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Abstract：
Sch47554 and Sch47555 are two angucyclines with antifungal activities against various yeasts and dermatophytes from Streptomyces sp. SCC-2136. The sch gene cluster contains several putative regulatory genes. Both schA4 and schA21 were predicted as the TetR family transcriptional regulators, whereas schA16 shared significant similarity to the AraC family transcriptional regulators. Although Sch47554 is the major product of Streptomyces sp. SCC-2136, its titer is only 6.72 mg/L. This work aimed to increase the production of this promising antifungal compound by investigating and manipulating the regulatory genes in the Sch47554 biosynthetic pathway. Disruption of schA4 and schA16 led to a significant increase in the production of Sch47554, whereas the titer was dramatically decreased when schA21 was disrupted. Overexpression of these genes gave opposite results. The highest titer of Sch47554 was achieved in Streptomyces sp. SCC-2136/ΔschA4 (27.94 mg/L), which is significantly higher than the wild type. Our results indicate that SchA4 and SchA16 are repressors, whereas SchA21 acts as an activator. This work thus provides an initial understanding of functional roles of regulatory elements in the biosynthesis of Sch47554. Several efficient producing strains of Sch47554 were constructed by disrupting or overexpressing particular regulatory genes, which can be further engineered for industrial production of this medicinally important molecule.
摘要：
Sch47554和Sch47555是两种异形霉素，对来自链霉菌属的各种酵母和皮肤癣菌具有抗真菌活性。SCC-2136.sch基因簇包含几个推定的调节基因。schA4和schA21都被预测为TetR家族转录调节因子，而schA16与AraC家族转录调节因子具有显著相似性。虽然Sch47554是链霉菌属的主要产物。SCC-2136,其效价仅为6.72mg/L。这项工作旨在通过研究和操纵Sch47554生物合成途径中的调节基因来增加这种有前途的抗真菌化合物的产量。schA4和schA16的破坏导致Sch47554的产量显着增加，而当schA21被破坏时，滴度急剧下降。这些基因的过表达给出了相反的结果。在链霉菌属中，Sch47554的滴度最高。SCC-2136/ΔschA4（27.94mg/L），显著高于野生型。我们的结果表明，SchA4和SchA16是抑制因子，而SchA21作为激活剂。因此，这项工作提供了对调节元件在Sch47554生物合成中的功能作用的初步了解。通过破坏或过表达特定的调控基因，构建了几种有效的生产Sch47554的菌株。可以进一步设计用于工业生产这种重要的药物分子。
