Incomplete beta-ketone processing as a mechanism for polyene structural variation in the FR-008/candicidin complex.
FR-008/candicidin is a heptaene macrolide with established antifungal activity, produced by Streptomyces sp. FR-008 as a complex mixture of compounds. Here, six components (FR-008-I to -VI) of the FR-008/candicidin complex were determined; III, V, and VI were confirmed as natural products, principally differing from each other at C-3 and C-9, while the other three were believed to originate from the respective conversions of the natural ones in vitro. Inactivation of KR21 and DH18, respectively, abolished production of V carrying a C-3 hydroxyl, and VI carrying a C-9 methylene. Combined inactivation created a mutant producing only III, with a C-3 ketone and a C-9 hydroxyl, and having antifungal activity superior to V and comparable to VI. Incomplete activities of KR21 and DH18 were, therefore, unambiguously identified as being involved in structural variations of FR-008 complex.
Laboratory of Microbial Metabolism and School of Life Science & Biotechnology, Shanghai Jiaotong University, Shanghai, China.
Yongjun
Y
Zhou
Jialiang
J
Li
Jing
J
Zhu
Shi
S
Chen
Linquan
L
Bai
Xiufen
X
Zhou
Houming
H
Wu
Zixin
Z
Deng
D000595:Amino Acid Sequence; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology; D001483:Base Sequence; D002174:Candicidin / Q000737:chemistry* / Q000494:pharmacology; D002853:Chromatography, Liquid; D017931:DNA Primers; D007659:Ketones / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D015394:Molecular Structure; D017354:Point Mutation; D017386:Sequence Homology, Amino Acid
D000935:Antifungal Agents; D017931:DNA Primers; D007659:Ketones; D002174:Candicidin