Expanding primary metabolism helps generate the metabolic robustness to facilitate antibiotic biosynthesis in Streptomyces

Schniete, Jana K. and Cruz-Morales, Pablo and Selem-Mojica, Nelly and Fernández-Martínez, Lorena T. and Hunter, Iain S. and Barona-Gómez, Francisco and Hoskisson, Paul A. (2018) Expanding primary metabolism helps generate the metabolic robustness to facilitate antibiotic biosynthesis in Streptomyces. mBio, 9. e02283-17.

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    Abstract

    Abstract 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. Whilst the biosynthesis of these specialized metabolites is directed by dedicated biosynthetic gene clusters, little attention has been focussed on how these organisms have evolved robustness into 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 specialised metabolite producing bacterial families exhibit gene family expansion in primary metabolism. Focussing on a gene duplication event we show that the two pyruvate kinases in the genome of S. coelicolor arose by an ancient duplication event and that each have evolved altered enzymatic kinetics, with Pyk1 having a 20-fold higher Kcat than Pyk2 (4703 sec-1 compared to 215 sec-1 respectively) yet both are constitutively expressed. The pyruvate kinase mutants were also found to be compromised in terms of fitness when compared to wild-type Streptomyces. These data suggest that expanding gene familes can help maintain cell functionality during metabolic perturbation such as nutrient limitation and/or specialized metabolite production. Importance The rise of antimicrobial resistant infections has prompted a resurgence in interest in understanding the production of specialized metabolites by Streptomyces such as antibiotics. 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.