Biochemistry

Cutting to Size

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Science  28 Oct 2011:
Vol. 334, Issue 6055, pp. 434
DOI: 10.1126/science.334.6055.434-c
CREDIT: DUBOIS ET AL., J. BIOL. CHEM. 286, 35562 (2011)

For proteins and peptides synthesized on the ribosome, proteolytic cleavage is a common activation mechanism. Two papers extend this mechanism to nonribosomally synthesized peptides and peptide-polyketide hybrids, natural products of interest in drug development. Reimer et al. identified a gene, xcnG, in the biosynthetic gene cluster for production of the antibiotic xenocoumacin from Xenorhabdus nematophila. An xcnG deletion mutant did not synthesize xenocoumacin but did synthesize pre-xenocoumacin compounds. A pre-xenocoumacin compound added to Escherichia coli cells that expressed full-length xcnG was cleaved to give a xenocoumacin precursor. Homologs of xcnG were identified in other biosynthetic gene clusters. Dubois et al. independently investigated one such homolog, ClpB, an atypical biosynthetic protein in E. coli. They determined the structure of the periplasmic domain and showed that it belongs to a family of serine peptidases. C1pB showed peptidase activity, and mutagenesis experiments confirmed the importance of active site residues in cytopathic activity. Homologs to XCNG and ClpB included larger proteins with ABC export domains, suggesting that inactive prodrugs might be secreted and synchronously cleaved for activation.

Nat. Chem. Biol. 7, 10.1038/NCHEMBIO.688 (2011); J. Biol. Chem. 286, 35562 (2011).

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