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有机化学
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有机化学 ›› 2017, Vol. 37 ›› Issue (12): 3262-3266.DOI: 10.6023/cjoc201708007 上一篇    下一篇

研究简报

小单孢菌TP-A0468中两个基因簇协作完成新蒽环化合物的生物合成

周弘扬a, 罗光彩a, 张转b, 周强b, 翟鑫a, 唐功利a,b   

  1. a 沈阳药科大学中药学院 基于靶点的药物设计与研究教育部重点实验室 沈阳 110016;
    b 中国科学院上海有机化学研究所 生命有机化学国家重点实验室 上海 200032
  • 收稿日期:2017-08-04 修回日期:2017-09-01 发布日期:2017-09-26
  • 通讯作者: 翟鑫, 唐功利 E-mail:gltang@sioc.ac.cn;zhaixin_syphu@126.com
  • 基金资助:

    国家自然科学基金（No.81373307）和上海市科学技术委员会（No.14XD1404500）资助项目.

Cooperation of Two Biosynthetic Gene Clusters in the Biosynthesis of New Anthracycline Polyketide

Zhou Hongyanga, Luo Guangcaia, Zhang Zhuanb, Zhou Qiangb, Zhai Xina, Tang Gong-Lia,b   

  1. a Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016;
    b State Key Laboratory of Bio-Organic and Natural Product Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032
  • Received:2017-08-04 Revised:2017-09-01 Published:2017-09-26
  • Contact: 10.6023/cjoc201708007 E-mail:gltang@sioc.ac.cn;zhaixin_syphu@126.com
  • Supported by:

    Project supported by the National Natural Science Foundation of China (No. 81373307) and the Science and Technology Comission Shanghai Municipality (No. 14XD1404500).

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补充材料

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越野他汀（kosinostatin，KST）产生菌小单孢菌TP-A0468菌株基因组中包含了负责产生越野他汀、利福霉素等多种次级代谢产物的生物合成基因簇.在越野他汀生物合成研究中，从越野他汀生物合成基因簇中腺苷酰化酶基因kstB1的缺失突变株小单孢菌TP-A0468 △kstB1中分离到了新蒽环化合物554B.经质谱和核磁共振鉴定，其糖基部分是4-乙酰基-2，3，6-三脱氧己糖，而非越野他汀中的4-乙酰基-2，6-二脱氧己糖，表明其生物合成过程中发生了一步额外的3，4-脱水反应.然而KST生物合成基因簇中并不包含相应的己糖3，4-脱水酶基因.通过对基因组序列进行生物信息学分析，在利福霉素生物合成基因簇中发现了一个编码己糖3，4-脱水酶的基因orf6.基因删除实验显示orf6失活的突变株不再产生554B，表明该基因与4-乙酰基-2，3，6-三脱氧己糖的生物合成相关.结果表明小单孢菌TP-A0468可以利用不同生物合成基因簇中的基因协同介导天然产物的生物合成.

关键词: 蒽环化合物, 己糖3,4-脱水酶, 生物合成, 基因簇协作

Micromonospora sp. TP-A0468 harbors multiple biosynthetic gene clusters encoding the biosynthesis of secondary metabolites, including kosinostatin (KST) and rifamycins. In our study on the biosynthesis of KST, a new anthracycline polyketide 554B was isolated from the kstB1 deletion mutant △kstB1 and identified as shunt product of KST pathway bearing 4-acetyl-2,3,6-deoxyhexosyl moiety. The unexpected elimination of C-3' hydroxyl suggests a 3,4-dehydratase involved in the biosynthesis of 554B, of which the encoding gene was proposed to located beyond the kst gene cluster. Bioinformatic analysis revealed orf6 of rifamycin biosynthetic gene cluster (rif) was the candidate of required 3,4-dehydratase gene. Deletion of orf6 abolished the production of 554B, confirming the involvement of orf6 in the biosynthesis of 554B. Our study attributed orf6 to the origin of 2,3,6-deoxyhexosyl and unveiled the cooperation between biosynthetic gene clusters in Micromonospora sp. TP-A0468.

Key words: anthracycline, hexose 3,4-dehydratase, biosynthesis, gene cluster cooperation