TY  - INPR
A1  - Bozhüyük, Kenan A. J.
A1  - Präve, Leonard
A1  - Kegler, Carsten
A1  - Kaiser, Sebastian
A1  - Shi, Yan-Ni
A1  - Kuttenlochner, Wolfgang
A1  - Schenk, Leonie
A1  - Mohiuddin, T. M.
A1  - Groll, Michael
A1  - Hochberg, Georg K. A.
A1  - Bode, Helge Björn
T1  - Evolution inspired engineering of megasynthetases
T2  - bioRxiv
N2  - Many clinically used drugs are derived from or inspired by bacterial natural products that often are biosynthesised via non-ribosomal peptide synthetases (NRPS), giant megasynthases that activate and join individual amino acids in an assembly line fashion. Since NRPS are not limited to the incorporation of the 20 proteinogenic amino acids, their efficient manipulation would allow the biotechnological generation of complex peptides including linear, cyclic and further modified natural product analogues, e.g. to optimise natural product leads. Here we describe a detailed phylogenetic analysis of several bacterial NRPS that led to the identification of a new recombination breakpoint within the thiolation (T) domain that is important for natural NRPS evolution. From this, an evolution-inspired eXchange Unit between T domains (XUT) approach was developed which allows the assembly of NRPS fragments over a broad range of GC contents, protein similarities, and extender unit specificities, as demonstrated for the specific production of a proteasome inhibitor designed and assembled from five different NRPS fragments.
Y1  - 2022
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/73131
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-731318
IS  - 2022.12.02.518901 Version 2
ER  -