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Structural determinants of macrocyclization in substrate-controlled lanthipeptide biosynthetic pathways.

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Bobeica SC, Zhu L, Acedo JZ, Tang W, van der Donk WA
OpenAccess logo Chem Sci 11 12854-12870 (2020)
Related entries: 6ve9, 6vgt, 6vhj, 6vjq, 7ju9, 7jvf

Cited: 19 times
EuropePMC logo PMID: 34094481

Abstract

Lanthipeptides are characterized by thioether crosslinks formed by post-translational modifications. The cyclization process that favors a single ring pattern over many other possible ring patterns has been the topic of much speculation. Recent studies suggest that for some systems the cyclization pattern and stereochemistry is determined not by the enzyme, but by the sequence of the precursor peptide. However, the factors that govern the outcome of the cyclization process are not understood. This study presents the three-dimensional structures of seven lanthipeptides determined by nuclear magnetic resonance spectroscopy, including five prochlorosins and the two peptides that make up cytolysin, a virulence factor produced by Enterococcus faecalis that is directly linked to human disease. These peptides were chosen because their substrate sequence determines either the ring pattern (prochlorosins) or the stereochemistry of cyclization (cytolysins). We present the structures of prochlorosins 1.1, 2.1, 2.8, 2.10 and 2.11, the first three-dimensional structures of prochlorosins. Our findings provide insights into the molecular determinants of cyclization as well as why some prochlorosins may be better starting points for library generation than others. The structures of the large and small subunits of the enterococcal cytolysin show that these peptides have long helical stretches, a rare observation for lanthipeptides characterized to date. These helices may explain their pore forming activity and suggest that the small subunit may recognize a molecular target followed by recruitment of the large subunit to span the membrane.

Articles - 6vlj mentioned but not cited (2)

  1. Structural determinants of macrocyclization in substrate-controlled lanthipeptide biosynthetic pathways. Bobeica SC, Zhu L, Acedo JZ, Tang W, van der Donk WA. Chem Sci 11 12854-12870 (2020)
  2. Exploring structural signatures of the lanthipeptide prochlorosin 2.8 using tandem mass spectrometry and trapped ion mobility-mass spectrometry. Jeanne Dit Fouque K, Hegemann JD, Santos-Fernandez M, Le TT, Gomez-Hernandez M, van der Donk WA, Fernandez-Lima F. Anal Bioanal Chem 413 4815-4824 (2021)


Reviews citing this publication (2)

  1. Mechanism of Action of Ribosomally Synthesized and Post-Translationally Modified Peptides. Ongpipattanakul C, Desormeaux EK, DiCaprio A, van der Donk WA, Mitchell DA, Nair SK. Chem Rev 122 14722-14814 (2022)
  2. Emulating nonribosomal peptides with ribosomal biosynthetic strategies. Mordhorst S, Ruijne F, Vagstad AL, Kuipers OP, Piel J. RSC Chem Biol 4 7-36 (2023)

Articles citing this publication (15)

