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Functional and Structural Basis for Targeted Modification of Non-Ribosomal Peptlde Synthetases


In plants, the biosynthesis of the pharmaceutical paclitaxel includes the transfer of β-amino-β-phenylpropanoyls from coenzyme A to the custom peptide synthesis by an acyl CoA-dependent acyltransferase. The CoA ligase that biosynthesizes key β-amino-β-phenylpropanoyl CoAs in plants has not yet been isolated or characterized. In a screen for an alternative catalyst, a multienzyme, nonribosomal peptidyl synthetase on the pathway that produces tyrocidines was identified as a surrogate CoA ligase. 

The tridomain starter module (Phe-ATE) of the tyrocidine synthetase A normally activates (S)-α-phenylalanine to an adenylate phosphate anhydride in the adenylation domain. The activated phenylalanine intermediate is then thioesterified by the pendent (i.e. covalent) pantetheine attached to the adjacent thiolation domain. In the current project, the adenylation and thiolation domains were found to function as a CoA ligase, making α-, β-phenylalanyl, and, more importantly, phenylisoserinyl CoA. The latter two are known substrates of a phenylpropanoyltransferase (BAPT) on the 

For the development and production of pharmacologically important compounds based on natural scaffolds simple and effective techniques that can combine chemistry, genetics and molecular biology are indispensable. The NRPSs can provide such interesting tools to generate and modify novel products. The recently gained structural and mechanistic information on NRPSs have made this class of multienzymes a powerful native tool box that would help to achieve this goal. Rearrangements of domains and modules in combination with the elucidation of chemoenzymatic reactions highly increases the potential of these special enzymes.
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