Rational biosynthetic engineering for optimization of geldanamycin analogues.
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.
Kim
Woncheol
W
Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Korea.
Lee
Dongho
D
Hong
Seong Su
SS
Na
Zhu
Z
Shin
Jin Chul
JC
Roh
Su Heun
SH
Wu
Cheng-Zhu
CZ
Choi
Oksik
O
Lee
Kyeong
K
Shen
Yue-Mao
YM
Paik
Sang-Gi
SG
Lee
Jung Joon
JJ
Hong
Young-Soo
YS
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
D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; C541735:DHQ3 compound; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D048630:Polyketide Synthases; C001277:geldanamycin