TAILIEUCHUNG - Báo cáo khoa học: Biochemical characterization of recombinant dihydroorotate dehydrogenase from the opportunistic pathogenic yeast Candida albicans

Candida albicansis the most prevalent yeast pathogen in humans, and recently it has become increasingly resistant to the current antifungal agents. In this study we investigatedC. albicansdihydroorotate dehydroge-nase (DHODH, EC ), which catalyzes the fourth step ofde novo pyrimidine synthesis, as a new target for controlling infection. | ềFEBS Journal Biochemical characterization of recombinant dihydroorotate dehydrogenase from the opportunistic pathogenic yeast Candida albicans Elke Zameitat1 Zoran Gaikovic Wolfgang Knecht2 1 Jure Piskur2 1 and Monika Loffler1 1 Institute for PhysiologicalChemistry Philipps-University Marburg Germany 2 BioCentrum-DTU TechnicalUniversity of Denmark Lyngby Denmark Keywords antimycotics Candida albicans dihydroorotate dehydrogenase pyrimidines redoxal Correspondence E. Zameitat or M. Loftier Institute for PhysiologicalChemistry Philipps-University Karl-von-Frisch-Str. 1 D-35033 Marburg Germany Fax 49 6421 2865116 Tel 49 6421 2865022 E-mail zameitat@ loeffler@ Present address AstraZeneca R D Môlndal SE-431 83 Molndal Sweden flZGene A S Anker Engelundsvej1 Building 301 2800 Lyngby Denmark Department of Celland Organism Biology Lund University Solvegatan 35 SE-223 62 Lund Sweden Candida albicans is the most prevalent yeast pathogen in humans and recently it has become increasingly resistant to the current antifungal agents. In this study we investigated C. albicans dihydroorotate dehydrogenase DHODH EC which catalyzes the fourth step of de novo pyrimidine synthesis as a new target for controlling infection. We propose that the enzyme is a member of the DHODH family 2 which comprises mitochondrially bound enzymes with quinone as the direct electron acceptor and oxygen as the final electron acceptor. Full-length DHODH and N-terminally truncated DHODH which lacks the targeting sequence and the transmembrane domain were subcloned from C. albicans recombinant-ly expressed in Escherichia coli purified and characterized for their kinetics and substrate specificity. An inhibitor screening with 28 selected compounds was performed. Only the dianisidine derivative redoxal and the biphenyl quinoline-carboxylic acid derivative brequinar sodium which are known to be potent inhibitors of mammalian DHODH markedly reduced C. albicans DHODH activity. .

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