Abyssomicin biosynthesis: formation of an unusual polyketide, antibiotic-feeding studies and genetic analysis.
Abyssomicin biosynthesis: formation of an unusual polyketide, antibiotic-feeding studies and genetic analysis.
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DOI：
10.1002/cbic.201100172
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发表时间：
2011-06-14
期刊：
影响因子：
3.2
通讯作者：
Suessmuth, Roderich D.
中科院分区：
文献类型：
--
作者：
Gottardi, Elvira M.;Krawczyk, Joanna M.;von Suchodoletz, Hanna;Schadt, Simone;Muehlenweg, Agnes;Uguru, Gabriel C.;Pelzer, Stefan;Fiedler, Hans-Peter;Bibb, Mervyn J.;Stach, James E. M.;Suessmuth, Roderich D.
由海洋放线菌Verrucosispora maris AB-18-032产生的Abyssomicin C对革兰氏阳性菌（包括耐甲氧西林金黄色葡萄球菌（MRSA））具有活性，并在四氢叶酸合成过程中抑制对氨基苯甲酸盐的形成;它是第一种对这种治疗靶点具有活性的天然产物。为了研究这种小但结构复杂的次级代谢产物的生物合成，我们使用13 C标记的聚酮化合物构建块进行了饲养研究。阿育霉素C的形成需要两个丙酸盐，五个乙酸盐和一个葡萄糖衍生的代谢产物。对深海霉素生物合成基因簇的鉴定和测序显示，海洋疣孢菌AB-18-032 DNA的57 kb片段含有深海霉素生物合成所需的所有基因。通过基因失活和互补实验（首次对该属成员进行遗传操作）证实了生物合成基因簇的身份，并提出了一个AbyssomicinC生物合成的模型。对新型抗生素的探索导致了对以前未被审查和极端栖息地的探索，如深海，洞穴，沙漠和山脉，以分离具有未开发的生物合成潜力的新微生物菌株。[1，2]同时，合理的方法已经确定了新的治疗有用的细菌靶标。[2，3]叶酸途径在细菌中对于芳香族氨基酸和嘌呤核苷酸的合成是必需的，并且在发病机制中起着重要作用。该途径也存在于藻类、高等植物、真菌和顶复门寄生虫中，但不存在于哺乳动物中，因此是开发新治疗化合物的极好的潜在靶标。[4]到目前为止，只有合成药物
Abyssomicin C, produced by the marine actinomycete Verrucosispora maris AB-18-032, is active against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA) and inhibits p-aminobenzoate formation during tetrahydrofolate synthesis; it is the first natural product active against this therapeutic target. To investigate the biosynthesis of this small but structurally complex secondary metabolite, we carried out feeding studies using 13C labelled polyketide building blocks. Formation of abyssomicin C requires two propionates, five acetates and one glucose-derived metabolite. Identification and sequencing of the abyssomicin biosynthetic gene cluster revealed a 57kb segment of Verrucosispora maris AB-18-032 DNA that contained all of the genes necessary for abyssomicin biosynthesis. The identity of the biosynthetic gene cluster was confirmed by gene inactivation and complementation experiments (the first genetic manipulation of a member of this genus) and a model for abyssomicinC biosynthesis is proposed.The search for novel antibiotics has led to the exploration of previously unscrutinised and extreme habitats, such as the deep oceans, caves, deserts and mountains, to isolate new microbial strains with untapped biosynthetic potential.[1, 2] Concomitantly, rational approaches have identified new therapeutically useful bacterial targets.[2, 3] The folate pathway is essential in bacteria for the synthesis of aromatic amino acids and purine nucleotides, and plays an essential role in pathogenesis. The pathway is also present in algae, higher plants, fungi and apicomplexan parasites, but absent from mammals, and is, thus, an excellent potential target for the development of new therapeutic compounds.[4] So far, only synthetic drugs are
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DOI：
10.1016/j.str.2009.10.018
发表时间：
2010-01-13
期刊：
Structure (London, England : 1993)
影响因子：
--
作者：
Akey DL;Razelun JR;Tehranisa J;Sherman DH;Gerwick WH;Smith JL
通讯作者：
Smith JL
影响因子：
4.4
作者：
Beye, M;Poch, A;Lehrach, H
通讯作者：
Lehrach, H
影响因子：
4.3
作者：
Herold, K;Gollmick, FA;Hertweck, C
通讯作者：
Hertweck, C
影响因子：
16.6
作者：
Keller, Simone;Schadt, Heiko S.;Suessmuth, Roderich D.
通讯作者：
Suessmuth, Roderich D.
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