6月7日，國(guó)際微生物學(xué)權(quán)威期刊Molecular Microbiology在線發(fā)表了我所姜衛(wèi)紅研究組的學(xué)術(shù)論文“Differential regulation of antibiotic biosynthesis by DraR-K, a novel two-component system in Streptomyces coelicolor”,。該研究揭示了天藍(lán)色鏈霉菌中新型雙組分系統(tǒng)DraR-K參與抗生素生物合成差異調(diào)控的分子機(jī)制。
雙組分系統(tǒng)(Two-component system,，TCS)是生物體感受外界刺激，調(diào)節(jié)細(xì)胞生理代謝和行為的信號(hào)傳導(dǎo)系統(tǒng)，由組氨酸激酶和應(yīng)答調(diào)控蛋白組成。TCS廣泛存在于微生物中,，參與調(diào)控初級(jí)與次級(jí)代謝,、形態(tài)分化、滲透壓以及致病性等重要生理過(guò)程,。鏈霉菌是自然界中最主要的抗生素產(chǎn)生菌,，對(duì)其開(kāi)展抗生素合成相關(guān)TCS的研究不僅有助于認(rèn)識(shí)其復(fù)雜的調(diào)控網(wǎng)絡(luò)，還可以指導(dǎo)工業(yè)菌株的遺傳改造,。
姜衛(wèi)紅組的博士研究生郁珍瑜和蘆銀華副研究員的工作發(fā)現(xiàn)，雙組分系統(tǒng)DraR-K能夠在高氮環(huán)境中被激活,，進(jìn)而正調(diào)控放線紫紅素(ACT)的合成,，同時(shí)負(fù)調(diào)控十一烷基靈菌紅素(RED)和黃色色素yCPK的生物合成。這些調(diào)控過(guò)程是由抗生素合成途徑特異性調(diào)控基因介導(dǎo)的,。同時(shí),，精確定位了DraR在下游靶基因actII-ORF4和kasO上游調(diào)控區(qū)的DNA結(jié)合序列；基于靶基序,，預(yù)測(cè)和鑒定了DraR-K的regulon,，并進(jìn)一步揭示DraR-K通過(guò)影響初級(jí)代謝間接參與抗生素生物合成調(diào)控的可能途徑。有趣的是,，draR-K的同源基因廣泛存在于不同鏈霉菌中,。除蟲(chóng)鏈霉菌draR-K的同源基因draR-Ksav的缺失導(dǎo)致阿維菌素產(chǎn)量大幅度提高，而寡霉素的產(chǎn)量卻下降,，提示由DraR-K介導(dǎo)的抗生素生物合成的差異調(diào)控機(jī)制在鏈霉菌中比較保守,。這種由TCS介導(dǎo)的抗生素生物合成的差異調(diào)控機(jī)制在鏈霉菌中尚屬首次發(fā)現(xiàn)。
該工作得到了中國(guó)科學(xué)院創(chuàng)新2020,、科技部973計(jì)劃,、國(guó)家自然科學(xué)基金委等項(xiàng)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
