Intermediates in monensin biosynthesis: A late step in biosynthesis of the polyether ionophore monensin is crucial for the integrity of cation binding.
Intermediates in monensin biosynthesis: A late step in biosynthesis of the polyether ionophore monensin is crucial for the integrity of cation binding.
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DOI：
10.3762/bjoc.10.34
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发表时间：
2014
影响因子：
2.7
通讯作者：
Leadlay PF
中科院分区：
文献类型：
--
作者：
Hüttel W;Spencer JB;Leadlay PF
聚醚抗生素，如莫能菌素，是通过在假定的聚氧化物前体上操作的定向环扩张级联进行生物合成的。所得到的结构含有熔融环醚和亲脂性主链，可与某些金属阳离子形成强的电离性配合物。在这项工作中，我们证明了莫能菌素的生物合成，以及醚的形成，后期羟基化步骤对莫能菌素钠复合物的正确形成至关重要。我们研究了莫能菌素生物合成的最后两个步骤，即P450单加氧酶MonD催化的羟基化和甲基转移酶MonE催化的o -甲基化。在产莫能菌素过量的肉桂链霉菌中，相应的基因在框架内被删除。突变体以优异的产量产生预期的莫能菌素衍生物（ΔmonD: 1.13 g L−1去羟基莫能菌素；ΔmonE: 0.50 g L−1去甲基莫能菌素；双突变体ΔmonDΔmonE: 0.34 g L−1去羟基去甲基莫能菌素）。从去羟基莫能菌素和去甲基莫能菌素纯化后得到单晶。x射线结构分析表明，二甲基莫能菌素钠与莫能菌素钠的构象非常相似。相反，在去羟基莫能菌素钠复合物中，钠离子的配位有显著不同。这表明莫能菌素钠复合物的最终构成需要这一剪裁步骤以及聚醚的形成。
Polyether antibiotics such as monensin are biosynthesised via a cascade of directed ring expansions operating on a putative polyepoxide precursor. The resulting structures containing fused cyclic ethers and a lipophilic backbone can form strong ionophoric complexes with certain metal cations. In this work, we demonstrate for monensin biosynthesis that, as well as ether formation, a late-stage hydroxylation step is crucial for the correct formation of the sodium monensin complex. We have investigated the last two steps in monensin biosynthesis, namely hydroxylation catalysed by the P450 monooxygenase MonD and O-methylation catalysed by the methyl-transferase MonE. The corresponding genes were deleted in-frame in a monensin-overproducing strain of Streptomyces cinnamonensis. The mutants produced the expected monensin derivatives in excellent yields (ΔmonD: 1.13 g L−1 dehydroxymonensin; ΔmonE: 0.50 g L−1 demethylmonensin; and double mutant ΔmonDΔmonE: 0.34 g L−1 dehydroxydemethylmonensin). Single crystals were obtained from purified fractions of dehydroxymonensin and demethylmonensin. X-ray structure analysis revealed that the conformation of sodium dimethylmonensin is very similar to that of sodium monensin. In contrast, the coordination of the sodium ion is significantly different in the sodium dehydroxymonensin complex. This shows that the final constitution of the sodium monensin complex requires this tailoring step as well as polyether formation.
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影响因子：
--
作者：
Gallimore, AR;Stark, CBW;Spencer, JB
通讯作者：
Spencer, JB
影响因子：
15
作者：
DUAX, WL;SMITH, GD;STRONG, PD
通讯作者：
STRONG, PD
影响因子：
--
作者：
Harvey, Barbara M.;Mironenko, Tatiana;Haydock, Stephen F.
通讯作者：
Haydock, Stephen F.
影响因子：
64.5
作者：
Gupta PB;Onder TT;Jiang G;Tao K;Kuperwasser C;Weinberg RA;Lander ES
通讯作者：
Lander ES
DOI：
10.1073/pnas.0337542100
发表时间：
2003-02-18
影响因子：
11.1
作者：
Gust, B;Challis, GL;Chater, KF
通讯作者：
Chater, KF