Mechanistic insights into polycycle formation by reductive cyclization in ikarugamycin biosynthesis.
Ikarugamycin is a member of the polycyclic tetramate macrolactams (PTMs) family of natural products with diverse biological activities. The biochemical mechanisms for the formation of polycyclic ring systems in PTMs remain elusive. The enzymatic mechanism of constructing an inner five-membered ring in ikarugamycin is reported. A three-gene-cassette ikaABC from the marine-derived Streptomyces sp. ZJ306 is sufficient for conferring ikarugamycin production in a heterologous host. IkaC catalyzes a reductive cyclization reaction to form the inner five-membered ring by a Michael addition-like reaction. This study provides the first biochemical evidence for polycycle formation in PTMs and suggests a reductive cyclization strategy which may be potentially applicable in general to the corresponding ring formation in other PTMs.
Key Laboratory of Tropical Marine Bio-resources and Ecology, RNAM Center for Marine Microbiology, Guangdong Key Laboratory of Marine Materia Medica, South China Sea Institute of Oceanology, Chinese Academy of Sciences, 164 West Xingang Road, Guangzhou 510301 (China).
Guangtao
G
Zhang
Wenjun
W
Zhang
Qingbo
Q
Zhang
Ting
T
Shi
Liang
L
Ma
Yiguang
Y
Zhu
Sumei
S
Li
Haibo
H
Zhang
Yi-Lei
YL
Zhao
Rong
R
Shi
Changsheng
C
Zhang
D003500:Cyclization; D007769:Lactams / Q000378:metabolism*; D010084:Oxidation-Reduction
D007769:Lactams; C074292:ikarugamycin
biosynthesis; heterologous expression; ikarugamycin; polycyclic tetramate macrolactams; reductive cyclization