Academician Deng Zixin's team deciphered the enzymatic mechanism of chlorinase molecules in nucleoside drug biosynthesis

On October 28, the team of academician Deng Zixin from the School of Pharmacy of Wuhan University and the Institute of Pharmacy of Zhongnan Hospital published the internationally renowned journal ACS Catalysis (American Chemical Society?) in the field of catalysis Catalyzing) titled "Structural Insight into the Catalytic Mechanism of Non-Heme Iron Halogenase AdaV in 2′-Chloropentostatin Biosynthesis ().
Catalytic mechanism of non-heme iron-dependent chlorinase in the biosynthesis of 2′-chloropenstatin)
".
Wuhan University is the sole signatory of the paper, Professor Chen Wenqing and Professor Zhang Zhengyu are the co-corresponding authors of the paper, and doctoral students Zhai Guoqing and Gong Rong are the co-first authors
of the paper.

Chlorinated natural products are a kind of microbial secondary metabolites with diverse structures and a variety of biological activities, and chlorinated groups can significantly improve the properties of organic compound molecules and achieve directional activation of inert carbon, so chlorinated reactions are of great
significance in the pharmaceutical and chemical industries.
Compared to the chemical synthesis of carbon-chlorine (C-Cl) bonds, chlorinase can achieve compound-specific chlorine substitution under unmatched mild conditions, of which non-heme iron-dependent chlorinase can The use of free radicals to achieve chlorinated carbons of inert fatty carbons has also made it one of the topics of
greatest interest to scientists in recent years.
2′-Chloropenstatin, as the first chloropurine nucleoside antibiotic to be discovered, is one of the important lead drugs for the clinical treatment of leukemia, not only that, the chlorinated group in the antibiotic is rare and very unique, but for a long time, the molecular enzymatic mechanism of the related chlorinated enzymatic reaction has been unresolved
.

Chen Wenqing's research group and Zhang Zhengyu's research group worked closely to identify the non-heme iron-dependent chlorinase AdaV in Madura actinomycetes through systematic genetics and in vitro biochemical experiments to be responsible for the chlorinated biosynthesis of 2′-chloropenstatin.
Furthermore, it was found that the protein could specifically catalyze the formation of 2′-chlorodeoxyadenylate from the free small molecule compound deoxyadenylate, and finally realize the biosynthesis of 2′-chloropenstatin through subsequent enzymatic reaction steps.
Further structural biology research revealed that AdaV protein used a very interesting dual-regulatory catalytic model to achieve precise control of its chlorinated function, and elucidated the molecular mechanism of the interconversion between the chloroidation function and hydroxylation function of the protein.
It can be expected that the relevant research will provide a good research foundation and application example for the function analysis, rational transformation and efficient discovery of chlorinated enzymes in natural medicines in the future, and also show that related chlorinated enzymes have excellent potential
for synthetic biology applications as a new generation of green biocatalysts.

The team of Academician Deng Zixin of Wuhan University has long been committed to the metabolic engineering and synthetic biology research of important microbial drugs, and in recent years, the team has obtained a number of landmark research results with important display in the research field of microbial drug biosynthesis and synthetic biology, and has become a new force
with international influence in this field.
The research was supported
by Professor Sun Jiazhong of Zhongnan Hospital of Wuhan University, the National Key Research and Development Program of Synthetic Biology, the National Natural Science Foundation of China, and Hubei Medical Leading Talents.

Links to papers: https://pubs.
acs.
org/doi/10.
1021/acscatal.
2c04608