In vitro reconstitution of a PKS pathway for the biosynthesis of galbonolides in Streptomyces sp. LZ35.
The galbonolides are 14-membered macrolide antibiotics with a macrocyclic backbone similar to that of erythromycins. Galbonolides exhibit broad-spectrum antifungal activities. Retro-biosynthetic analysis suggests that the backbone of galbonolides is assembled by a type I modular polyketide synthase (PKS). Unexpectedly, the galbonolide biosynthetic gene cluster, gbn, in Streptomyces sp. LZ35 encodes a hybrid fatty acid synthase (FAS)-PKS pathway. In vitro reconstitution revealed the functions of GbnA (an AT-ACP didomain protein), GbnC (a FabH-like enzyme), and GbnB (a novel multidomain PKS module without AT and ACP domains) responsible for assembling the backbone of galbonolides, respectively. To our knowledge, this study is the first biochemical characterization of a hybrid FAS-PKS pathway for the biosynthesis of 14-membered macrolides. The identification of this pathway provides insights into the evolution of PKSs and could facilitate the design of modular pools for synthetic biology.
State Key Laboratory of Microbial Technology, School of Life Science, Shandong University, No. 27 Shanda South Road, Jinan Shandong 250100 (P. R. China).
Chao
C
Liu
Jing
J
Zhu
Yaoyao
Y
Li
Juanli
J
Zhang
Chunhua
C
Lu
Haoxin
H
Wang
Yuemao
Y
Shen
D055162:Biocatalysis; D007783:Lactones / Q000378:metabolism; D005810:Multigene Family; D048630:Polyketide Synthases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D013302:Streptomyces / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism*
D007783:Lactones; C047784:rustmicin; D048630:Polyketide Synthases
biosynthesis; galbonolides; hybrid pathway; macrolides; polyketides