Elucidation of Biosynthesis and Self-Resistance Mechanism of the Antibiotic Ascamycin

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February 29, 2024

Function prediction of unknown biosynthetic enzymes using AI

A joint research group of RIKEN CSRS and the National Institute of Infectious Diseases (NIID) has successfully predicted the function of unknown alanyl-tRNA synthetase-like enzymes catalyzing aminoacylation reaction using the protein 3D structure prediction artificial intelligence program AlphaFold2, and elucidated a new biosynthesis mechanism and self-resistance mechanism of ascamycin, a nucleoside antibiotic isolated from Streptomyces sp. 80H647. In this study, the team introduced additional transcriptional regulators, AdpA and BldA, into the producing strain to enhance ascamycin production. Gene expression analysis and structure-function prediction identified two alanyl-tRNA synthetase-like enzymes (AcmD and AcmF): AcmF efficiently catalyzes the aminoacylation reaction of the ascamycin biosynthetic intermediate (dealanylascamycin), and this reaction uses alanyl-tRNAAla provided by AcmD as substrate. In addition, the team has successfully produced the glycylated and serylated ascamycin derivatives using the AcmD-AcmF enzyme pair. The results of this research are expected to lead to chemoenzymatic creation of natural compounds with new bioactivity.

Original article
ACS Catalysis doi: 10.1021/acscatal.3c05667
Y. Zheng, N. Morita, H. Takagi, Y. Shiozaki-Sato, J. Ishikawa, K. Shin-ya, S. Takahashi,
"Alanyl-tRNA Synthetase-like Enzyme-Catalyzed Aminoacylation in Nucleoside Sulfamate Ascamycin Biosynthesis".
Shunji Takahashi; Unit Leader
Yu Zheng; Special Postdoctoral Researcher
Natural Product Biosynthesis Research Unit