Division of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705-2222, USA.
J Antibiot (Tokyo). 2010 Aug;63(8):482-5. doi: 10.1038/ja.2010.55. Epub 2010 Jun 16.
Manipulation of pathway regulation is an efficient strategy to increase specific secondary metabolite production. In this study, we successfully improved the production of both the enediyne antitumor antibiotic C-1027 and a heptaene, an early metabolite of the C-1027 pathway, by manipulating the three regulatory genes, sgcR1, sgcR2 and sgcR3, within the C-1027 biosynthetic gene cluster. SgcR3 has previously been established as an activator, and we now propose that SgcR1 and SgcR2 are also positive regulators based on their upregulation effects on titer and/or timing of heptaene and C-1027 production in Streptomyces globisporus. Specifically, overexpression of sgcR1 significantly improved the production of heptaene (about fivefold) and C-1027 (two- to threefold) compared with the wild-type strain. However, the titers of heptaene and C-1027 were not increased by overexpressing all the three activators together, underscoring the complexity of C-1027 biosynthetic pathway regulation. The possibility of exploiting the heptaene as a readily identifiable and unique indicator for rapidly detecting enediyne production was also assessed.
通路调控的操作为提高特定次生代谢产物的产量提供了一种有效的策略。在本研究中，我们成功地通过操纵 C-1027 生物合成基因簇中的三个调节基因 sgcR1、sgcR2 和 sgcR3，提高了烯二炔抗肿瘤抗生素 C-1027 和庚烯，即 C-1027 途径的早期代谢物的产量。此前已经证实 SgcR3 是一种激活剂，根据其对庚烯和 C-1027 产量的上调作用，我们现在提出 SgcR1 和 SgcR2 也是正调控因子。在球形链霉菌中。具体来说，与野生型菌株相比，sgcR1 的过表达显著提高了庚烯（约五倍）和 C-1027（两倍至三倍）的产量。然而，过表达所有三个激活剂并没有增加庚烯和 C-1027 的产量，这突显了 C-1027 生物合成途径调控的复杂性。还评估了将庚烯用作快速检测烯二炔产生的易于识别和独特的指示剂的可能性。
