Comparative genomics and transcriptomics analyses provide insights into the high yield and regulatory mechanism of Norvancomycin biosynthesis in Amycolatopsis orientalis NCPC 2-48.
Comparative genomics and transcriptomics analyses provide insights into the high yield and regulatory mechanism of Norvancomycin biosynthesis in Amycolatopsis orientalis NCPC 2-48.
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比较基因组学和转录组学分析提供了对东方无枝霉 NCPC 2-48 中去甲万古霉素生物合成的高产率和调控机制的见解
DOI：
10.1186/s12934-021-01521-6
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发表时间：
2021-02-02
影响因子：
6.4
通讯作者：
Hong B
中科院分区：
文献类型：
--
作者：
Li X;Zhang C;Zhao Y;Lei X;Jiang Z;Zhang X;Zheng Z;Si S;Wang L;Hong B
在我国，去甲万古霉素已广泛用于临床治疗耐甲氧西林金黄色葡萄球菌（MRSA）和耐甲氧西林表皮葡萄球菌（MRSE）感染。东方拟无枝酸菌（Amycolatopsis orientalis）NCPC 2 - 48是从东方拟无枝酸菌（A.东方梭菌CPCC 200066已应用于华北制药集团去甲万古霉素的工业化大生产。然而，去甲万古霉素生物合成途径中潜在的高产和调控机制尚未得到解决。在这里，我们对A. orientalis CPCC 200066和NCPC 2 - 48。这两个基因组非常相似，同一性超过99.9%，在去甲万古霉素生物合成基因簇中没有发现重复和结构变异。比较转录组学分析表明，去甲万古霉素的生物合成基因，以及去甲万古霉素的生物合成前体的一些初级代谢途径普遍上调。AoStrR1和AoLuxR1是去甲万古霉素簇中的两个簇定位调控基因，在高产菌株中48 h分别上调23.3倍和5.8倍。AoStrR1和AoLuxR1在CPCC 200066中的过表达导致去甲万古霉素产量的增加，表明它们在去甲万古霉素生物合成中的积极作用。此外，AoStrR1可以通过与至少8个去甲万古霉素生物合成基因或操纵子的启动子直接相互作用来调节去甲万古霉素的生产。我们的研究结果表明，NCPC 2 - 48的高产可以归因于其簇中去甲万古霉素生物合成基因以及负责其前体供应的基因的表达水平增加。去甲万古霉素生物合成基因可能受AoStrR1和AoLuxR1调控，其中AoStrR1可能是去甲万古霉素生物合成的最终途径特异性调控因子。这些结果有助于进一步阐明去甲万古霉素工业化生产菌株生物合成的整体性和途径特异性调控机制。
Norvancomycin has been widely used in clinic to treat against MRSA (Methicillin-resistant Staphylococcus aureus) and MRSE (Methicillin-resistant Staphylococcus epidermidis) infections in China. Amycolatopsis orientalis NCPC 2-48, a high yield strain derived from A. orientalis CPCC 200066, has been applied in industrial large-scale production of norvancomycin by North China Pharmaceutical Group. However, the potential high-yield and regulatory mechanism involved in norvancomycin biosynthetic pathway has not yet been addressed. Here we sequenced and compared the genomes and transcriptomes of A. orientalis CPCC 200066 and NCPC 2-48. These two genomes are extremely similar with an identity of more than 99.9%, and no duplication and structural variation was found in the norvancomycin biosynthetic gene cluster. Comparative transcriptomic analysis indicated that biosynthetic genes of norvancomycin, as well as some primary metabolite pathways for the biosynthetic precursors of norvancomycin were generally upregulated. AoStrR1 and AoLuxR1, two cluster-situated regulatory genes in norvancomycin cluster, were 23.3-fold and 5.8-fold upregulated in the high yield strain at 48 h, respectively. Over-expression of AoStrR1 and AoLuxR1 in CPCC 200066 resulted in an increase of norvancomycin production, indicating their positive roles in norvancomycin biosynthesis. Furthermore, AoStrR1 can regulate the production of norvancomycin by directly interacting with at least 8 promoters of norvancomycin biosynthetic genes or operons. Our results suggested that the high yield of NCPC 2-48 can be ascribed to increased expression level of norvancomycin biosynthetic genes in its cluster as well as the genes responsible for the supply of its precursors. The norvancomycin biosynthetic genes are presumably regulated by AoStrR1 and AoLuxR1, of them AoStrR1 is possibly the ultimate pathway-specific regulator for the norvancomycin production. These results are helpful for further clarification of the holistic and pathway-specific regulatory mechanism of norvancomycin biosynthesis in the industrial production strain.
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发现具有任意插入和删除的序列基序。
影响因子：
4.3
作者：
Frith, Martin C.;Saunders, Neil F. W.;Kobe, Bostjan;Bailey, Timothy L.
通讯作者：
Bailey, Timothy L.
影响因子：
14.9
作者：
Kanehisa M;Araki M;Goto S;Hattori M;Hirakawa M;Itoh M;Katayama T;Kawashima S;Okuda S;Tokimatsu T;Yamanishi Y
通讯作者：
Yamanishi Y
DOI：
10.1093/bioinformatics/btp472
发表时间：
2009-10-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Nicol JW;Helt GA;Blanchard SG Jr;Raja A;Loraine AE
通讯作者：
Loraine AE
影响因子：
10.7
作者：
Kumar, Sudhir;Stecher, Glen;Tamura, Koichiro
通讯作者：
Tamura, Koichiro
生物合成中间体与 AtrA 的结合调节球孢链霉菌产生力达霉素
影响因子：
3.6
作者：
Li, Xingxing;Yu, Tengfei;Hong, Bin
通讯作者：
Hong, Bin