A backup plan for self-protection: S-methylation of holomycin biosynthetic intermediates in Streptomyces clavuligerus.
A backup plan for self-protection: S-methylation of holomycin biosynthetic intermediates in Streptomyces clavuligerus.
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DOI：
10.1002/cbic.201200536
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发表时间：
2012-11-26
期刊：
影响因子：
3.2
通讯作者：
Walsh, Christopher T.
中科院分区：
文献类型：
--
作者：
Li, Bo;Forseth, Ry R.;Bowers, Albert A.;Schroeder, Frank C.;Walsh, Christopher T.
二硫代吡洛酮类抗生素霍霉素的生物合成涉及一对烯醇对环二硫化物的闭合。我们已经证明，二硫醇氧化酶HlmI负责二硫化物的形成，这种酶也起着自我保护的作用。在本研究中，我们研究如何。clavuligerusdeals与拟议中的有毒二硫酚中间体whenhlmIis删除。我们使用差分核磁共振光谱和质谱分析了hlmideletion突变体以及野生型菌株和过量生产全霉素的菌株的代谢组。鉴定出ΔhlmIstrains特有的一些代谢物。在这些代谢物中，烯醇已经被单甲基化和二甲基化的组合所失能。我们还观察到一种有趣的二聚体硫醚加合物，在野生型菌株中含量低，在ΔhlmIstrains中含量高。这些新型代谢物的结构突出了二氢二硫代吡洛酮支架的反应性。此外，生物测定表明，通过S‐烷基化修饰乙硫醇战斗部提供了一种宿主解毒策略，这种策略在产生这种生物活性二硫化物天然产物的多种物种中是共享的。
Biosynthesis of the dithiolopyrrolone antibiotic holomycin inStreptomyces clavuligerusinvolves the closure of a pair of enethiols to a cyclic disulfide. We have shown that the dithiol oxidase HlmI is responsible for the disulfide formation and this enzyme also plays a role in self‐protection. In the present study, we examine howS. clavuligerusdeals with the proposed toxic dithiol intermediates whenhlmIis deleted. We used differential NMR spectroscopy and mass spectrometry to profile the metabolomes ofhlmIdeletion mutants along with the wild‐type strain and a holomycin‐overproducing strain. A number of metabolites unique to ΔhlmIstrains were identified. In these metabolites the enethiols have been incapacitated by a combination of mono‐ and di‐S‐methylation. We also observed an intriguing dimeric thioether adduct in low quantities in the wild‐type strain and at much higher levels in the ΔhlmIstrains. The structures of these novel metabolites highlight the reactivity of the dihydrodithiolopyrrolone scaffold. Furthermore, bioassays suggest that modification of the enethiol warhead by S‐alkylation provides a host strategy for detoxification, one that is shared amongst multiple species producing such bioactive disulfide natural products.
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影响因子：
15
作者：
Forseth, Ry R.;Fox, Ellen M.;Chung, DaWoon;Howlett, Barbara J.;Keller, Nancy P.;Schroeder, Frank C.
通讯作者：
Schroeder, Frank C.
影响因子：
5.1
作者：
Sun, Yi;Takada, Kentaro;Matsunaga, Shigeki
通讯作者：
Matsunaga, Shigeki
影响因子：
3.2
作者：
Hjelmgaard, Thomas;Givskov, Michael;Nielsen, John
通讯作者：
Nielsen, John
DOI：
10.1073/pnas.0610503104
发表时间：
2007-01-30
影响因子：
11.1
作者：
Butcher, Rebecca A.;Schroeder, Frank C.;Clardy, Jon
通讯作者：
Clardy, Jon
影响因子：
3.2
作者：
TIPPER, DJ
通讯作者：
TIPPER, DJ