期刊
CHEMISTRY & BIOLOGY
卷 17, 期 5, 页码 495-503出版社
CELL PRESS
DOI: 10.1016/j.chembiol.2010.04.009
关键词
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资金
- National Natural Science Foundation of China [20832009, 30525001, 90713012, 20921091]
- Ministry of Science and Technology of China [2009ZX09501-008]
- 973 Program [2010CB833200]
- Chinese Academy of Sciences [KJCX2-YW-H08, KSCX2-YW-G-06]
- Science and Technology Commission of Shanghai Municipality [09QH1402700]
The enzymes 6-methylsalicylic acid (6-MSA) synthases (6-MSASs) are involved in the building of an aryl moiety in many bioactive secondary metabolites produced by fungi and bacteria. Using the bacterial 6-MSAS ChIB1 in the biosynthesis of spirotetronate antibiotic chlorothricin (CHL) as a model, functional analysis of its dehydratase (DH) and ketoreductase (KR) domains by site-specific mutagenesis revealed that selective ketoreduction is not essential for polyketide chain extension. Promiscuity of the ketoacylsynthase domain in beta functionality recognition allows for engineering ChIB1 to an orsellinic acid (OSA) synthase (OSAS) by inactivating KR at the active site. The engineered ChIB1 is compatible with the enzymes for late-stage tailoring in CHL biosynthesis, featuring specific protein recognitions that facilitate variable aryl group incorporation. The resulting spirotetronates, which bear an OSA-derived aryl group, exhibited antibacterial activities comparable to those of the parent products.
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