title: Rational biosynthetic engineering for optimization of geldanamycin analogues.
abstract: Tailor made: We report the rational biosynthesis of C15 hydroxylated non-quinone geldanamycin analogues by site-directed mutagenesis of the geldanamycin polyketide synthase (PKS), together with a combination of post-PKS tailoring genes. Rational biosynthetic engineering allowed the generation of geldanamycin derivatives, such as DHQ3 illustrated in the figure, which had superior pharmacological properties in comparison to the parent compound. A rational biosynthetic engineering approach was applied to the optimization of the pharmacological properties of the benzoquinone ansamycin, geldanamycin. Geldanamycin and its natural or semisynthetic derivatives have the potential to serve as anticancer chemotherapeutic agents. However, these first-generation Hsp90 inhibitors share an unfavorable structural feature that causes both reduced efficacy and toxicity during clinical evaluation. We report the rationally designed biosynthesis of C15 hydroxylated non-quinone geldanamycin analogues by site-directed mutagenesis of the geldanamycin polyketide synthase (PKS), together with a combination of post-PKS tailoring genes. A 15-hydroxyl-17-demethoxy non-quinone analogue, DHQ3, exhibited stronger inhibition of Hsp90 ATPase activity (4.6-fold) than geldanamycin. Taken together, the results of the present study indicate that rational biosynthetic engineering allows the generation of derivatives of geldanamycin with superior pharmacological properties.
authors.affiliation: Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Korea.
authors.forename: Woncheol
authors.initials: W
authors.lastname: Kim
authors.forename: Dongho
authors.initials: D
authors.lastname: Lee
authors.forename: Seong Su
authors.initials: SS
authors.lastname: Hong
authors.forename: Zhu
authors.initials: Z
authors.lastname: Na
authors.forename: Jin Chul
authors.initials: JC
authors.lastname: Shin
authors.forename: Su Heun
authors.initials: SH
authors.lastname: Roh
authors.forename: Cheng-Zhu
authors.initials: CZ
authors.lastname: Wu
authors.forename: Oksik
authors.initials: O
authors.lastname: Choi
authors.forename: Kyeong
authors.initials: K
authors.lastname: Lee
authors.forename: Yue-Mao
authors.initials: YM
authors.lastname: Shen
authors.forename: Sang-Gi
authors.initials: SG
authors.lastname: Paik
authors.forename: Jung Joon
authors.initials: JJ
authors.lastname: Lee
authors.forename: Young-Soo
authors.initials: YS
authors.lastname: Hong
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000903:Antibiotics, Antineoplastic / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D016227:Benzoquinones / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D005818:Genetic Engineering; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D047029:Lactams, Macrocyclic / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D008969:Molecular Sequence Data; D005810:Multigene Family; D016297:Mutagenesis, Site-Directed; D048630:Polyketide Synthases / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment
chemical_list: D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; C541735:DHQ3 compound; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D048630:Polyketide Synthases; C001277:geldanamycin