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J Biol Chem, Vol. 274, Issue 31, 21581-21588, July 30, 1999
From the Freie Universität Berlin, Institut für
Kristallographie, Takustraße 6, D-14195 Berlin, Germany
The combinatorial reorganization of distinct
modules of multimodular peptide synthetases is of increasing interest
for the generation of new peptides with optimized bioactive properties. Each module is at least composed of enzymatic domains responsible for
the adenylation, thioester formation, and condensation of an amino acid
residue of the final peptide product. We analyzed various possible
fusion sites for the recombination of peptide synthetases and evaluated
the impact of different recombination strategies on the amino acid
adenylation and acyl-thioester formation activities of peptide
synthetase modules. Hybrid bimodular peptide synthetases were generated
by recombination of the corresponding reading frames encoding for
L-glutamic acid- and L-leucine-specific modules of surfactin synthetase SrfA-A at presumed inner- and intradomainic regions. We demonstrate that fusions at a
previously postulated hinge region, dividing the amino acid adenylating
domains of peptide synthetase modules into two subdomains, and at the highly conserved 4'-phosphopantetheine binding motif in acyl-thioester forming domains resulted in enzymatically active hybrid domains. By
contrast, most manipulations in condensation domains like deletions, the complete exchange or the construction of chimeric domains considerably reduced or completely abolished the amino acid adenylation and thioester formation activity of the hybrid module.
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