title: Phylogenetic Studies, Gene Cluster Analysis, and Enzymatic Reaction Support Anthrahydroquinone Reduction as the Physiological Function of Fungal 17β-Hydroxysteroid Dehydrogenase.
abstract: 17β-Hydroxysteroid dehydrogenase (17β-HSDcl) from the filamentous fungus Curvularia lunata (teleomorph Cochliobolus lunatus) catalyzes NADP(H)-dependent oxidoreductions of androgens and estrogens. Despite detailed biochemical and structural characterization of 17β-HSDcl, its physiological function remains unknown. On the basis of amino acid sequence alignment, phylogenetic studies, and the recent identification of the physiological substrates of the homologous MdpC from Aspergillus nidulans and AflM from Aspergillus parasiticus, we propose an anthrahydroquinone as the physiological substrate of 17β-HSDcl. This is also supported by our analysis of a secondary metabolite biosynthetic gene cluster in C. lunata m118, containing 17β-HSDcl and ten other genes, including a polyketide synthase probably involved in emodin formation. Chemoenzymatic reduction of emodin by 17β-HSDcl in the presence of sodium dithionite verified this hypothesis. On the basis of these results, the involvement of a 17β-HSDcl in the biosynthesis of other anthrahydroquinone-derived natural products is proposed; hence, 17β-HSDcl should be more appropriately referred to as a polyhydroxyanthracene reductase (PHAR).
authors.affiliation: Institut für Pharmazeutische Wissenschaften, Albert-Ludwigs-Universität Freiburg, Albertstrasse 25, 79104, Freiburg, Germany.
authors.forename: Leon
authors.initials: L
authors.lastname: Fürtges
authors.affiliation: Institut für Pharmazeutische Wissenschaften, Albert-Ludwigs-Universität Freiburg, Albertstrasse 25, 79104, Freiburg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Conradt
authors.affiliation: Institut für Pharmazeutische Wissenschaften, Albert-Ludwigs-Universität Freiburg, Albertstrasse 25, 79104, Freiburg, Germany.|Roche Pharma AG, Emil-Barell-Strasse 1, 79639, Grenzach-Wyhlen, Germany.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Schätzle
authors.affiliation: Centre of Biomedical Research, SGPGIMS Campus, Raebareli Road, Lucknow, 226014, Uttar Pradesh, India.
authors.forename: Shailesh Kumar
authors.initials: SK
authors.lastname: Singh
authors.affiliation: National Institute of Chemistry, Hajdrihova 19, 1000, Ljubljana, Slovenia.
authors.forename: Nada
authors.initials: N
authors.lastname: Kraševec
authors.affiliation: Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000, Ljubljana, Slovenia.
authors.forename: Tea Lanišnik
authors.initials: TL
authors.lastname: Rižner
authors.affiliation: Institut für Pharmazeutische Wissenschaften, Albert-Ludwigs-Universität Freiburg, Albertstrasse 25, 79104, Freiburg, Germany.
authors.forename: Michael
authors.identifier: http://orcid.org/0000-0002-2742-4992
authors.initials: M
authors.lastname: Müller
authors.affiliation: Centre of Biomedical Research, SGPGIMS Campus, Raebareli Road, Lucknow, 226014, Uttar Pradesh, India.
authors.forename: Syed Masood
authors.initials: SM
authors.lastname: Husain
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D000880:Anthraquinones / Q000737:chemistry / Q000378:metabolism*; D001203:Ascomycota / Q000201:enzymology* / Q000235:genetics; D055162:Biocatalysis; D004642:Emodin / Q000737:chemistry / Q000378:metabolism; D005810:Multigene Family; D010084:Oxidation-Reduction; D010802:Phylogeny
chemical_list: D000880:Anthraquinones; C419462:cytoskyrin A; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase; D004642:Emodin; C027113:chrysophanic acid
keywords: anthrahydroquinones; asymmetric synthesis; enzyme catalysis; gene annotation; oxidoreductases