Chen Yihua's research group from the Institute of Microbiology, Chinese Academy of Sciences discovered a novel initiation mechanism for polyketides

Chen Yihua’s research group at the Institute of Microbiology, Chinese Academy of Sciences has been committed to the biosynthesis and synthetic biology of microbial natural products.
On the basis of revealing and understanding the unique biosynthetic mechanisms of different natural products, it is designed and modified using the concept of synthetic biology.
More natural products with new structures and excellent activity
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In recent years, the biosynthetic mechanisms of streptothricin, heptosidin, and leucoxanthin have been successfully analyzed.
Relevant research has provided new ideas for drug development and design, and has promoted the development of natural product drugs
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Research results and reviews have been published in international authoritative journals such as PNAS, Nat Commun, JACS, Angew Chem Int Ed, Adv Sci and Nat Prod Rep
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In the work just published (Nat Commun, 2021, 12:4499), the research team discovered a novel and widespread online modification initiation mechanism for methyl esterification of polyketides
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Figure 1: The biosynthesis of methyl esterification on-line modification of the starting polyketide compound ART.
Natural polyketone products are an important part of the natural products of microorganisms, which have good medicinal value and other important physiological functions
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The compound Aurantinin (ART) is a type of polyene polyketone compound with a unique 6/7/8/5 tetracyclic complex structure.
In this study, the author first identified the biosynthetic gene cluster of ART and analyzed the differences in the structure of the compound ART.
The formation of methyl groups studied the assembly process of its polyketone chains
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In the course of this research, the author discovered a methyltransferase gene art28, which is necessary for the biosynthesis of ART, but its corresponding catalytic methyl group was not found in the ART structure.
This result caused the author’s interest
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Through further research, the author discovered that Art28 is an oxygen methyltransferase, which specifically catalyzes the online methyl esterification of malonyl-ACP (malonyl-ACP) during the initiation of polyketone biosynthesis, which is responsible for connecting the malonyl-ACP to the ACP.
The carboxylic acid at the acyl end undergoes methyl esterification to form malonyl ACP methyl ester, which then initiates the extension of the polyketone chain
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The study also found that the methyl ester group has been present throughout the entire biosynthesis process, until finally the esterase Art9 hydrolyzes the methyl ester at the end of the intermediate product ART 9B to form a carboxylic acid, which is then pumped out of the cell to form the final active product ART B
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The carboxyl methyl esterification and demethylation mechanism discovered in the process of ART biosynthesis, on the one hand, prevents the terminal carboxyl group from undergoing other side reactions during the biosynthesis process, and also protects the producing bacteria from the toxic effects of the compound
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Finally, the author also analyzed the versatility of the homologous proteins of Art28 protein in other biosynthetic gene clusters, and found that this unique polyketone initiation mechanism is widely present in different kinds of bacteria and gene clusters
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The discovery of this methyl esterification initiation mechanism not only enriches the biosynthesis initiation methods of polyketides, but also expands the diversity of bacteria using modification to achieve self-protection strategies, and at the same time helps to deepen the biosynthesis of polyketides.
The understanding of the mechanism lays the foundation for the further use of synthetic biology to obtain more polyketides with good biological activity
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Figure 2: Initiation method for online modification of polyketide compounds.
On July 23, 2021, the international comprehensive authoritative journal "Nature Communications" published an online research article entitled "Initiating polyketide biosynthesis by on-line methyl esterification" and reported This novel online methyl esterification method initiates the biosynthesis of polyketides
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Li Pengwei, an associate researcher at the Institute of Microbiology, Chinese Academy of Sciences, is the first author of the paper, and researcher Chen Yihua is the corresponding author
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The research was funded by the National Key Research and Development Program of Synthetic Biology, the National Natural Science Foundation of China, and the cooperation project between the Chinese Academy of Sciences and Inner Mongolia
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Professor Lu Zhaoxin from Nanjing Agricultural University, researcher Zhong Jin from the Institute of Microbiology, and Professor Horsman from Laurier University in Canada provided important guidance and assistance for the completion of the work
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