Mechanistic Understanding of Lanthipeptide Biosynthetic Enzymes

Overview

Journal Chem Rev

Publisher American Chemical Society

Specialty Chemistry

Date 2017 Jan 31

PMID 28135077

Citations 207

Authors

Lindsay M Repka

Jonathan R Chekan

Satish K Nair

Wilfred A van der Donk

Affiliations

Soon will be listed here.

Abstract

Lanthipeptides are ribosomally synthesized and post-translationally modified peptides (RiPPs) that display a wide variety of biological activities, from antimicrobial to antiallodynic. Lanthipeptides that display antimicrobial activity are called lantibiotics. The post-translational modification reactions of lanthipeptides include dehydration of Ser and Thr residues to dehydroalanine and dehydrobutyrine, a transformation that is carried out in three unique ways in different classes of lanthipeptides. In a cyclization process, Cys residues then attack the dehydrated residues to generate the lanthionine and methyllanthionine thioether cross-linked amino acids from which lanthipeptides derive their name. The resulting polycyclic peptides have constrained conformations that confer their biological activities. After installation of the characteristic thioether cross-links, tailoring enzymes introduce additional post-translational modifications that are unique to each lanthipeptide and that fine-tune their activities and/or stability. This review focuses on studies published over the past decade that have provided much insight into the mechanisms of the enzymes that carry out the post-translational modifications.

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References

Franke C, Tiemersma J, Venema G, Kok J . Membrane topology of the lactococcal bacteriocin ATP-binding cassette transporter protein LcnC. Involvement of LcnC in lactococcin a maturation. J Biol Chem. 1999; 274(13):8484-90. DOI: 10.1074/jbc.274.13.8484. View

Karakas Sen A, Narbad A, Horn N, Dodd H, Parr A, Colquhoun I . Post-translational modification of nisin. The involvement of NisB in the dehydration process. Eur J Biochem. 1999; 261(2):524-32. DOI: 10.1046/j.1432-1327.1999.00303.x. View

Hightower K, Fierke C . Zinc-catalyzed sulfur alkyation:insights from protein farnesyltransferase. Curr Opin Chem Biol. 1999; 3(2):176-81. DOI: 10.1016/s1367-5931(99)80030-1. View

Immonen T, Saris P . Characterization of the nisFEG operon of the nisin Z producing Lactococcus lactis subsp. lactis N8 strain. DNA Seq. 1999; 9(5-6):263-74. DOI: 10.3109/10425179809008466. View

Rozema D, Poulter C . Yeast protein farnesyltransferase. pKas of peptide substrates bound as zinc thiolates. Biochemistry. 1999; 38(40):13138-46. DOI: 10.1021/bi990794y. View

Friedman M . Chemistry, biochemistry, nutrition, and microbiology of lysinoalanine, lanthionine, and histidinoalanine in food and other proteins. J Agric Food Chem. 1999; 47(4):1295-319. DOI: 10.1021/jf981000+. View

Vertesy L, Aretz W, Bonnefoy A, Ehlers E, Kurz M, Markus A . Ala(0)-actagardine, a new lantibiotic from cultures of Actinoplanes liguriae ATCC 31048. J Antibiot (Tokyo). 1999; 52(8):730-41. DOI: 10.7164/antibiotics.52.730. View

van Kraaij C, de Vos W, Siezen R, Kuipers O . Lantibiotics: biosynthesis, mode of action and applications. Nat Prod Rep. 1999; 16(5):575-87. DOI: 10.1039/a804531c. View

Breukink E, Wiedemann I, van Kraaij C, Kuipers O, Sahl H, de Kruijff B . Use of the cell wall precursor lipid II by a pore-forming peptide antibiotic. Science. 1999; 286(5448):2361-4. DOI: 10.1126/science.286.5448.2361. View

10.

Ryan M, JACK R, Josten M, Sahl H, Jung G, Ross R . Extensive post-translational modification, including serine to D-alanine conversion, in the two-component lantibiotic, lacticin 3147. J Biol Chem. 1999; 274(53):37544-50. DOI: 10.1074/jbc.274.53.37544. View

11.

McAuliffe O, Hill C, Ross R . Identification and overexpression of ltnl, a novel gene which confers immunity to the two-component lantibiotic lacticin 3147. Microbiology (Reading). 2000; 146 ( Pt 1):129-138. DOI: 10.1099/00221287-146-1-129. View

12.

Giacomini A, Squartini A, Nuti M . Nucleotide sequence and analysis of plasmid pMD136 from Pediococcus pentosaceus FBB61 (ATCC43200) involved in pediocin A production. Plasmid. 2000; 43(2):111-22. DOI: 10.1006/plas.1999.1447. View

13.

Burrage S, Raynham T, Williams G, Essex J, Allen C, Cardno M . Biomimetic synthesis of lantibiotics. Chemistry. 2000; 6(8):1455-66. DOI: 10.1002/(sici)1521-3765(20000417)6:8<1455::aid-chem1455>3.0.co;2-m. View

14.

Kupke T, Uebele M, Schmid D, Jung G, Blaesse M, Steinbacher S . Molecular characterization of lantibiotic-synthesizing enzyme EpiD reveals a function for bacterial Dfp proteins in coenzyme A biosynthesis. J Biol Chem. 2000; 275(41):31838-46. DOI: 10.1074/jbc.M004273200. View

15.

Uguen P, Le Pennec J, Dufour A . Lantibiotic biosynthesis: interactions between prelacticin 481 and its putative modification enzyme, LctM. J Bacteriol. 2000; 182(18):5262-6. PMC: 94678. DOI: 10.1128/JB.182.18.5262-5266.2000. View

16.

Liao D, Qian J, Chisholm D, Jordan D, Diner B . Crystal structures of the photosystem II D1 C-terminal processing protease. Nat Struct Biol. 2000; 7(9):749-53. DOI: 10.1038/78973. View

17.

McAuliffe O, Hill C, Ross R . Each peptide of the two-component lantibiotic lacticin 3147 requires a separate modification enzyme for activity. Microbiology (Reading). 2000; 146 ( Pt 9):2147-2154. DOI: 10.1099/00221287-146-9-2147. View

18.

Okeley N, Zhu Y, van der Donk W . Facile chemoselective synthesis of dehydroalanine-containing peptides. Org Lett. 2000; 2(23):3603-6. DOI: 10.1021/ol006485d. View

19.

Blaesse M, Kupke T, Huber R, Steinbacher S . Crystal structure of the peptidyl-cysteine decarboxylase EpiD complexed with a pentapeptide substrate. EMBO J. 2000; 19(23):6299-310. PMC: 305864. DOI: 10.1093/emboj/19.23.6299. View

20.

Chen P, Qi F, Novak J, Krull R, Caufield P . Effect of amino acid substitutions in conserved residues in the leader peptide on biosynthesis of the lantibiotic mutacin II. FEMS Microbiol Lett. 2001; 195(2):139-44. DOI: 10.1111/j.1574-6968.2001.tb10511.x. View