An Unusual Protector-Protege Strategy for the Biosynthesis of Purine Nucleoside Antibiotics

作者：Wu, Pan; Wan, Dan; Xu, Gudan; Wang, Gui; Ma, Hongmin; Wang, Tingting; Gao, Yaojie; Qi, Jianzhao; Chen, Xiaoxia; Zhu, Jian; Li, Yong-Quan; Deng, Zixin; Chen, Wenqing^*

来源：Cell Chemical Biology, 2017, 24(2): 171-181.

DOI：10.1016/j.chembiol.2016.12.012

• ADENOSINE-DEAMINASE
• STREPTOMYCES-ANTIBIOTICUS
• 2'-DEOXYCOFORMYCIN
• PENTOSTATIN
• INHIBITORS
• 9-BETA-D-ARABINOFURANOSYLADENINE
• COFORMYCIN
• SYSTEM

Pentostatin (PTN, deoxycoformycin) and arabinofuranosyladenine (Ara-A, vidarabine) are purine nucleoside antibiotics used clinically to treat hematological cancers and human DNA virus infections, respectively. PTN has a 1,3-diazepine ring, and Ara-A is an adenosine analog with an intriguing epimerization at the C-20 hydroxyl group. However, the logic underlying the biosynthesis of these interesting molecules has long remained elusive. Here, we report that the biosynthesis of PTN and Ara-A employs an unusual protector-protege strategy. To our surprise, we determined that a single gene cluster governs PTN and Ara-A biosynthesis via two independent pathways. Moreover, we verified that PenB functions as a reversible oxidoreductase for the final step of PTN. Remarkably, we provided the first direct biochemical evidence that PTN can protect Ara-A from deamination by selective inhibition of the host adenosine deaminase. These findings expand our knowledge of natural product biosynthesis and open the way for target-directed genome mining of Ara-A/PTN-related antibiotics.

• 出版日期2017-2-16
• 单位武汉大学; 浙江大学