Abstract
This minireview focusses on the use of bacteria to introduce dehydroresidues and (methyl)lanthionines in (poly)peptides. It mainly describes the broad exploitation of bacteria containing lantibiotic enzymes for the engineering of these residues in a wide variety of peptides in particular in peptides unrelated to lantibiotics. Lantibiotic dehydratases dehydrate serines and threonines present in peptides preceded by a lantibiotic leader peptide thus forming dehydroalanine and dehydrobutyrine, respectively. These dehydroresidues can be coupled to cysteines thus forming (methyl)lanthionines. This coupling is catalysed by lantibiotic cyclases. The design, synthesis, and export of microbially engineered dehydroresidue and or lanthionine-containing peptides in non-lantibiotic peptides are reviewed, illustrated by some examples which demonstrate the high relevance of these special residues. This minireview is the first with special focus on the microbial engineering of nonlantibiotic peptides by exploiting lantibiotic enzymes.
Similar content being viewed by others
References
Allred AJ, Diz DI, Ferrario CM, Chappell MC (2000) Pathways for angiotensin-(1-7) metabolism in pulmonary and renal tissues. Am J Physiol Renal Physiol 279:F841–F850
Bernardes GJ, Chalker JM, Errey JC, Davis BG (2008) Facile conversion of cysteine and alkyl cysteines to dehydroalanine on protein surfaces: versatile and switchable access to functionalized proteins. J Am Chem Soc 130:5052–5053
Bessalle R, Kapitkovsky A, Gorea A, Shalit I, Fridkin M (1990) All-d-magainin: chirality, antimicrobial activity and proteolytic resistance. FEBS Lett 274:151–155
Bierbaum G, Sahl HG (2009) Lantibiotics: mode of action, biosynthesis and bioengineering. Curr Pharm Biotechnol 10:2–18
Bierbaum G, Szekat C, Josten M, Heidrich C, Kempter C, Jung G, Sahl HG (1996) Engineering of a novel thioether bridge and role of modified residues in the lantibiotic Pep5. Appl Environ Microbiol 62:385–392
Chan WC, Bycroft BW, Lian L-Y, Roberts GCK (1989) Isolation and characterisation of two degradation products derived from the peptide antibiotic nisin. FEBS Lett 252:29–36
Chatterjee C, Miller LM, Leung YL, Xie L, Yi M, Kelleher NL, van der Donk WA (2005a) Lacticin 481 synthetase phosphorylates its substrate during lantibiotic production. J Am Chem Soc 127:15332–15333
Chatterjee C, Paul M, Xie L, van der Donk WA (2005b) Biosynthesis and mode of action of lantibiotics. Chem Rev 105:633–684
Chatterjee C, Patton GC, Cooper L, Paul M, van der Donk WA (2006) Engineering dehydro amino acids and thioethers into peptides using lacticin 481 synthetase. Chem Biol 13:1109–1117
Chen P, Qi FX, Novak J, Krull RE, Caufield PW (2001) Effect of amino acid substitutions in conserved residues in the leader peptide on biosynthesis of the lantibiotic mutacin II. FEMS Microbiol Lett 195:139–144
Consaul SA, Wright LF, Mahapatra S, Crick DC, Pavelka MS Jr (2005) An unusual mutation results in the replacement of diaminopimelate with lanthionine in the peptidoglycan of a mutant strain of Mycobacterium smegmatis. J Bacteriol 187:1612–1620
Cotter PD, Hill C, Ross RP (2005a) Bacterial lantibiotics: strategies to improve therapeutic potential. Curr Protein Pept Sci 6:61–75
