Expanding Primary Metabolism Helps Generate the Metabolic Robustness To Facilitate Antibiotic Biosynthesis in Streptomyces.
Expanding Primary Metabolism Helps Generate the Metabolic Robustness To Facilitate Antibiotic Biosynthesis in Streptomyces.
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DOI：
10.1128/mbio.02283-17
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发表时间：
2018-02-06
期刊：
影响因子：
6.4
通讯作者：
Hoskisson PA
中科院分区：
文献类型：
--
作者：
Schniete JK;Cruz-Morales P;Selem-Mojica N;Fernández-Martínez LT;Hunter IS;Barona-Gómez F;Hoskisson PA
通过基因复制或水平基因转移（HGT）扩大生物体的遗传库可以帮助适应。链霉菌属细菌是具有生物活性的专门代谢物的多产者，这些代谢物在自然界中具有适应性功能，并且在人类医学中具有广泛的用途。虽然这些专门的代谢物的生物合成是由专门的生物合成基因簇指导的，但很少有人关注这些生物体如何在其基因组中进化出稳健性，以促进在从营养生长到专门的代谢物产生和孢子形成的复杂代谢过渡期间为生物合成提供化学前体所需的代谢可塑性。在这里，我们研究遗传冗余放线菌，并表明，专门的代谢产物产生细菌家族表现出基因家族扩展的初级代谢。聚焦于基因复制事件，我们发现天蓝色链霉菌基因组中的两种丙酮酸激酶是由一个古老的复制事件产生的，并且每一种都进化出了改变的酶动力学，Pyk 1的kcat比Pyk 2高20倍（分别为4，703 s−1和215 s− 1），但两者都是组成型表达的。丙酮酸激酶突变体也被发现是妥协的健身方面相比，野生型链霉菌。这些数据表明，扩大基因家族可以帮助维持细胞功能代谢干扰，如营养限制和/或专门的代谢产物的生产。抗生素耐药性感染的兴起促使人们重新对链霉菌产生专门代谢产物（如抗生素）产生兴趣。编码相同酶功能的多个基因的存在是链霉菌生物学的一个方面，很少受到关注;然而，了解代谢扩张如何影响这些生物体可以帮助提高临床有用分子的生产。在这里，我们表明，扩大丙酮酸激酶的数量，使代谢适应，增加菌株的健身，并代表了一个很好的目标代谢工程的工业专门的代谢产物生产的细菌和激活的隐蔽专门的代谢产物。
The expansion of the genetic repertoire of an organism by gene duplication or horizontal gene transfer (HGT) can aid adaptation. Streptomyces bacteria are prolific producers of bioactive specialized metabolites that have adaptive functions in nature and have found extensive utility in human medicine. While the biosynthesis of these specialized metabolites is directed by dedicated biosynthetic gene clusters, little attention has been focused on how these organisms have evolved robustness in their genomes to facilitate the metabolic plasticity required to provide chemical precursors for biosynthesis during the complex metabolic transitions from vegetative growth to specialized metabolite production and sporulation. Here, we examine genetic redundancy in actinobacteria and show that specialized metabolite-producing bacterial families exhibit gene family expansion in primary metabolism. Focusing on a gene duplication event, we show that the two pyruvate kinases in the genome of Streptomyces coelicolor arose by an ancient duplication event and that each has evolved altered enzymatic kinetics, with Pyk1 having a 20-fold-higher kcat than Pyk2 (4,703 s−1 compared to 215 s−1, respectively), and yet both are constitutively expressed. The pyruvate kinase mutants were also found to be compromised in terms of fitness compared to wild-type Streptomyces. These data suggest that expanding gene families can help maintain cell functionality during metabolic perturbation such as nutrient limitation and/or specialized metabolite production. The rise of antimicrobial-resistant infections has prompted a resurgence in interest in understanding the production of specialized metabolites, such as antibiotics, by Streptomyces. The presence of multiple genes encoding the same enzymatic function is an aspect of Streptomyces biology that has received little attention; however, understanding how the metabolic expansion influences these organisms can help enhance production of clinically useful molecules. Here, we show that expanding the number of pyruvate kinases enables metabolic adaptation, increases strain fitness, and represents an excellent target for metabolic engineering of industrial specialized metabolite-producing bacteria and the activation of cryptic specialized metabolites.
影响因子：
3.7
作者：
Clark LC;Hoskisson PA
通讯作者：
Hoskisson PA