Production of 8-demethylgeldanamycin and 4,5-epoxy-8-demethylgeldanamycin from a recombinant strain of Streptomyces hygroscopicus.
Two new geldanamycin derivatives produced by genetic engineering of Streptomyces hygroscopicus strain K309-27-1 were isolated and characterized. Removal of the 8-methyl group of geldanamycin was achieved by replacing the AT4 domain of the polyketide synthase with a malonyl AT domain. The resulting strain produced 8-demethyl geldanamycin (2) and 4,5-epoxy-8-demethylgeldanamycin (3). The structures of both molecules were elucidated through interpretation of 1D and 2D NMR data as well as comparison with authentic geldanamycin derivatives. Compounds 2 and 3 displayed moderate cytotoxicity against the human breast cancer cell line SK-BR-3.
Buchanan
Greg O
GO
Kosan Biosciences, Inc., 3832 Bay Center Place, Hayward, California 94545, USA. buchanan@kosan.com
Regentin
Rika
R
Piagentini
Misty
M
Rascher
Andreas
A
McDaniel
Robert
R
Galazzo
Jorge L
JL
Licari
Peter J
PJ
D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D016227:Benzoquinones; D045744:Cell Line, Tumor; D005818:Genetic Engineering; D006801:Humans; D047029:Lactams, Macrocyclic; D015394:Molecular Structure; D011809:Quinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D013302:Streptomyces / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
C501147:4,5-epoxy-8-demethylgeldanamycin; C501146:8-demethylgeldanamycin; D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D047029:Lactams, Macrocyclic; D011809:Quinones; C001277:geldanamycin