Chen Yihua’s research group from the Institute of Microbiology, Chinese Academy of Sciences published a review on heptose-containing microbial natural product drugs in NPR
By: Date: 2021-03-27 Categories: foodtechnology Tags: ,
  Sugar plays a pivotal role in life activities. Different sugar groups can aggregate together to form the basic structure of cells such as cell walls. It can also modify proteins and different Small molecule compounds give them different characteristics. Glycosylation is a ubiquitous and very important life process in nature. Many important biomolecules such as nucleic acids, polysaccharides, proteins, lipids and secondary metabolites have glycosylation modifications. Glycoconjugates have diverse functions, can participate in the storage and transfer of intracellular information, maintain the integrity of cell structure, mediate intermolecular recognition and signal transduction, and are also related to the virulence of bacteria and chemical defense. In secondary metabolism, glycosylation can often improve the solubility and stability of microbial natural products, enhance their biological activity, and greatly promote the medicinal properties of natural products.

  heptose, as an important part of bacterial lipopolysaccharide LPS, is essential for the cell wall composition of gram-negative bacteria, bacterial infection and immune recognition. Among the natural products of bacteria, more than 100 compounds containing heptose structural units have been discovered so far, possessing rich and diverse biological activities such as anti-bacterial, anti-fungal, anti-parasitic, anti-tumor and anti-neuralgia. Structural analysis shows that the heptose unit can not only be used as a glycosyl modification group, but in many natural product structures, the heptose unit is the core backbone structure, which means that the heptose unit may directly determine the active function of the natural product.

  Septacidin is a secondary metabolite produced by Gram-positive bacteria. The structure contains the L-heptanose structural unit. It has anti-fungal and anti-tumor activity. In recent years, it has also been found to have the activity of inducing cell immunogenic death. KRN5500, a derivative of this type of compound, has entered clinical trials as an anti-tumor drug and pain inhibitor respectively. Hygromycin B and its resistance genes are commonly used screening systems in laboratories. At the same time, hygromycin B is used as an antiparasitic veterinary drug in poultry and livestock breeding. The structure of Hygromycin B contains a special D-heptanose structure. Chen Yihua’s research group discovered in previous studies that the synthesis of L-heptanose in heptosecide and the primary metabolism of gram-negative bacteria share the heptose synthesis pathway; one was discovered in the study of hygromycin B biosynthesis Brand new ADP-Aldroheptose. (PNAS, 2018, 115 (11), 2818-2823.)

   In 2020, the research team proved that the structure of N6-glycosylated adenine in heptosidin is composed of a special Fe(II)-dependent glycosyltransferase SepE Catalytic formation, and at the same time proved that SepF is a novel glycosidase, which can hydrolyze the CN glycosidic bond of the precursor compound of heptosidin to generate intermediate SEP-328. Interestingly, the glycosyltransferase SepE presents a very rare brown color. Through UV-Vis spectroscopy and ICP-OES/MS analysis, it is found that the SepE molecule contains a divalent ferrous ion. Point mutation analysis found that the ferrous ion in SepE plays an important role in AMP binding. The above research clarified the key step in the biosynthesis of heptosidin through in vivo knockout, product structure identification and in vitro enzymology experiments. At the same time, the entire synthesis pathway was deduced, and the biosynthesis mechanism of L-heptanose natural products was deepened. Understanding. The research results were published in the journal”Organic Letters”.

Chen Yihua’s research group from the Institute of Microbiology, Chinese Academy of Sciences published a review on heptose-containing microbial natural product drugs in NPRimage

  Figure 1. SepE in heptosecide biosynthesis Catalyzed with SepF to produce intermediate SEP-328 (8)

   Recently, the research group was invited to write a review”Heptose-containing bacterial natural products:structures,”Bioactivities, and biosyntheses” was published online. This review takes the important physiological significance of the heptose unit as the starting point, analyzes the heptose in natural products of bacterial origin and divides them into four categories according to their structure:furan-type heptose, highly reduced pyran-type heptose, L- Type Heptanose and D-Type Heptanose. Grouped by structure, the full text describes the structural characteristics and related biological activities of more than 100 natural products of bacterial origin that contain heptose structures discovered so far; summarizes the laws and research progress of their biosynthesis mechanisms, and focuses on the heptose structural unit Mechanism of biosynthesis. Finally, the structural characteristics and biosynthesis research progress of the heptose unit in the primary metabolism of bacteria are briefly described.

The change of    glycosyl unit can significantly affect the pharmacological properties of natural products. So far, there have been many successful cases of altering natural product glycosyl units through bioengineering methods. The prerequisite for the success of these cases requires an in-depth understanding of the biosynthetic mechanism of sugar-containing compounds. In the past few decades, there have been many reports on the structure, activity and biosynthetic mechanism of natural products containing heptose. However, there has been no relevant review to summarize. This review systematically summarizes related research and provides support for the biosynthesis and synthetic biology research of heptose-containing natural products.
Chen Yihua’s research group from the Institute of Microbiology, Chinese Academy of Sciences published a review on heptose-containing microbial natural product drugs in NPRimage(1)

   Figure 2. Important bacteria with heptose structure Natural products

   On the analysis of the formation mechanism of the N6-glycosylated adenine structure in heptanosid, Dr. Tang Wei from the Chen Yihua Research Group of the Institute of Microbiology, Chinese Academy of Sciences was the first The authors, associate researcher Guo Zhengyan and researcher Chen Yihua are the co-corresponding authors. Regarding the review of bacterial natural products containing heptose structure, associate researcher Guo Zhengyan is the first author, and researcher Chen Yihua is the corresponding author of the paper. The research work was funded by the Key R&D Program of the Ministry of Science and Technology, the Outstanding Youth Fund and General Program of the National Natural Science Foundation of China, and the Youth Innovation Promotion Association of the Chinese Academy of Sciences.