Engineering strategies for rational polyketide synthase design

Abstract

Covering: mid 1990s to 2018 Over the last two decades, diverse approaches have been explored to generate new polyketides by engineering polyketide synthases (PKSs). Although it has been proven possible to produce new compounds by designed PKSs, engineering strategies failed to make polyketides available via widely applicable rules and protocols. Still, organic synthetic routes have to be employed whenever new polyketides are needed for applications in medicine, agriculture, and industry. In light of the rising demand for commodity products from feedstock and for fast and cheap access to pharmaceutical compounds, the need for harnessing PKSs to produce such molecules is more urgent than ever before. In this review, we focus on a multitude of approaches to engineer modular PKSs by swapping and replacing PKS modules and domains, which we analyze in the light of recent structural and biochemical data. We conclude with an outlook on possible strategies on how to increase success rates of PKS engineering in future.

Isolation of two novel purple naphthoquinone pigments concomitant with the bioactive red bikaverin and derivates thereof produced by Fusarium oxysporum

“…Furthermore, the identification of all enzymes involved in the PKS pathway could also permit specific enzyme engineering, where catalytic activity and specificity could be improved, as well as novel chemical reactions created. Few attempts on engineering polyketide synthases (PKSs) enzymes were carried out with promising outcomes regarding pharmaceuticals and materials biosynthesis . In addition, because polyketide compounds were proven to have such versatile properties, new uses were considered and studied recently.…”

“…Few attempts on engineering polyketide synthases (PKSs) enzymes were carried out with promising outcomes regarding pharmaceuticals and materials biosynthesis. 50,51 In addition, because polyketide compounds were proven to have such versatile properties, new uses were considered and studied recently. Few of the more promising are the potential use of polyketide-based polymers, such as melanin, as functional material for cutting edge medical and technological applications.…”

Exploring the Promiscuous Enzymatic Activation of Unnatural Polyketide Extender Units in Vitro and in Vivo for Monensin Biosynthesis

“…Numerous approaches to introduce new‐to‐nature building blocks not supplied by the producing organism were investigated in previous studies …”

The Ketosynthase Domain Constrains the Design of Polyketide Synthases

“…between docking domains [5][6][7] or between the acyl carrier protein (ACP) and the ketosynthase (KS) at different stages in the catalytic cycle has been recognized ( Figure 1B), 4,[8][9][10] most strategies to modulate and adapt those interactions in chimeric modular PKSs have failed so far. [11][12][13][14] The 6-deoxyerythronolide B synthase (DEBS) is the prototypical example of this enzyme class and has served as a platform to study the structure, mechanism, and engineering potential of these enzymes ( Figure 1A). 15 In the past, numerous studies on DEBS have shed light on substrate tolerance, 6,16 protein-protein interaction specificities, 5,9,17,18 and structural characteristics [19][20][21] with broad relevance for the family of modular PKSs.…”