title: An Unusual Protector-Protégé Strategy for the Biosynthesis of Purine Nucleoside Antibiotics.
abstract: 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-2' 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-protégé 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.
authors.affiliation: Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, and School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.
authors.forename: Pan
authors.initials: P
authors.lastname: Wu
authors.affiliation: Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, and School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Wan
authors.affiliation: Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, and School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.
authors.forename: Gudan
authors.initials: G
authors.lastname: Xu
authors.affiliation: Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, and School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.
authors.forename: Gui
authors.initials: G
authors.lastname: Wang
authors.affiliation: Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, and School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.
authors.forename: Hongmin
authors.initials: H
authors.lastname: Ma
authors.affiliation: Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, and School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Wang
authors.affiliation: Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, and School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.
authors.forename: Yaojie
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, and School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.
authors.forename: Jianzhao
authors.initials: J
authors.lastname: Qi
authors.affiliation: Hangzhou Huadong Medicine Group Biotechnology Institute Co., Ltd., Hangzhou 310011, China.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Chen
authors.affiliation: Hangzhou Huadong Medicine Group Biotechnology Institute Co., Ltd., Hangzhou 310011, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Institute of Pharmaceutical Biotechnology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Yong-Quan
authors.initials: YQ
authors.lastname: Li
authors.affiliation: Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, and School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.
authors.forename: Zixin
authors.initials: Z
authors.lastname: Deng
authors.affiliation: Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, and School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China. Electronic address: wqchen@whu.edu.cn.
authors.forename: Wenqing
authors.initials: W
authors.lastname: Chen
mesh_terms: D000243:Adenosine Deaminase / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000096:biosynthesis* / Q000737:chemistry / Q000494:pharmacology; D001483:Base Sequence; D016000:Cluster Analysis; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D015649:Pentostatin / Q000096:biosynthesis* / Q000737:chemistry / Q000494:pharmacology; D017422:Sequence Analysis, DNA; D013303:Streptomyces antibioticus / Q000235:genetics; D014740:Vidarabine / Q000096:biosynthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D015649:Pentostatin; D000243:Adenosine Deaminase; D014740:Vidarabine
keywords: arabinofuranosyladenine; biosynthesis; gene cluster; pentostatin; protector-protégé strategy; purine nucleoside antibiotics