Cotter PD, O’Connor PM, Draper LA, Lawton EM, Deegan LH, Hill C, Ross RP (2005b) Posttranslational conversion of l-serines to d-alanines is vital for optimal production and activity of the lantibiotic lacticin 3147. Proc Natl Acad Sci USA 102:18584–18589
Fredriksen A, Vasstrand EN, Jensen HB (1991) Peptidoglycan precursor from Fusobacterium nucleatum contains lanthionine. J Bacteriol 173:900–902
Furgerson Ihnken LA, Chatterjee C, van der Donk WA (2008) In vitro reconstitution and substrate specificity of a lantibiotic protease. Biochemistry 47:7352–7363
Galande AK, Trent JO, Spatola AF (2003) Understanding base-assisted desulfurization using a variety of disulfide-bridged peptides. Biopolymers 71:534–551
Galonić DP, Van der Donk WA, Gin DY (2003) Oligosaccharide-peptide ligation of glycosyl thiolates with dehydropeptides: synthesis of S-linked mucin-related glycopeptide conjugates. Chemistry 9:5997–6006
Gilmore MS, Skaugen M, Nes I (1996) Enterococcus faecalis and lacticin S of Lactobacillus sake. Antonie Van Leeuwenhoek 69:129–138
Gross E, Morell JL (1971) The structure of nisin. J Am Chem Soc 93:4634–4635
Guo J, Wang J, Lee JS, Schultz PG (2008) Site-specific incorporation of methyl- and acetyl-lysine analogues into recombinant proteins. Angew Chem Int Ed Engl 47:6399–6401
Haas M, Kluskens L, Kuipers A, Rink R, Nelemans S, Moll G (2008) Cyclic angiotensin analogues. Patent Application WO 018792A2
Heidrich C, Pag U, Josten M, Metzger J, Jack RW, Bierbaum G, Jung G, Sahl HG (1998) Isolation, characterization, and heterologous expression of the novel lantibiotic epicidin 280 and analysis of its biosynthetic gene cluster. Appl Environ Microbiol 64:3140–3146
Heringer-Walther S, Eckert K, Schumacher SM, Uharek L, Wulf-Goldenberg A, Gembardt F, Fichtner I, Schultheiss HP, Rodgers K, Walther T (2009) Angiotensin-(1-7) stimulates hematopoietic progenitor cells in vitro and in vivo. Haematologica 94:857–860
Hong SY, Oh JE, Lee KH (1999) Effect of d-amino acid substitution on the stability, the secondary structure, and the activity of membrane active peptide. Biochem Pharmacol 58:1775–1780
Izaguirre G, Hansen JN (1997) Use of alkaline phosphatase as a reporter polypeptide to study the role of the subtilin leader segment and the SpaT transporter in the posttranslational modifications and secretion of subtilin in Bacillus subtilis 168. Appl Environ Microbiol 63:3965–3971
Kaletta C, Entian K-D, Jung G (1991) Prepeptide sequence of cinnamycin (Ro 09-0198): the first structural gene of a duramycin-type lantibiotic. Eur J Biochem 199:411–415
Karakas Sen A, Narbad A, Horn N, Dodd HM, Parr AJ, Colquhoun I, Gasson MJ (1999) Post-translational modification of nisin. The involvement of NisB in the dehydration process. Eur J Biochem 261:524–532
Kessler H, Steuernagel S, Will M, Jung G, Kellner R, Gillessen D, Kamiyami T (1988) The structure of the polycyclic nonadecapeptide Ro 09-0198. Helv Chim Acta 71:1924–1929
Kiesau P, Eikmanns U, Gutowski-Eckel Z, Weber S, Hammelmann M, Entian KD (1997) Evidence for a multimeric subtilin synthetase complex. J Bacteriol 179:1475–1481
Kim K-H, Seong BL (2001) Peptide amidation: production of peptide hormones in vivo and in vitro. Biotechnol Bioprocess Eng 6:244–251
Kluskens LD, Kuipers A, Rink R, de Boef E, Fekken S, Driessen AJ, Kuipers OP, Moll GN (2005) Post-translational modification of therapeutic peptides by NisB, the dehydratase of the lantibiotic nisin. Biochemistry 44:12827–12834