  1. Substrate Sequence Controls Regioselectivity of Lanthionine Formation by ProcM. Le T, Jeanne Dit Fouque K, Santos-Fernandez M, Navo CD, Jiménez-Osés G, Sarksian R, Fernandez-Lima FA, van der Donk WA. J Am Chem Soc 143 18733-18743 (2021)
  2. Trapped Ion Mobility Spectrometry, Ultraviolet Photodissociation, and Time-of-Flight Mass Spectrometry for Gas-Phase Peptide Isobars/Isomers/Conformers Discrimination. Miller SA, Jeanne Dit Fouque K, Ridgeway ME, Park MA, Fernandez-Lima F. J Am Soc Mass Spectrom 33 1267-1275 (2022)
  3. Class V Lanthipeptide Cyclase Directs the Biosynthesis of a Stapled Peptide Natural Product. Pei ZF, Zhu L, Sarksian R, van der Donk WA, Nair SK. J Am Chem Soc 144 17549-17557 (2022)
  4. Functional Expression and Characterization of the Highly Promiscuous Lanthipeptide Synthetase SyncM, Enabling the Production of Lanthipeptides with a Broad Range of Ring Topologies. Arias-Orozco P, Inklaar M, Lanooij J, Cebrián R, Kuipers OP. ACS Synth Biol 10 2579-2591 (2021)
  5. Structure-Activity Relationships of the Enterococcal Cytolysin. Rahman IR, Sanchez A, Tang W, van der Donk WA. ACS Infect Dis 7 2445-2454 (2021)
  6. Divergent Evolution of Lanthipeptide Stereochemistry. Sarksian R, van der Donk WA. ACS Chem Biol 17 2551-2558 (2022)
  7. Chirality-matched catalyst-controlled macrocyclization reactions. Hwang J, Mercado BQ, Miller SJ. Proc Natl Acad Sci U S A 118 e2113122118 (2021)
  8. Deep Learning-Driven Library Design for the De Novo Discovery of Bioactive Thiopeptides. Chang JS, Vinogradov AA, Zhang Y, Goto Y, Suga H. ACS Cent Sci 9 2150-2160 (2023)
  9. Investigating the Specificity of the Dehydration and Cyclization Reactions in Engineered Lanthipeptides by Synechococcal SyncM. Arias-Orozco P, Yi Y, Ruijne F, Cebrián R, Kuipers OP. ACS Synth Biol 12 164-177 (2023)
  10. Nocaviogua A and B: two lipolanthines from root-nodule-associated Nocardia sp. Chang S, Luo Y, He N, Huang X, Chen M, Yuan L, Xie Y. Front Chem 11 1233938 (2023)
  11. Sequence controlled secondary structure is important for the site-selectivity of lanthipeptide cyclization. Mi X, Desormeaux EK, Le TT, van der Donk WA, Shukla D. Chem Sci 14 6904-6914 (2023)
  12. Darobactin Substrate Engineering and Computation Show Radical Stability Governs Ether versus C-C Bond Formation. Woodard AM, Peccati F, Navo CD, Jiménez-Osés G, Mitchell DA. J Am Chem Soc 146 14328-14340 (2024)
  13. Synthesis of Fluorescent Lanthipeptide Cytolysin S Analogues by Late-Stage Sulfamidate Ring Opening. Mazo N, Rahman IR, Navo CD, Peregrina JM, Busto JH, van der Donk WA, Jiménez-Osés G. Org Lett 25 1431-1435 (2023)
  14. syn-Elimination of glutamylated threonine in lanthipeptide biosynthesis. Sarksian R, Zhu L, van der Donk WA. Chem Commun (Camb) 59 1165-1168 (2023)
  15. Expression and Subcellular Localization of Lanthipeptides in Human Cells. Eslami SM, Padhi C, Rahman IR, van der Donk WA. ACS Synth Biol 13 2128-2140 (2024)


Related citations provided by authors (5)

  1. Correction: Structural determinants of macrocyclization in substrate-controlled lanthipeptide biosynthetic pathways.. Bobeica SC, Zhu L, Acedo JZ, Tang W, van der Donk WA Chem Sci 11 12871-12876 (2020)
  2. Structural characterization of four prochlorosins: a novel class of lantipeptides produced by planktonic marine cyanobacteria.. Tang W, van der Donk WA Biochemistry 51 4271-9 (2012)
  3. The sequence of the enterococcal cytolysin imparts unusual lanthionine stereochemistry.. Tang W, van der Donk WA Nat Chem Biol 9 157-9 (2013)
  4. Catalytic promiscuity in the biosynthesis of cyclic peptide secondary metabolites in planktonic marine cyanobacteria.. Li B, Sher D, Kelly L, Shi Y, Huang K, Knerr PJ, Joewono I, Rusch D, Chisholm SW, van der Donk WA Proc Natl Acad Sci U S A 107 10430-5 (2010)
  5. Evolutionary radiation of lanthipeptides in marine cyanobacteria.. Cubillos-Ruiz A, Berta-Thompson JW, Becker JW, van der Donk WA, Chisholm SW Proc Natl Acad Sci U S A 114 E5424-E5433 (2017)

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