An Amphipathic Alpha-Helix Guides Maturation of the Ribosomally-Synthesized Lipolanthines.

Angewandte Chemie
Vincent WiebachRoderich D Süssmuth

Abstract

The recently discovered strongly anti-Gram-positive lipolanthines represent a new group of lipidated, ribosomally synthesized and post-translationally modified peptides (RiPPs). They are bicyclic octapeptides with a central quaternary carbon atom (avionin), which is installed through the cooperative action of the class-III lanthipeptide synthetase MicKC and the cysteine decarboxylase MicD. Genome mining efforts indicate a widespread distribution and unprecedented biosynthetic diversity of lipolanthine gene clusters, combining elements of RiPPs, polyketide and non-ribosomal peptide biosynthesis. Utilizing NMR spectroscopy, we show that a (θxx)θxxθxxθ (θ=L, I, V, M or T) motif, which is conserved in the leader peptides of all class-III and -IV lanthipeptides, forms an amphipathic α-helix in MicA that destines the peptide substrate for enzymatic processing. Our results provide general rules of substrate recruitment and enzymatic regulation during lipolanthine maturation. These insights will facilitate future efforts to rationally design new lanthipeptide scaffolds with antibacterial potency.

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Citations

Sep 17, 2020·Natural Product Reports·Manuel Montalbán-LópezWilfred A van der Donk
Jan 14, 2021·Biochemical Society Transactions·Fleur Ruijne, Oscar P Kuipers
Feb 9, 2021·Current Opinion in Biotechnology·Chunyu Wu, Wilfred A van der Donk
Aug 17, 2021·Journal of the American Chemical Society·Alexander A VinogradovHiroaki Suga
Aug 31, 2021·RSC Chemical Biology·Julian D Hegemann, Roderich D Süssmuth
Sep 8, 2021·Chembiochem : a European Journal of Chemical Biology·Julian D Hegemann, Roderich D Süssmuth

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Methods Mentioned

BETA
circular dichroism
nuclear magnetic resonance
NMR
amino acid exchange
lipidation

Software Mentioned

CSI3
TALOS +

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