Identification of a new class of lanthionine synthetases provides insight into the mechanism and evolution of cyclic peptide biosynthesis

Bibb, Mervyn J.

Claesen, Jan

Goto, Yuki

Li, Bo

Shi, Yanxiang

van der Donk, Wilfred A.

English

PubMed

Goto Yuki

Li Bo

Claesen Jan

Shi Yanxiang

Bibb Mervyn J.

van der Donk Wilfred A.

Public Library of Science (PLOS)

Discovery of Unique Lanthionine Synthetases Reveals New Mechanistic and Evolutionary Insights

Lantibiotic synthetases are remarkable biocatalysts generating conformationally constrained peptides with a variety of biological activities by repeatedly utilizing two simple posttranslational modification reactions: dehydration of Ser/Thr residues and intramolecular addition of Cys thiols to the resulting dehydro amino acids. Since previously reported lantibiotic synthetases show no apparent homology with any other known protein families, the molecular mechanisms and evolutionary origin of these enzymes are unknown. In this study, we present a novel class of lanthionine synthetases, termed LanL, that consist of three distinct catalytic domains and demonstrate in vitro enzyme activity of a family member from Streptomyces venezuelae. Analysis of individually expressed and purified domains shows that LanL enzymes install dehydroamino acids via phosphorylation of Ser/Thr residues by a protein kinase domain and subsequent elimination of the phosphate by a phosphoSer/Thr lyase domain. The latter has sequence homology with the phosphothreonine lyases found in various pathogenic bacteria that inactivate host mitogen activated protein kinases. A LanC-like cyclase domain then catalyzes the addition of Cys residues to the dehydro amino acids to form the characteristic thioether rings. We propose that LanL enzymes have evolved from stand-alone protein Ser/Thr kinases, phosphoSer/Thr lyases, and enzymes catalyzing thiol alkylation. We also demonstrate that the genes for all three pathways to lanthionine-containing peptides are widespread in Nature. Given the remarkable efficiency of formation of lanthionine-containing polycyclic peptides and the latter's high degree of specificity for their cognate cellular targets, it is perhaps not surprising that (at least) three distinct families of polypeptide sequences have evolved to access this structurally and functionally diverse class of compounds

Yuki Goto

Bo Li

Jan Claesen

Yanxiang Shi

Mervyn J Bibb

Wilfred A van der Donk

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Discovery of Unique Lanthionine Synthetases Reveals New Mechanistic and Evolutionary Insights

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