Efficient biosynthesis of nucleoside cytokinin angustmycin A containing an unusual sugar system

Authors: YU, LE - University Of Wuhan; ZHOU, WENTING - University Of Wuhan; SHE, YIXUAN - University Of Wuhan; MA, HONGMIN - University Of Wuhan; CAI, YOU-SHENG - University Of Wuhan; JIANG, MING - Shanghai Jiaotong University; DENG, ZIXIN - Jiaotong University; Price, Neil; CHEN, WENQING - University Of Wuhan

Submitted to: Nature Communications
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/26/2021
Publication Date: 11/17/2021
Citation: Yu, L., Zhou, W., She, Y., Ma, H., Cai, Y., Jiang, M., Deng, Z., Price, N.P., Chen, W. 2021. Efficient biosynthesis of nucleoside cytokinin angustmycin A containing an unusual sugar system. Nature Communications. 12. Article 6633. https://doi.org/10.1038/s41467-021-26928-y.
DOI: https://doi.org/10.1038/s41467-021-26928-y

Interpretive Summary: Angustmycins (AGM) are antimicrobial agents that are made by various soil-dwelling bacteria. In addition to their antibacterial properties, they have also been shown to promote the growth of plant stems and roots, similar to the plant hormone cytokinin. Almost nothing was known about how AGM are made by the soil bacteria even though they were first described more than 60 years ago. In this paper, we identified six genes called AgmA - F that are needed to make AGM. We also show that these genes can be expressed in other bacteria, which are then also able to produce AGM in even greater quantities. This discovery opens the way for rational and rapid discovery of more AGM-related antibiotics and plant hormones.

Technical Abstract: Angustmycin A has anti-mycobacterial and cytokinin activities, and contains an intriguing structure in which an unusual sugar with C5'-C6' dehydration is linked to adenine via an N-glycosidic bond. However, the logic underlying the biosynthesis of this molecule has long remained obscure. Here, we address angustmycin A biosynthesis by the full deciphering of its pathway. We demonstrate that AgmD, C, A, E, and B function as D-allulose 6-phosphate 3-epimerase, D-allulose 6-phosphate pyrophosphokinase, adenine phosphoallulosyltransferase, phosphoribohydrolase, and phosphatase, respectively, and that these collaboratively catalyze the relay reactions to biosynthesize angustmycin C. Additionally, we provide evidence that AgmF is a noncanonical dehydratase for the final step to angustmycin A via a self-sufficient strategy for cofactor recycling. Finally, we have reconstituted the entire six-enzyme pathway in vitro and in E. coli leading to angustmycin A production. These results expand the enzymatic repertoire regarding natural product biosynthesis, and also open the way for rational and rapid discovery of other angustmycin related antibiotics.