6月7日，国际微生物学权威期刊Molecular Microbiology在线发表了我所姜卫红研究组的学术论文“Differential regulation of antibiotic biosynthesis by DraR-K, a novel two-component system in Streptomyces coelicolor”。该研究揭示了天蓝色链霉菌中新型双组分系统DraR-K参与抗生素生物合成差异调控的分子机制。
双组分系统(Two-component system，TCS)是生物体感受外界刺激，调节细胞生理代谢和行为的信号传导系统，由组氨酸激酶和应答调控蛋白组成。TCS广泛存在于微生物中，参与调控初级与次级代谢、形态分化、渗透压以及致病性等重要生理过程。链霉菌是自然界中最主要的抗生素产生菌，对其开展抗生素合成相关TCS的研究不仅有助于认识其复杂的调控网络，还可以指导工业菌株的遗传改造。
姜卫红组的博士研究生郁珍瑜和芦银华副研究员的工作发现，双组分系统DraR-K能够在高氮环境中被激活，进而正调控放线紫红素(ACT)的合成，同时负调控十一烷基灵菌红素(RED)和黄色色素yCPK的生物合成。这些调控过程是由抗生素合成途径特异性调控基因介导的。同时，精确定位了DraR在下游靶基因actII-ORF4和kasO上游调控区的DNA结合序列；基于靶基序，预测和鉴定了DraR-K的regulon，并进一步揭示DraR-K通过影响初级代谢间接参与抗生素生物合成调控的可能途径。有趣的是，draR-K的同源基因广泛存在于不同链霉菌中。除虫链霉菌draR-K的同源基因draR-Ksav的缺失导致阿维菌素产量大幅度提高，而寡霉素的产量却下降，提示由DraR-K介导的抗生素生物合成的差异调控机制在链霉菌中比较保守。这种由TCS介导的抗生素生物合成的差异调控机制在链霉菌中尚属首次发现。
该工作得到了中国科学院创新2020、科技部973计划、国家自然科学基金委等项目的支持。（生物谷Bioon.com）
doi:10.1111/j.1365-2958.2012.08126.x
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Differential regulation of antibiotic biosynthesis by DraR-K, a novel two-component system in Streptomyces coelicolor
Zhenyu Yu1,2, Hong Zhu1, Fujun Dang1, Weiwen Zhang3, Zhongjun Qin1, Sheng Yang1, Huarong Tan4, Yinhua Lu1,*, Weihong Jiang1,*
A novel two-component system (TCS) designated as DraR-K (sco3063/sco3062) was identified to be involved in differential regulation of antibiotic biosynthesis in Streptomyces coelicolor. The S. coelicolor mutants with deletion of either or both of draR and draK exhibited significantly reduced actinorhodin (ACT) but increased undecylprodigiosin (RED) production on minimal medium (MM) supplemented separately with high concentration of different nitrogen sources. These mutants also overproduced a yellow-pigmented type I polyketide (yCPK) on MM with glutamate (Glu). It was confirmed that DraR-K activates ACT but represses yCPK production directly through the pathway-specific activator genes actII-ORF4 and kasO, respectively, while its role on RED biosynthesis was independent of pathway-specific activator genes redD/redZ. DNase I footprinting assays revealed that the DNA binding sites for DraR were at −124 to −98 nt and −24 to −1 nt relative to the respective transcription start point of actII-ORF4 and kasO. Comparison of the binding sites allowed the identification of a consensus DraR-binding sequence, 5′-AMAAWYMAKCA-3′ (M: A or C; W: A or T; Y: C or T; K: G or T). By genome screening and gel-retardation assay, 11 new targets of DraR were further identified in the genome of S. coelicolor. Functional analysis of these tentative targets revealed the involvement of DraR-K in primary metabolism. DraR-K homologues are widely spread in different streptomycetes. Interestingly, deletion of draR-Ksav (sav_3481/sav_3480, homologue of draR-K) in the industrial model strain S. avermitilis NRRL-8165 led to similar abnormal antibiotic biosynthesis, showing higher avermectin while slightly decreased oligomycin A production, suggesting that DraR-K-mediated regulation system might be conserved in streptomycetes. This study further reveals the complexity of TCS in regulation of antibiotic biosynthesis in Streptomyces
