Engineered Biosynthesis of Geldanamycin Analogs for Hsp90 Inhibition

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Presentation transcript:

Engineered Biosynthesis of Geldanamycin Analogs for Hsp90 Inhibition Kedar Patel, Misty Piagentini, Andreas Rascher, Zong-Qiang Tian, Greg O. Buchanan, Rika Regentin, Zhihao Hu, C.R. Hutchinson, Robert McDaniel Chemistry & Biology Volume 11, Issue 12, Pages 1625-1633 (December 2004) DOI: 10.1016/j.chembiol.2004.09.012 Copyright © 2004 Elsevier Ltd Terms and Conditions

Figure 1 Geldanamycin, 17-AAG, and Related Ansamycin Polyketides Chemistry & Biology 2004 11, 1625-1633DOI: (10.1016/j.chembiol.2004.09.012) Copyright © 2004 Elsevier Ltd Terms and Conditions

Figure 2 Genetics and Chemistry of Geldanamycin Biosynthesis Progeldanamycin is the presumed polyketide product of the GdmPKS (encoded by gdmA1, A2, and A3) and GdmF (the lactam-forming amide synthase). The GdmPKS consists of an AHBA loading domain and seven extension modules. Each module catalyzes one round of chain elongation using malonyl-CoA (module 6), methylmalonyl-CoA (modules 1, 3, 5, and 7), or methoxymalonyl-ACP (modules 2 and 6). Each module also modifies the β-carbonyl from each elongation to a hydroxyl (modules 3 and 5), alkene (modules 4 and 7), or methylene (modules 1, 2, and 6). Progeldanamycin is converted to geldanamycin by five steps, the precise order of which has not been determined. (KS-ketosynthase, AT-acyltransferase, DH-dehydratase, ER-enolreductase, KR-ketoreductase, ACP-acyl carrier protein). Chemistry & Biology 2004 11, 1625-1633DOI: (10.1016/j.chembiol.2004.09.012) Copyright © 2004 Elsevier Ltd Terms and Conditions

Figure 3 Junctions Used for AT Domain Substitutions Green sequences correspond to geldanamycin flanking regions, blue to rapamycin ATs, and red to amino acids introduced by restriction site engineering. Chemistry & Biology 2004 11, 1625-1633DOI: (10.1016/j.chembiol.2004.09.012) Copyright © 2004 Elsevier Ltd Terms and Conditions

Figure 4 Geldanamycin Analogs Produced by AT Substitutions in the GdmPKS Chemistry & Biology 2004 11, 1625-1633DOI: (10.1016/j.chembiol.2004.09.012) Copyright © 2004 Elsevier Ltd Terms and Conditions