Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, and School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.
Hangzhou Huadong Medicine Group Biotechnology Institute Co., Ltd., Hangzhou 310011, China.
Cell Chem Biol. 2017 Feb 16;24(2):171-181. doi: 10.1016/j.chembiol.2016.12.012. Epub 2017 Jan 19.
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.
戊二烯（PTN，脱氧咖啡霉素）和阿拉伯呋喃糖腺嘌呤（Ara-A，阿糖腺苷）是临床上用于治疗血液系统癌症和人类 DNA 病毒感染的嘌呤核苷抗生素。PTN 具有 1,3-二氮杂环戊烷环，而 Ara-A 是一种腺苷类似物，在 C-2' 羟基处具有有趣的差向异构化。然而，这些有趣分子的生物合成逻辑长期以来一直难以捉摸。在这里，我们报告说 PTN 和 Ara-A 的生物合成采用了一种不寻常的保护剂-保护蛋白策略。令我们惊讶的是，我们确定单个基因簇通过两条独立的途径控制 PTN 和 Ara-A 的生物合成。此外，我们验证了 PenB 作为 PTN 最后一步的可逆氧化还原酶。值得注意的是，我们提供了第一个直接的生化证据，表明 PTN 可以通过选择性抑制宿主腺苷脱氨酶来保护 Ara-A 免受过氧化氢酶的脱氨作用。这些发现扩展了我们对天然产物生物合成的认识，并为靶向 Ara-A/PTN 相关抗生素的基因组挖掘开辟了道路。