Kluskens LD, Nelemans SA, Rink R, de Vries L, Meter-Arkema A, Wang Y, Walther T, Kuipers A, Moll GN, Haas M (2009) Angiotensin-(1-7) with thioether bridge: an ACE-resistant, potent Ang-(1-7) analogue. J Pharmacol Exp Ther 328:849–854
Kuipers OP, Rollema HS, Yap WM, Boot HJ, Siezen RJ, de Vos WM (1992) Engineering dehydrated amino acid residues in the antimicrobial peptide nisin. J Biol Chem 267:24340–24346
Kuipers A, de Boef E, Rink R, Fekken S, Kluskens LD, Driessen AJ, Leenhouts K, Kuipers OP, Moll GN (2004) NisT, the transporter of the lantibiotic nisin can transport fully modified, dehydrated and unmodified prenisin and fusions of the leader peptide with non-lantibiotic peptides. J Biol Chem 279:22176–22182
Kuipers A, Wierenga J, Rink R, Kluskens LD, Driessen AJ, Kuipers OP, Moll GN (2006) Sec-mediated transport of post-translationally dehydrated peptides in Lactococcus lactis. Appl Environ Microbiol 72:7626–7633
Kuipers A, Meijer-Wierenga J, Rink R, Kluskens LD, Moll GN (2008) Mechanistic dissection of the enzyme complexes involved in the biosynthesis of lacticin 3147 and nisin. Appl Environ Microbiol 74:6591–6597
Kuipers A, Rink R, Moll GN (2009) Translocation of a thioether-bridged azurin peptide fragment via the sec pathway in Lactococcus lactis. Appl Environ Microbiol 75:3800–3802
Langeveld B, van Gilst WH, Tio RA, Zijlstra F, Roks AJ (2005) Angiotensin-(1-7) attenuates neointimal formation after stent implantation in the rat. Hypertension 45:138–141
Lee MV, Ihnken LA, You YO, McClerren AL, van der Donk WA, Kelleher NL (2009) Distributive and directional behavior of lantibiotic synthetases revealed by high-resolution tandem mass spectrometry. J Am Chem Soc 131:12258–12264
Levengood MR, van der Donk WA (2006) Dehydroalanine-containing peptides: preparation from phenylselenocysteine and utility in convergent ligation strategies. Nat Protoc 1:3001–3010
Levengood MR, van der Donk WA (2008) Use of lantibiotic synthetases for the preparation of bioactive constraint peptides. Bioorg Med Chem Lett 18:3025–3028
Levengood MR, Patton GC, van der Donk WA (2007) The leader peptide is not required for post-translational modification by lacticin 481 synthetase. J Am Chem Soc 129:10314–10315
Levengood MR, Kerwood CC, Chatterjee C, van der Donk WA (2009) Investigation of the substrate specificity of lacticin 481 synthetase by using nonproteinogenic amino acids. Chembiochem 10:911–919
Li B, van der Donk WA (2007) Identification of essential catalytic residues of the cyclase NisC involved in the biosynthesis of nisin. J Biol Chem 282:21169–21175
Li B, Yu JP, Brunzelle JS, Moll GN, van der Donk WA, Nair SK (2006) Structure and mechanism of the lantibiotic cyclase involved in nisin biosynthesis. Science 311:1464–1467
Linetsky M, Hill JMW, LeGrand RD, Hu F (2004) Dehydroalanine crosslinks in human lens. Exp Eye Res 79:499–512
Lombardi A, D’Agostino B, Nastri F, D’Andrea LD, Filippelli A, Falciani M, Rossi F, Pavone V (1998) A novel superpotent neurokinin A receptor antagonist containing dehydroalanine. Bioorg Med Chem Lett 8:1153–1156
Loot AE, Roks AJ, Henning RH, Tio RA, Suurmeijer AJ, Boomsma F, van Gilst WH (2002) Angiotensin-(1-7) attenuates the development of heart failure after myocardial infarction in rats. Circulation 105:1548–1550
