Recent Advances in Re-engineering Modular PKS and NRPS Assembly Lines
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pISSN 1226-8372 eISSN 1976-3816
REVIEW PAPER
Recent Advances in Re-engineering Modular PKS and NRPS Assembly Lines Charlotte Beck, Jaime Felipe Guerrero Garzón, and Tilmann Weber
Received: 18 August 2020 / Revised: 9 October 2020 / Accepted: 11 October 2020 © The Korean Society for Biotechnology and Bioengineering and Springer 2020
Abstract Polyketides such as the antibiotic erythromycin or the immunosuppressant rapamycin, and non-ribosomal peptides, such as the antibiotics penicillin or vancomycin, are important classes of natural products. The core of these molecules are biosynthesized by large polyketide synthases (PKS) and non-ribosomal peptide synthetases (NRPS), respectively. The modular architecture of these enzymatic assembly lines makes them interesting candidates for synthetic biology approaches. The re-engineering efforts aim to understand the molecular structure, produce new compounds, produce analogs of known compounds, tag the products or improve activity and/or yield. Here, we first consider the definition of PKS and NRPS modules, then give an overview of different strategies for re-engineering and finally review recent examples of PKS and NRPS reengineering. Keywords: antibiotics, secondary metabolites, polyketide, non-ribosomal peptide, PKS, NRPS, synthetic biology
1. Introduction Bacteria are a vast resource for bioactive compounds, because of their rich secondary metabolomes. With modern advances in whole genome sequencing and genome mining, rational designs and modifications can be made for production of novel compounds or activation of silent clusters [1-3]. Charlotte Beck†, Jaime Felipe Guerrero Garzón†, Tilmann Weber* The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kemitorvet, Building 220, 2800 Kgs. Lyngby, Denmark Tel: +45-24-89-6132 E-mail: [email protected] †
shared first authorship
Polyketides (PKs) and non-ribosomal peptides (NRPs) are two of the largest and most diverse groups within natural products including many important drugs like erythromycin, rapamycin, penicillin, and vancomycin. Despite the fact that polyketides and non-ribosomal peptides are not chemically related, they share certain similarities regarding their biosynthesis. Type I PKs and NRPs are biosynthesised by huge multimodular enzymatic machineries, polyketide synthases (PKSs), and non-ribosomal peptide synthetases (NRPSs), respectively [4,5], that build a molecular assembly line. Generally, each enzymatic module is capable of incorporating one building block, also referred to as “extender unit”, into the nascent polymeric chain; carboxyacyl monomers in the case of PKs [6], and amino acids in the case of NRPs [7]. The modules within PKSs and NRPSs contain sets of catalytic domains that play similar roles in both assembly lines. For each type of module, there exist a gatekeeper domain which is responsible for the selection and loading of the correct extender unit or monomer within each elongation step (AT domains in case of PKSs, and A domains for NRPSs) [8,9], a c
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