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首页> 外文期刊>The Journal of Antibiotics: An International Journal >Generation of New Epothilones by Genetic Engineering of a Polyketide Synthase in Myxococcus xanthus
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Generation of New Epothilones by Genetic Engineering of a Polyketide Synthase in Myxococcus xanthus

机译:通过基因工程的xythus粘球菌中的聚酮合酶的遗传工程产生新的上皮素。

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摘要

Epothilones,potent cytotoxic agents and potential anticancer drugs,are complex polyketides produced by a modular polyketide synthase (PKS).The epothilone PKS genes were introduced and expressed in Myxococcus xanthus and engineered to generate novel unnatural natural products which can be used as new scaffolds for chemical modification.Inactivation of the KR domain in module 6 of the epo PKS resulted in accumulation of 9-oxoepothilone D and its isomer 8-epi-9-oxoepothilone D as the major products.Modification of the KR domain in module 4 resulted in the production of the expected compound 12,13-dihydro-13-oxoepothilone C in trace amounts,and the unexpected compound 11,12-dehydro-12,13-dihydro-13-oxoepothilone D as the major product.The other expected compound,12,13-dihydro-13-oxoepothilone D,was not detected.The unexpected 13-oxo derivative produced indicates that the ER domain of module 5 has substrate-specificity requirements and suggests a second enzymatic role for the domain.
机译:上皮激素,潜在的细胞毒剂和潜在的抗癌药是由模块化聚酮化合物合酶(PKS)产生的复杂的聚酮化合物。埃博霉素PKS基因被引入并在黄色粘球菌中表达,并被工程化以产生新的非天然天然产物,可以用作新的天然支架材料化学修饰.epo PKS模块6中KR结构域的失活导致9-氧杂泛酮D及其异构体8-epi-9-氧杂泛酮D的积累为主要产物。模块4中KR结构域的修饰导致少量生产预期的化合物12,13-二氢-13-氧杂噻吩酮C,并以主要化合物意外的化合物11,12-dehydro-12,13-二氢-13-氧杂噻吩酮D.其他预期的化合物12 ,未检测到,13-二氢-13-氧杂噻吩酮D。产生的意外的13-氧代衍生物表明模块5的ER结构域具有底物特异性要求,并暗示了该结构域的第二种酶促作用。

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