title: CYP53A15 of Cochliobolus lunatus, a target for natural antifungal compounds.
abstract: A novel cytochrome P450, CYP53A15, was identified in the pathogenic filamentous ascomycete Cochliobolus lunatus. The protein, classified into the CYP53 family, was capable of para hydroxylation of benzoate. Benzoate is a key intermediate in the metabolism of aromatic compounds in fungi and yet basically toxic to the organism. To guide functional analyses, protein structure was predicted by homology modeling. Since many naturally occurring antifungal phenolic compounds are structurally similar to CYP53A15 substrates, we tested their putative binding into the active site of CYP53A15. Some of these compounds inhibited CYP53A15. Increased antifungal activity was observed when tested in the presence of benzoate. Some results suggest that CYP53A15 O-demethylation activity is important in detoxification of other antifungal substances. With the design of potent inhibitors, CYP53 enzymes could serve as alternative antifungal drug targets.
authors.affiliation: Lek Pharmaceuticals d d, Verovskova 57, SI-1000 Ljubljana, Slovenia. barbara.podobnik@sadoz.com
authors.forename: Barbara
authors.initials: B
authors.lastname: Podobnik
authors.forename: Jure
authors.initials: J
authors.lastname: Stojan
authors.forename: Ljerka
authors.initials: L
authors.lastname: Lah
authors.forename: Nada
authors.initials: N
authors.lastname: Krasevec
authors.forename: Matej
authors.initials: M
authors.lastname: Seliskar
authors.forename: Tea Lanisnik
authors.initials: TL
authors.lastname: Rizner
authors.forename: Damjana
authors.initials: D
authors.lastname: Rozman
authors.forename: Radovan
authors.initials: R
authors.lastname: Komel
mesh_terms: D000935:Antifungal Agents / Q000737:chemistry* / Q000494:pharmacology; D001203:Ascomycota / Q000187:drug effects / Q000201:enzymology*; D001547:Benzaldehydes / Q000737:chemistry / Q000494:pharmacology; D050565:Benzoate 4-Monooxygenase / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics; D019817:Benzoic Acid / Q000494:pharmacology; D002384:Catalysis; D003001:Cloning, Molecular; D015169:Colony Count, Microbial; D004926:Escherichia coli / Q000201:enzymology / Q000235:genetics; D005054:Eugenol / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D005656:Fungal Proteins / Q000737:chemistry* / Q000235:genetics; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D013329:Structure-Activity Relationship; D013943:Thymol / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000935:Antifungal Agents; D001547:Benzaldehydes; D005656:Fungal Proteins; D011994:Recombinant Proteins; D013943:Thymol; D005054:Eugenol; C036643:isoeugenol; D019817:Benzoic Acid; C100058:vanillin; D050565:Benzoate 4-Monooxygenase