期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 142, 期 40, 页码 17093-17104出版社
AMER CHEMICAL SOC
DOI: 10.1021/jacs.0c07050
关键词
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资金
- National Key Research and Development Program of China [2018YFA0901800]
- National Natural Science Foundation of China [21807110, 31870076]
- China Postdoctoral Science Foundation [2019T120162]
- Agricultural Science and Technology Innovation Program of the Chinese Academy of Agricultural Sciences (CAAS-ASTIP)
- Joint Genomics Institute of the U.S. Department of Energy [1349]
- USDA National Institute of Food and Agriculture [ARZT-1361640-H12-224]
- Higher Education Institutional Excellence Program of the Ministry of Human Capacities in Hungary [NKFIH-1150-6/2019]
- U.S. National Institutes of Health [NIGMS 5R01GM114418]
Combinatorial biosynthesis with fungal polyketide synthases (PKSs) promises to produce unprecedented bioactive unnatural natural products (uNPs) for drug discovery. Genome mining of the dothideomycete Rhytidhysteron rufulum uncovered a collaborating highly reducing PKS (hrPKS)-nonreducing PKS (nrPKS) pair. These enzymes produce trace amounts of rare S-type benzenediol macrolactone congeners with a phenylacetate core in a heterologous host. However, subunit shuffling and domain swaps with voucher enzymes demonstrated that all PKS domains are highly productive. This contradiction led us to reveal novel programming layers exerted by the starter unit acyltransferase (SAT) and the thioesterase (TE) domains on the PKS system. First, macrocyclic vs linear product formation is dictated by the intrinsic biosynthetic program of the TE domain. Next, the chain length of the hrPKS product is strongly influenced in trans by the off-loading preferences of the nrPKS SAT domain. Last, TE domains are size-selective filters that facilitate or obstruct product formation from certain priming units. Thus, the intrinsic programs of the SAT and TE domains are both part of the extrinsic program of the hrPKS subunit and modulate the observable metaprogram of the whole PKS system. Reconstruction of SAT and TE phylogenies suggests that these domains travel different evolutionary trajectories, with the resulting divergence creating potential conflicts in the PKS metaprogram. Such conflicts often emerge in chimeric PKSs created by combinatorial biosynthesis, reducing biosynthetic efficiency or even incapacitating the system. Understanding the points of failure for such engineered biocatalysts is pivotal to advance the biosynthetic production of uNPs.
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