The Schmeing Lab

Visualizing and understanding nature’s biosynthetic macromolecular machines

NRPS tailoring domains

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Tailoring domains in NRPSs allow products to access far more chemical space and are commonly found in these synthetases. For example, cyclosporin synthetase contains methyltransferase domains; daptomycin (Cubicin) synthetase, epimerization domains; bactitracin (BACiiM) synthetase, a heterocyclization domain. These domains enable key functionalities of the product by providing protease resistance, enabling novel interactions, improving affinity or allowing product to assume its active conformation. We use structural biology, chemical biology, biochemistry and biophysics to show how tailoring domains are embedded into megaenzymes and act in their synthetic cycle. For example, our studies with the formylation (F) domain of linear gramicidin synthetase visualized how a horizontal gene transfer of a sugar formyltransferase gene produced the F domain, and how it interacts productively with the core NRPS domains. Other tailoring domains of particular interest to the lab include oxidase and reductase domains.

Relevant Schmeing lab papers: Fortinez et al, Nature Comm 2022; Fortinez at al, JACS 2022; Alonzo et al, Nature Chem Biol 2020; Reimer et al, Science 2019; Reimer et al, ACS Chem Bio 2018; Reimer et al, Nature, 2016; Alonzo et al, PLOS One, 2015