4,5-双氢-7-去氨甲酰基-7-羟基-19-S-甲基格尔德霉素及其与格尔德霉素生物合成PKS后修饰的关系  

4,5-dihydro-7-descarbamoyl-7-hydroxyl-19-S-methylgeldanamycin and its bioconversion by post-PKS tailoring system of geldanamycin biosynthesis

作　　者：牛沂菲 武临专[1] 赫卫清[1] 李京艳[1] 刘昕[1] 倪四阳[1] 林灵[1] 王红远[1] 孙桂芝[1] 李书芬[1] 王以光[1] 

机构地区：[1]卫生部抗生素生物工程重点实验室,中国医学科学院/北京协和医学院医药生物技术研究所,北京100050

出　　处：《中国抗生素杂志》2012年第1期39-44,共6页Chinese Journal of Antibiotics

基　　金：科技部"重大新药创制"科技重大专项(2009ZX09501-008)

摘　　要：目的在吸水链霉菌17997格尔德霉素生物合成PKS后修饰gdmN-变株发酵产物中寻找新格尔德霉素衍生物。方法 gdmN-变株发酵上清液乙酸乙酯提取后,进行硅胶板TLC分析;对一个红色目标化合物进行了HPLC和高分辨质谱分析,并对其进行了1H-和13C-核磁共振(NMR)分析;对红色目标化合物在吸水链霉菌17997格尔德霉素PKS基因阻断变株中进行了生物转化实验。结果在gdmN-变株发酵产物中发现了1个预期的红色目标化合物(4,5-双氢-7-去氨甲酰基-7-羟基-19-S-甲基格尔德霉素);该目标化合物可被格尔德霉素生物合成PKS后修饰系统7-O-氨甲酰化,生成4,5-双氢-19-S-甲基格尔德霉素。结论在gdmN-变株中发现了4,5-双氢-7-去氨甲酰基-7-羟基-19-S-甲基格尔德霉素;该化合物可被格尔德霉素PKS后修饰系统继续7-O-氨甲酰化,但不能C-4,5氧化。Objective To search for novel geldanmycin derivative（s） from the gdmN mutant of Streptomyces hygroscopicus 17997. Methods The fermentation supernatant ofgdmN mutant was extracted with ethylacetate, and then separated by silica gel TLC. An expected red compound of interest was analyzed by HPLC and HR-ESI（＋）-MS. The red compound was then purified for further 1H- and 13C- NMR confirmation. Bioconversion of the red compound was performed in a geldanamycin polyketide synthase gene disruption mutant of Streptomyces hygroscopicus 17997. Results The expected red compound was identified as 4,5-dihydro-7-descarbomoyl-7-hydroxy-19-S- methylgeldanamycin. It could be bioconverted to 4,5-dihydro-19-S-methylgeldanamycin. Conclusion A novel geldanamycin derivative, 4,5-dihydro-7-descarbomoyl-7-hydroxy-19-S-methylgeldanamycin, was characterized in the gdmN mutant of Streptomyces hygroscopicus 17997. 19-S-methylation of 4,5-dihydro-7-descarbomoyl-7- hydroxygeldanamycin does not interfere its carbamoylation, but blocks its C4,5-oxidation by the post-PKS tailoring process of geldanamycin biosynthesis.

关 键 词：4 5-双氢-7-去氨甲酰基-7-羟基-19-S甲基格尔德霉素 gdmN 格尔德霉素生物合成 PKS后修饰 

分 类 号：Q939.9[生物学—微生物学]