Evolution natural product biosynthesis

As outlined above the chemical structure space accessible to small drug-like molecules is so vast that it cannot be covered by chemical synthesis in a comprehensive and meaningful manner. During evolution nature herself has explored only a tiny fraction of chemical space in the biosynthesis of low molecular weight natural products. The same is true for the evolution of the targets bound and modulated by natural products, for example proteins. It has been estimated that during the evolution of a protein consisting of about 100 amino acids only a tiny fraction of all amino acid combinations could have been biosynthesized. However, in protein evolution, structure is even more conserved than the sequence since similar structures can be formed by very different sequences. Thus the protein structure space explored by nature is limited in size. ... 

In avermectin Bl, there is a double bond between C-22 and C-23, whereas in avermectin B2 R OH. The product ratio of B2 to Bl is 1.6 1. Since the Bl analog is much more effective as an antiparasite, there is a desire to improve the B1 B2 ratio, which can be achieved by a dehydratase domain [88, 89]. Its directed evolution and mutant screening led to a mutant giving an excellent fermentation titer of Bl B2 = 1 0.07 [90, 91]. As a result of understanding the biosynthesis, pathway engineering, and directed evolution, a biologically superior new product, doramectin (Dectomax ), was evolved from a mixture of eight natural products. 

Terpenes form the largest and structurally one of the most intriguing classes of natural products. When looking at their structures, it becomes clear that the evolution of terpene biosynthesis must have been one of the biggest challenges... 

Polyketides form a group of diverse and structurally complex bioactive natural products. Their biosynthesis is directed by multi-domain polyketide megasynthases (PKSs), which extend the acyl chain by a series of condensation and optional reduction steps. Phylogenetic work has shown that, in a particular group of type I systems known as Irons-AT PKSs, the ketosynthase (KS) domains potentially harbour specificity towards the nature of the first four carbons of the intermediate substrate (e.g. beta-hydroxy, enoyl, methyl-branched). These results suggest a close link between KS evolution and substrate specificity. 

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