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Biological Chemistry

New Family Of Cyclic Peptides Identified

Chemical Biology: Never-before-seen cross-link places streptide in new family

by Celia Henry Arnaud
April 23, 2015 | A version of this story appeared in Volume 93, Issue 17

Princeton University researchers have uncovered a new family of naturally occurring cyclic peptides (Nat. Chem. 2015, DOI: 10.1038/nchem.2237).

Cyclic peptides play many roles in bacterial biology, such as helping microbes communicate with one another. They’re also of interest to science because some of them have antimicrobial activity.

In previous studies, French researchers discovered a short peptide released by Streptococcus thermophilus, a model bacterium often used in yogurt production. But they didn’t determine a structure or biosynthesis mechanism for the peptide, which is thought to be part of the bacterium’s communication system.

Mohammad R. Seyedsayamdost, Kelsey R. Schramma, and Leah B. Bushin of Princeton have now obtained the structure via mass spectrometry and nuclear magnetic resonance. And they determined that the peptide, which they call streptide after its bacterium, contains a never-before-seen cross-link between the side chains of its tryptophan and one of its lysine residues. This novel cross-link makes streptide the first in a new family of peptides.

The researchers determined that streptide begins as a 30-member amino acid chain. A radical SAM (S-adenosylmethionine-cleaving) enzyme cyclizes the chain, forming the new cross-link. Afterward, the peptide is trimmed to a 9-mer.

“The radical SAM enzyme that makes the cross-link is very interesting,” says Wilfred A. van der Donk, a chemistry professor at the University of Illinois, Urbana-Champaign, who studies macrocyclic peptides. “New cyclization strategies can represent powerful new methodology in the toolbox for making cyclic peptides, provided the enzyme has tolerance for different peptide sequences.”

“Adding this chemotype to the bestiary of known, naturally occurring macrocyclic peptides is highly valuable,” says Adrian Whitty, a chemistry professor at Boston University who studies synthetic macrocycles. Such new classes of naturally occurring macrocycles can help researchers design molecules with good pharmacological properties, he says.

There’s still a lot of new chemistry to be discovered in the molecules produced by bacteria, Seyedsayamdost says, both with regard to the structure of the molecules and the enzymatic mechanisms by which they’re made.



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