School of Life Sciences, Institute of Physical Science and Information Technology, Anhui University, Hefei, 230601, China.
School of Life Sciences, Anhui Agricultural University, Hefei, 230036, China.
Appl Microbiol Biotechnol. 2022 Oct;106(19-20):6551-6566. doi: 10.1007/s00253-022-12153-0. Epub 2022 Sep 9.
TetR family transcriptional regulators (TFRs) are widespread in actinomycetes, which exhibit diverse regulatory modes in antibiotic biosynthesis. Nitrogen regulators play vital roles in modulation of primary and secondary metabolism. However, crosstalk between TFR and nitrogen regulator has rarely been reported in actinomycetes. Herein, we demonstrated that a novel TFR, SACE_4839, was negatively correlated with erythromycin yield in Saccharopolyspora erythraea A226. SACE_4839 indirectly suppressed erythromycin synthetic gene eryAI and resistance gene ermE and directly inhibited its adjacent gene SACE_4838 encoding a homologue of nitrogen metabolite repression (NMR) regulator NmrA (herein named NmrR). The SACE_4839-binding sites within SACE_4839-nmrR intergenic region were identified. NmrR positively controlled erythromycin biosynthesis by indirectly stimulating eryAI and ermE and directly repressing SACE_4839. NmrR was found to affect growth viability under the nitrogen source supply. Furthermore, NmrR directly repressed glutamine and glutamate utilization-related genes SACE_1623, SACE_5070 and SACE_5979 but activated nitrate utilization-associated genes SACE_1163, SACE_4070 and SACE_4912 as well as nitrite utilization-associated genes SACE_1476 and SACE_4514. This is the first reported NmrA homolog for modulating antibiotic biosynthesis and nitrogen metabolism in actinomycetes. Moreover, combinatorial engineering of SACE_4839 and nmrR in the high-yield S. erythraea WB resulted in a 68.8% increase in erythromycin A production. This investigation deepens the understanding of complicated regulatory network for erythromycin biosynthesis. KEY POINTS: • SACE_4839 and NmrR had opposite contributions to erythromycin biosynthesis. • NmrR was first identified as a homolog of another nitrogen regulator NmrA. • Cross regulation between SACE_4839 and NmrR was revealed.
TetR 家族转录调节因子（TFRs）广泛存在于放线菌中，它们在抗生素生物合成中表现出多种调节模式。氮调节剂在初级和次级代谢的调节中起着至关重要的作用。然而，TFR 和氮调节剂之间的串扰在放线菌中很少有报道。本文中，我们证实了一种新型 TFR SACE_4839 与红链霉菌 A226 中的红霉素产量呈负相关。SACE_4839 间接抑制红霉素合成基因 eryAI 和抗性基因 ermE，并直接抑制其相邻基因 SACE_4838，该基因编码氮代谢物抑制（NMR）调节剂 NmrA 的同源物（此处命名为 NmrR）。鉴定了 SACE_4839-nmrR 基因间区的 SACE_4839 结合位点。NmrR 通过间接刺激 eryAI 和 ermE 并直接抑制 SACE_4839 来正向调控红霉素生物合成。发现 NmrR 会影响氮源供应下的生长活力。此外，NmrR 直接抑制谷氨酰胺和谷氨酸利用相关基因 SACE_1623、SACE_5070 和 SACE_5979，但激活硝酸盐利用相关基因 SACE_1163、SACE_4070 和 SACE_4912 以及亚硝酸盐利用相关基因 SACE_1476 和 SACE_4514。这是首次报道的用于调节放线菌中抗生素生物合成和氮代谢的 NmrA 同源物。此外，在高产红链霉菌 WB 中对 SACE_4839 和 nmrR 进行组合工程改造，使红霉素 A 的产量增加了 68.8%。这项研究加深了对红霉素生物合成复杂调控网络的理解。 关键点： • SACE_4839 和 NmrR 对红霉素生物合成有相反的贡献。 • NmrR 首次被鉴定为另一种氮调节剂 NmrA 的同源物。 • 揭示了 SACE_4839 和 NmrR 之间的交叉调节。
