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 r...

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Autores principales:	Yuki Goto, Bo Li, Jan Claesen, Yanxiang Shi, Mervyn J Bibb, Wilfred A van der Donk
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/d8ade89d6f5344008dc28ab3ce01cc01
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spelling	oai:doaj.org-article:d8ade89d6f5344008dc28ab3ce01cc012021-11-25T05:34:20ZDiscovery of unique lanthionine synthetases reveals new mechanistic and evolutionary insights.1544-91731545-788510.1371/journal.pbio.1000339https://doaj.org/article/d8ade89d6f5344008dc28ab3ce01cc012010-03-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20351769/pdf/?tool=EBIhttps://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885Lantibiotic 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 GotoBo LiJan ClaesenYanxiang ShiMervyn J BibbWilfred A van der DonkPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 8, Iss 3, p e1000339 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Yuki Goto Bo Li Jan Claesen Yanxiang Shi Mervyn J Bibb Wilfred A van der Donk Discovery of unique lanthionine synthetases reveals new mechanistic and evolutionary insights.
description	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.
format	article
author	Yuki Goto Bo Li Jan Claesen Yanxiang Shi Mervyn J Bibb Wilfred A van der Donk
author_facet	Yuki Goto Bo Li Jan Claesen Yanxiang Shi Mervyn J Bibb Wilfred A van der Donk
author_sort	Yuki Goto
title	Discovery of unique lanthionine synthetases reveals new mechanistic and evolutionary insights.
title_short	Discovery of unique lanthionine synthetases reveals new mechanistic and evolutionary insights.
title_full	Discovery of unique lanthionine synthetases reveals new mechanistic and evolutionary insights.
title_fullStr	Discovery of unique lanthionine synthetases reveals new mechanistic and evolutionary insights.
title_full_unstemmed	Discovery of unique lanthionine synthetases reveals new mechanistic and evolutionary insights.
title_sort	discovery of unique lanthionine synthetases reveals new mechanistic and evolutionary insights.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/d8ade89d6f5344008dc28ab3ce01cc01
work_keys_str_mv	AT yukigoto discoveryofuniquelanthioninesynthetasesrevealsnewmechanisticandevolutionaryinsights AT boli discoveryofuniquelanthioninesynthetasesrevealsnewmechanisticandevolutionaryinsights AT janclaesen discoveryofuniquelanthioninesynthetasesrevealsnewmechanisticandevolutionaryinsights AT yanxiangshi discoveryofuniquelanthioninesynthetasesrevealsnewmechanisticandevolutionaryinsights AT mervynjbibb discoveryofuniquelanthioninesynthetasesrevealsnewmechanisticandevolutionaryinsights AT wilfredavanderdonk discoveryofuniquelanthioninesynthetasesrevealsnewmechanisticandevolutionaryinsights
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Discovery of unique lanthionine synthetases reveals new mechanistic and evolutionary insights.

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