A pharmaceutical model for the molecular evolution of microbial natural products

Abstract

Microbes are talented chemists with the ability to generate tremendously complex and diverse natural products which harbor potent biological activities. Natural products are produced using sets of specialized biosynthetic enzymes encoded by secondary metabolism pathways. Here, we present a two‐step evolutionary model to explain the diversification of biosynthetic pathways that account for the proliferation of these molecules. We argue that the appearance of natural product families has been a slow and infrequent process. The first step led to the original emergence of bioactive molecules and different classes of natural products. However, much of the chemical diversity observed today has resulted from the endless modification of the ancestral biosynthetic pathways. The second step rapidly modulates the pre‐existing biological activities to increase their potency and to adapt to changing environmental conditions. We highlight the importance of enzyme promiscuity in this process, as it facilitates both the incorporation of horizontally transferred genes into secondary metabolic pathways and the functional differentiation of proteins to catalyze novel chemistry. We provide examples where single point mutations or recombination events have been sufficient for new enzymatic activities to emerge. A unique feature in the evolution of microbial secondary metabolism is that gene duplication is not essential but offers opportunities to synthesize more complex metabolites. Microbial natural products are highly important for the pharmaceutical industry due to their unique bioactivities. Therefore, understanding the natural mechanisms leading to the formation of diverse metabolic pathways is vital for future attempts to utilize synthetic biology for the generation of novel molecules.

Enzyme promiscuity and evolution in light of cellular metabolism

“…Katherine Ryan and co‐authors [9] describe one of the most frequently tinkering actions of evolution – emergence of oxygenases, and other unusual pyridoxal phosphate‐dependent enzymes. Other unconventional cases of recruitment of enzymes to perform completely new reactions are described by Mikko Metsä‐Ketelä and David Fewer [10], who also propose a new, general model for the evolution of natural products biosynthesis.…”

Thioesterase-mediated side chain transesterification generates potent Gq signaling inhibitor FR900359

“…TE phylogenetic analysis additionally suggests a close evolutionary relationship of the transesterifying FrsA TE and the macrocylizing FrsG TE , all together pointing at the evolution of all parts of frsA from ancestors within the BGC. It has been suggested, that some specialized microbial natural products may have evolved from ancestral metabolites, that had once been the end product of a biosynthetic pathway 1,47 . These ancestor molecules may have served as templates for structural variations based on evolutionary processes 47 .…”

“…It has been suggested, that some specialized microbial natural products may have evolved from ancestral metabolites, that had once been the end product of a biosynthetic pathway 1,47 . These ancestor molecules may have served as templates for structural variations based on evolutionary processes 47 . Bioinformatics studies, such as the reconstruction of the evolutionary history of the large natural product families of glycopeptides 57 and type II PK 58 , support this theory.…”

“…Finally, the evolutionary origin of the transesterifying FrsA TE was investigated. Generally, TE domains share low sequence homologies and are known to exhibit broad substrate promiscuities 6 , which is regarded as a prerequisite for the evolution of enzymes to catalysts with altered properties 1,47,48 . Indeed, no domain with high sequence homology was found in the database; its sequence identity to FrsG TE , catalyzing macrolactonization of 2, is 42% ( Supplementary Fig.…”

The FEBS Journal in 2021: a sharp reminder that science really matters

“…We published two Special Issues during the past year, the first on ‘Enzyme Promiscuity and Evolution’ (Fig. 1), edited by Dan Tawfik (The Weizmann Institute, Israel), which contained a range of excellent reviews comprehensively covering all aspects of this topic [1–11]. We also published a Special Issue on ‘Pseudoenzymes’ (Fig.…”