Lubelski J, Khusainov R, Kuipers OP (2009) Directionality and coordination of dehydration and ring formation during biosynthesis of the lantibiotic nisin. J Biol Chem 284:25962–25972
McClerren AL, Cooper LE, Quan C, Thomas PM, Kelleher NL, van der Donk WA (2006) Discovery and in vitro biosynthesis of haloduracin, a two-component lantibiotic. Proc Natl Acad Sci USA 103:17243–17248
Menon J, Soto-Pantoja DR, Callahan MF, Cline JM, Ferrario CM, Tallant EA, Gallagher PE (2007) Angiotensin-(1-7) inhibits growth of human lung adenocarcinoma xenografts in nude mice through a reduction in cyclooxygenase-2. Cancer Res 67:2809–2815
Meyer C, Bierbaum G, Heidrich C, Reis M, Suling J, Iglesias-Wind MI, Kempter C, Molitor E, Sahl H-G (1995) Nucleotide sequence of the lantibiotic Pep5 biosynthetic gene cluster and functional analysis of PepP and PepC. Eur J Biochem 232:478–489
Miller LM, Chatterjee C, van der Donk WA, Kelleher NL (2006) The dehydratase activity of lacticin 481 synthetase is highly processive. J Am Chem Soc 128:1420–1421
Moll GN, Kuipers A, Rink R, Driessen AJM, Kuipers OP (2006) Methods for the production and secretion of modified peptides. Patent Application WO 062398
Murkin AS, Tanner ME (2002) Dehydroalanine-based inhibition of a peptide epimerase from spider venom. J Org Chem 67:8389–8394
Nagao J, Harada Y, Shioya K, Aso Y, Zendo T, Nakayama J, Sonomoto K (2005) Lanthionine introduction into nukacin ISK-1 prepeptide by co-expression with modification enzyme NukM in Escherichia coli. Biochem Biophys Res Commun 336:507–513
Nagao J, Aso Y, Shioya K, Nakayama J, Sonomoto K (2007) Lantibiotic engineering: molecular characterization and exploitation of lantibiotic-synthesizing enzymes for peptide engineering. J Mol Microbiol Biotechnol 13:235–242
Nagao J, Morinaga Y, Islam MR, Asaduzzaman SM, Aso Y, Nakayama J, Sonomoto K (2009) Mapping and identification of the region and secondary structure required for the maturation of the nukacin ISK-1 prepeptide. Peptides 30:1412–1420
Neis S, Bierbaum G, Josten M, Pag U, Kempter C, Jung G, Sahl HG (1997) Effect of leader peptide mutations on biosynthesis of the lantibiotic Pep5. FEMS Microbiol Lett 149:249–255
Okeley NM, Zhu Y, van der Donk WA (2000) Facile chemoselective synthesis of dehydroalanine-containing peptides. Org Lett 2:3603–3606
Ösapay G, Prokai L, Kim HS, Medzihradszky KF, Coy DH, Liapakis G, Reisine T, Melacini G, Zhu Q, Wang SH, Mattern RH, Goodman M (1997) Lanthionine-somatostatin analogs: synthesis, characterization, biological activity, and enzymatic stability studies. J Med Chem 40:2241–2251
Patton GC, Paul M, Cooper LE, Chatterjee C, van der Donk WA (2008) The importance of the leader sequence for directing lanthionine formation in lacticin 481. Biochemistry 47:7342–7351
Paul LK, Izaguirre G, Hansen JN (1999) Studies of the subtilin leader peptide as a translocation signal in Escherichia coli K12. FEMS Microbiol Lett 176:45–50
Paul M, Patton GC, van der Donk WA (2007) Mutants of the zinc ligands of lacticin 481 synthetase retain dehydration activity but have impaired cyclisation activity. Biochemistry 46:6268–6276
