATPase.
Assuntos
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Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Paracoccidioides / Proteínas Fúngicas / Fluconazol / Transportadores de Cassetes de Ligação de ATP / Genes Fúngicos / Antifúngicos Tipo de estudo: Prognostic_studies Limite: Humans País/Região como assunto: America do sul / Brasil Idioma: En Revista: Yeast Assunto da revista: MICROBIOLOGIA Ano de publicação: 2003 Tipo de documento: Article País de publicação: Reino Unido
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Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Paracoccidioides / Proteínas Fúngicas / Fluconazol / Transportadores de Cassetes de Ligação de ATP / Genes Fúngicos / Antifúngicos Tipo de estudo: Prognostic_studies Limite: Humans País/Região como assunto: America do sul / Brasil Idioma: En Revista: Yeast Assunto da revista: MICROBIOLOGIA Ano de publicação: 2003 Tipo de documento: Article País de publicação: Reino Unido