Panorama of aromatic polyketones (schematic) Courtesy of Westlake University
World of aromatic polyketone compounds Courtesy of Westlake University
The team of Zhang Lijun, a distinguished researcher at Westlake University, explored the evolutionary process and structural diversity of aromatic polyketone compounds derived from bacteria, and drew the world’s first panoramic map of aromatic polyketones. Recently, the results were published in German Applied Chemistry, the corresponding author of the paper is Zhang Lijun, and the co-first author is Chen Shanchong, a doctoral student at Westlake University, and Zhang Chi, an assistant researcher.
Zhang Lijun’s challenge this time is a class of polyketone compounds in the family of polyketone compounds – aromatic polyketone compounds derived from bacteria – it is the core component of many important drugs, including doxorubicin for treating tumors and the antibacterial drug tetracycline, and because its synthetic “production line” is very special, it is a combination of enzymes responsible for synthetic products, “prediction” is very difficult. The traditional drug discovery method, that is, from animals, plants, microorganisms, one by one, isolate and identify new natural products, and study and learn methods one by one, can only accumulate individual cases, and cannot give answers efficiently. But bioinformatics, a research method that uses computers to search, process, and utilize biological data, has brought the dawn of discovery to natural products.
Based on the team’s preliminary research and data analysis, Zhang Lijun’s team believes that CLF (Chain Length Factor) plays a key role in the biosynthesis of aromatic polyketone molecules. Each polyketone molecule requires this enzyme, and the CLF enzyme of different types of polyketone molecules will have different amino acid sequences. The team set its sights on 167 gene clusters that had been studied (i.e., characterized) and knew about the correspondence between natural products (i.e., a list or classes of genes in bacterial strains that encode biosynthetic enzymes). Their analysis found that the information characteristics of the amino acid sequences of the CLF proteins in these gene clusters correspond to the structural characteristics of different compounds. At the same time, with the help of the “bridge” of the CLF, the research team came up with a calculation method and numerical line that can “decide” whether the gene cluster can produce different compounds, 88% – comparing the amino acid sequences of the two CLF, more than 88% are the same, which means that their final synthetic product compounds are also the same; below 88%, different compounds will be produced – thus predicting the “uniqueness” of the final compound.
The research team further extracted data on biosynthetic enzymes for 3254 bacterial-derived aromatic polyketone compounds from public genomic databases— 3254 enzymes derived from all the microbes (bacteria) that have been sequenced today. Then, they applied the first step of the research method to these 3254 enzymes, and constructed a global “phylogenetic tree” that describes the correspondence between the “enzyme amino acid sequence- compound structure”. At the same time, they incorporated bacterial strain information into the chart, which in turn obtained the correspondence between the strain and the compound.
Based on this blueprint chart, the team analyzed the global abundance, distribution, and structural diversity of aromatic polyketones. From this, they estimated the total number of aromatic polyketone molecules in nature— the “population” of bacterial-derived aromatic polyketone natural products, about 3,000.
Through further analysis, they screened out seven strains, targeting two bacteria that produce novel polyketone compounds. By culturing the strains in the laboratory, they identified novel aromatic polyketone molecules in the final product formed after fermentation of both strains, including the oryzanaphthopyran with a novel backbone isolated from a rare strain of eosinophilic actinomycetes. These findings, in turn, corroborate the practical value of the panoramas obtained by the Institute in the study of such natural products. (Source: China Science Daily Wen Caifei Zhang Chi)
Related paper information:https://doi.org/10.1002/anie.202202286