Pereira RM, Dos Santos RA, Teixeira MM, Leite VH, Costa LP, da Costa Dias FL, Barcelos LS, Collares GB, Simões e Silva AC (2007) The renin-angiotensin system in a rat model of hepatic fibrosis: evidence for a protective role of angiotensin-(1-7). J Hepatol 46:674–681
Rew Y, Malkmus S, Svensson C, Yaksh TL, Chung NN, Schiller PW, Cassel JA, DeHaven RN, Goodman M (2002) Synthesis and biological activities of cyclic lanthionine enkephalin analogues: delta-opioid receptor selective ligands. J Med Chem 45:3746–3754
Rink R, Kuipers A, de Boef E, Leenhouts KJ, Driessen AJM, Moll GN, Kuipers OP (2005) Lantibiotic structures as guidelines for the design of peptides that can be modified by lantibiotic enzymes. Biochemistry 44:8873–8882
Rink R, Kluskens LD, Kuipers A, Driessen AJ, Kuipers OP, Moll GN (2007a) NisC, the cyclase of the lantibiotic nisin, can catalyze cyclisation of designed non-lantibiotic peptides. Biochemistry 46:13179–13189
Rink R, Wierenga J, Kuipers A, Kluskens LD, Driessen AJ, Kuipers OP, Moll GN (2007b) Production of dehydroamino acid-containing peptides by Lactococcus lactis. Appl Environ Microbiol 73:1792–1796
Rink R, Wierenga J, Kuipers A, Kluskens LD, Driessen AJ, Kuipers OP, Moll GN (2007c) Dissection and modulation of the four distinct activities of nisin by mutagenesis of rings A and B and by C-terminal truncation. Appl Environ Microbiol 73:5809–5816
Santos RA, Campagnole-Santos MJ, Andrade SP (2000) Angiotensin-(1-7): an update. Regul Pept 91:45–62
Santos RA, Ferreira AJ, Nadu AP, Braga AN, de Almeida AP, Campagnole-Santos MJ, Baltatu O, Iliescu R, Reudelhuber TL, Bader M (2004) Expression of an angiotensin-(1-7)-producing fusion protein produces cardioprotective effects in rats. Physiol Genomics 17:292–299
Santos RA, Frézard F, Ferreira AJ (2005) Angiotensin-(1-7): blood, heart, and blood vessels. Curr Med Chem Cardiovasc Hematol Agents 3:383–391
Schindler C, Bramlage P, Kirch W, Ferrario CM (2007) Role of the vasodilator peptide angiotensin-(1-7) in cardiovascular drug therapy. Vasc Health Risk Manag 3:125–137
Schnell N, Entian KD, Schneider U, Götz F, Zähner H, Kellner R, Jung G (1988) Prepeptide sequence of epidermin, a ribosomally synthesized antibiotic with four sulphide-rings. Nature 333:276–278
Seebeck FP, Szostak JW (2006) Ribosomal synthesis of dehydroalanine-containing peptides. J Am Chem Soc 128:7150–7151
Seo JS, Holmquist B, Strydom D (2003) Procede d’amidation de peptide. WO099853
Siddiqui MI, Kataria S, Ahuja V, Rao GS (2001) A peptide inhibitor of HIV-1 protease using alpha, beta-dehydro residues: a structure based computer model. Indian J Biochem Biophys 38:90–95
Siegers K, Heinzmann S, Entian KD (1996) Biosynthesis of lantibiotic nisin. Posttranslational modification of its prepeptide occurs at a multimeric membrane-associated lanthionine synthetase complex. J Biol Chem 271:12294–12301
Tomkinson B, Grehn L, Fransson B, Zetterqvist O (1994) Use of dehydroalanine-containing peptide as an efficient inhibitor of tripeptidyl peptidase II. Arch Biochem Biophys 314:276–279
Tugyi R, Mezö G, Fellinger E, Andreu D, Hudecz F (2005) The effect of cyclisation on the enzymatic degradation of herpes simplex virus glycoprotein D derived epitope peptide. J Pept Sci 11:642–649
Twomey D, Ross RP, Ryan M, Meaney B, Hill C (2002) Lantibiotics produced by lactic acid bacteria: structure, function and applications. Antonie Van Leeuwenhoek 82:165–185
