Small molecule * alcohol antibiotic synthesis

As a widely-occurring organic compound, small-molecule thiols have long been regarded as "scavengers" that eliminate harmful substances in living bodies. Now scientists have discovered that they have the constructive function of "directing" the precise synthesis of antibiotics, in addition to removing toxic protective functions. This discovery rewrites the traditional understanding of small molecule mercaptans in humans and is expected to bring about changes in related biochemical manufacturing technologies for pharmaceutical chemicals.

The British "Nature" magazine published online on January 14th the Liu Wen team of the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, made a breakthrough in the biosynthesis mechanism of lincomycin.

According to reports, small-molecule thiols are organic compounds with a thiol functional group that are widely found in almost all biological systems such as animals, plants, and microorganisms. For a long time, whether in the eyes of chemists or biologists, these "mercury brothers" have mainly played the physiological role of "scavenger."

The Liu Wen team’s discovery broke through the cognitive impediment of the physiological role of small molecule thiols: that small molecule thiols can not only serve as well-known “protective” roles, but also can play a “constructive” role for guidance as never before. And participate in the in vivo assembly of active functional molecules.

"As the sixth largest element after carbon, hydrogen, oxygen, nitrogen and phosphorus, sulfur is essential for life and widely exists in various biological systems, but it is a biochemical mechanism for how to effectively introduce it into active functional molecules. But little is known about it.” Liu Wen said that small molecules of mercaptans can remove the most damaging free radicals and detoxify harmful substances generated by various endogenous and exogenous factors. The responsibility is heavy but it is calm and low-key. Or missing and obscure.

The cooperation of two small molecules of thiols, ergothioneine and desorption thiols in Streptomyces lincoln, "directed" the biosynthesis of lincomycin accurately and orderly. Lincomycin is an anti-infective antibiotic that contains sulfur and has been widely used for clinical treatment of patients infected with penicillin (penicillin) antibiotics for more than half a century.

However, before such an important drug, no one knew how it was produced. Liu Wen's assistant and associate researcher Zhao Qunfei and his doctoral student Wang Min brought the "mercapt brothers" to the stage behind the scenes.

“Ergothioneine mediates the activation, transfer and modification of octacarbose units, while actinol thiol exchanges with ergothioneine to become a donor of sulfur. The former is renamed Polly in a mature forest. Completely invisible in the molecules of cancinomycin; the latter in a self-sacrificing way to achieve the phoenix nirvana biosynthesis of lincomycin." Liu Wen explained.

The team found that small molecule thiols dominated the biosynthesis of lincomycin through two rare S-glucosylation reactions, representing not only the first paradigm of ergothioneine involved in the biochemical reaction, but also providing a line of release. The thiol-dependent sulfur element introduces a new mode.

As a highly effective broad-spectrum anti-infective antibiotic, the market demand for lincomycin is huge. China is the world's largest producer of lincomycin, and Henan Tianfang Pharmaceutical Co., Ltd. alone has an annual output of more than 1,000 tons. Similar to the production of other large antibiotic products, domestic manufacturers of lincomycin often face problems such as low fermentation titers and complex product components. It is difficult to effectively solve these problems by means of the transformation of traditional strains.

Industry experts anticipate that the discovery of the mechanism of biosynthesis of lincomycin at the core of the thiol chemistry has created conditions for the targeted genetic transformation of industrial production strains of lincomycin, providing components optimized during the fermentation process. With the improvement of production, the theoretical basis for reducing production costs and reducing environmental pollution is achieved. At the same time, related discoveries have laid a molecular foundation for the design and creation of new types of artificial "life cells" and the realization of "bio-manufacture" of new bio-based chemicals containing sugar units in "cell factories."

“The emergence of new scientific theories, new inventions, and new engineering technologies is often due to breakthroughs in depth and breadth, which will lead to breakthroughs. Working on the depth of disciplines and exploring at the intersections will make science itself deeper. Development at a higher level and level, said Ding Kuiling, academician of the Chinese Academy of Sciences and director of the Shanghai Institute of Organic Chemistry. The original discovery of small molecule thiols in the new functions of biological systems fully embodies the advantages of synthetic chemistry and synthetic biology, which will have a bearing on the development of biomedical manufacturing technologies for related medicinal chemicals including lincomycin. Important guidance.

The research and application of the key technology for the genetic transformation of antibiotic-producing strains guided by the chemical concept is one of the three major breakthroughs in the “One-Three-Five” Plan of the Shanghai Institute of Organic Chemistry. In fact, the Shanghai Institute of Organic Chemistry and Henan Tianfang Pharmaceutical Co., Ltd. are transferring and reforming the implementation results of Lincomycin production technology reform. “This again shows that without the original innovation of basic research, there is no real high-tech.” Ding Kuiling said.