Evolution of chemical diversity by coordinated gene swaps in type II polyketide gene clusters

Abstract

Natural product biosynthetic pathways generate molecules of enormous structural complexity and exquisitely tuned biological activities. Studies of natural products have led to the discovery of many pharmaceutical agents, particularly antibiotics. Attempts to harness the catalytic prowess of biosynthetic enzyme systems, for both compound discovery and engineering, have been limited by a poor understanding of the evolution of the underlying gene clusters. We developed an approach to study the evolution of biosynthetic genes on a cluster-wide scale, integrating pairwise gene coevolution information with large-scale phylogenetic analysis. We used this method to infer the evolution of type II polyketide gene clusters, tracing the path of evolution from the single ancestor to those gene clusters surviving today. We identified 10 key gene types in these clusters, most of which were swapped in from existing cellular processes and subsequently specialized. The ancestral type II polyketide gene cluster likely comprised a core set of five genes, a roster that expanded and contracted throughout evolution. A key C24 ancestor diversified into major classes of longer and shorter chain length systems, from which a C20 ancestor gave rise to the majority of characterized type II polyketide antibiotics. Our findings reveal that (i) type II polyketide structure is predictable from its gene roster, (ii) only certain gene combinations are compatible, and (iii) gene swaps were likely a key to evolution of chemical diversity. The lessons learned about how natural selection drives polyketide chemical innovation can be applied to the rational design and guided discovery of chemicals with desired structures and properties.evolution | polyketide | natural products | gene cluster

Characterisation of Early-Life Fecal Microbiota in Susceptible and Healthy Pigs to Post-Weaning Diarrhoea

“…Moreover the predictive pathway involved in the biosynthesis of type II polyketide products was sharply lowered in H group. These organic compounds have a strong antimicrobial activity and in addition, their coding genes are mainly hosted by Actinobacteria phylum and Escherichia coli species [50,51]. The relative abundance of polyketide synthases is strongly associated to Escherichia coli overgrowth, initiation of inflammation, and intestinal inflammatory bowel diseases [52].…”

Using natural products for drug discovery: the impact of the genomics era

“…BGCs generally encode two groups of biosynthetic enzymes – one group generates key biosynthetic precursors and assembles the core scaffold while the other group derivatizes the scaffolds [116]. Understanding nature’s logic of encoding chemical diversity will enable rational engineering of biosynthetic pathways to obtain analogs of privileged natural product scaffolds or novel natural product-like scaffolds that may be challenging to synthesize chemically for drug discovery [116, 117]. …”

“…From an evolution perspective, enzymes may already be engaged in a biosynthetic pathway before the respective genes are physically recruited into the BGC through a mechanism that is yet to be determined [116]. Acyl carrier protein (ACP)-less PKS clusters suggest an alternative biosynthetic route or the possible recruitment of ACPs from outside the cluster [117]. Additionally, highly divergent BGCs in terms of both cluster architecture and gene sequence can have similar chemical outputs.…”

Structure and Dynamic Basis of Molecular Recognition Between Acyltransferase and Carrier Protein in E. coli Fatty Acid Synthesis

“…[1][2][3][4] FASs and PKSs exist as either multidomain megasynthases (type I) or as discrete monofunctional enzymes (type II). They both share a common evolutionary origin, [3][4][5][6][7] Figure 1). In contrast to type II FAS ATs, which only accept malonyl-CoA units, some ATs from PKSs accept a broader array of acyl-CoA units, as well as acyl-ACP units, increasing the structural diversity of their final products.…”