Uguen P, Hindre T, Didelot S, Marty C, Haras D, Le Pennec JP, Vallee-Rehel K, Dufour A (2005) Maturation by LctT is required for biosynthesis of full-length lantibiotic lacticin 481. Appl Environ Microbiol 71:562–565
van der Meer JR, Rollema HS, Siezen R, Beerthuyzen MM, Kuipers OP, de Vos WM (1994) Influence of amino acid substitutions in the nisin leader peptide on biosynthesis and secretion of nisin by Lactococcus lactis. J Biol Chem 269:3555–3562
van Kraaij C, Breukink E, Noordermeer MA, Demel RA, Siezen RJ, Kuipers OP, de Kruijff B (1998) Pore formation by nisin involves translocation of its C-terminal part across the membrane. Biochemistry 37:16033–16040
van Saparoea HB, Bakkes PJ, Moll GN, Driessen AJ (2008) Distinct contributions of the nisin biosynthesis enzymes NisB and NisC and transporter NisT to prenisin production by Lactococcus lactis. Appl Environ Microbiol 74:5541–5548
Weber E, Esch FS, Böhlen P, Paterson S, Corbett AD, McKnight AT, Kosterlitz HW, Barchas JD, Evans CJ (1983) Metorphamide: isolation, structure, and biologic activity of an amidated opioid octapeptide from bovine brain. Proc Natl Acad Sci USA 80:7362–7366
Widdick DA, Dodd HM, Barraille P, White J, Stein TH, Chater KF, Gasson MJ, Bibb MJ (2003) Cloning and engineering of the cinnamycin biosynthetic gene cluster from Streptomyces cinnamoneus cinnamoneus DSM 40005. Proc Natl Acad Sci U S A 100:4316–4321
Willey JM, van der Donk WA (2007) Lantibiotics: peptides of diverse structure and function. Annu Rev Microbiol 61:477–501
Willey JM, Willems A, Kodani S, Nodwell JR (2006) Morphogenetic surfactants and their role in the formation of aerial hyphae in Streptomyces coelicolor. Mol Microbiol 59:731–742
Xie L, Miller LM, Chatterjee C, Averin O, Kelleher NL, van der Donk WA (2004) Lacticin 481: in vitro reconstitution of lantibiotic synthetase activity. Science 303:679–681
Yamada K, Iyer SN, Chappell MC, Ganten D, Ferrario CM (1998) Converting enzyme determines plasma clearance of angiotensin-(1-7). Hypertension 32:496–502
You YO, van der Donk WA (2007) Mechanistic investigation of the dehydration reaction of lacticin 481 synthetase using site-directed mutagenesis. Biochemistry 46:5991–6000
You YO, Levengood MR, Furgerson Ihnken LA, Knowlton AK, van der Donk WA (2009) Lacticin 481 synthetase as a general serine/threonine kinase. Chem Biol 4:379–385
Zhang X, Ni W, van der Donk WA (2007) On the regioselectivity of thioether formation by lacticin 481 synthetase. Org Lett 9:3343–3346
Zhou H, Schmidt DM, Gerlt JA, van der Donk WA (2003) Chemical and enzymatic synthesis of fluorinated-dehydroalanine-containing peptides. Chembiochem 4:1206–1215
Zhu Y, van der Donk WA (2001) Convergent synthesis of peptide conjugates using dehydroalanines for chemoselective ligations. Org Lett 3:1189–1192
Zimmermann N, Freund S, Fredenhagen A, Jung G (1993) Solution structures of the lantibiotics duramycin B and C. Eur J Biochem 216:419–428
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Moll, G.N., Kuipers, A. & Rink, R. Microbial engineering of dehydro-amino acids and lanthionines in non-lantibiotic peptides. Antonie van Leeuwenhoek 97, 319–333 (2010). https://doi.org/10.1007/s10482-010-9418-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10482-010-9418-4