Nature's Way To Make the Lantibiotics - Journal of Chemical

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Products of Chemistry

George B. Kauffman California State University Fresno, CA 93740

Nature’s Way To Make the Lantibiotics Heather A. Relyea and Wilfred A. van der Donk* Department of Chemistry, University of Illinois, Urbana, IL 61801; *[email protected]

Antibiotics such as penicillins, cephalosporins, and quinolones (Figure 1) are our first line of defense against infections by pathogenic bacteria (1). One major problem is the development of bacterial resistance to our arsenal of these agents (2, 3). Even vancomycin (Figure 2), often referred to as the drug of last resort against multi-drug resistant strains, is becoming less effective. In general, bacterial resistance to antibiotics results from a variety of processes (1), including (i) structural changes (mutations) in the target that make it no longer susceptible to the antibiotic, (ii) production of bacterial enzymes that break down the antibiotic, and (iii) development of efflux pumps that expel the antibiotic from the bacterium before it is killed by the compound. It is clear that as infectious bacteria become less susceptible to existing antibiotics, the development of new antibiotics is critical to ward off a return of the infectious diseases that have been kept under control in the industrialized world for most of the 20th century. Ideally, these new antibiotics will have different

Figure 1. Structures of some commercially used antibacterial agents representing major structural classes. Penicillins are represented by amoxycillin; cephalosporins are represented by cephalexin; and Cipro, the drug used to treat anthrax, represents the fluoroquinolones. The core structure of each class of compounds is shown in blue.

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modes of action such that pathogenic bacteria cannot employ existing resistance mechanisms. Many of the clinically used antibiotics are natural products or derivatives thereof. The bacteria and fungi that make these compounds in nature do so to eliminate other organisms that compete with them for nutrients. In the past decade there has been a renewed interest in how microorganisms produce these compounds. Many natural antibiotics have structures that are difficult to synthesize using synthetic organic chemistry, and, even when they have succumbed to total synthesis, the routes usually have consisted of too many synthetic steps to be commercially attractive. On the other hand, the synthetic schemes used by producing organisms are typically very efficient, but they receive relatively little attention in chemical education. This is unfortunate, because the biosynthetic enzymes that are nature’s organic chemistry tools are very efficient catalysts of chemical reactions and will likely find increased use in future production of pharmaceuticals. These applications involve either the enzymes themselves (4) or microorganisms that are engineered to contain the biosynthetic machinery (5). Such approaches are already used in the chemical industry for fermentation of organisms that produce valuable natural products as well as for the enzymatic synthesis of fine chemicals (6–9). This article will focus on the current knowledge of the biosynthesis and mode of action of a class of compounds called lantibiotics. We refer to other reviews for a discussion of other natural products with antibacterial activity such as the polyketides and nonribosomal peptides (10), isoprenoids (11), and other compounds (1). The U.S. Food and Drug Administration has declared the bacterium Lactococcus lactis commonly found in milk as “generally regarded as safe” for applications in the food in-

Figure 2. Vancomycin, the “drug of last resort,” is a non-ribosomal peptide. Its peptide backbone is shown in blue.

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dustry. Certain strains of this bacterium produce the lantibiotic nisin (Figure 3), a peptide with antibacterial activity against multi-drug resistant bacteria (12) as well as food-borne pathogens like Listeria monocytogenes and Clostridium botuli-

num (13, 14). With an estimated 76 million cases of foodrelated illness in the United States each year (15) translating into a cost of $6.5–34.9 billion in 1997 (16), research into the modes of action and biosynthesis of nisin has increased

Figure 3. Nisin. The typical three letter abbreviations are used for the common amino acids, whereas unusual structures are drawn out, showing the atom connectivity. Lanthionines and methyllanthionines in nisin are shown in blue.

Figure 4. Structural motifs found in lantibiotics. (A short-hand notation for these modifications is presented underneath the structure.)

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dramatically in the past decade. Intriguingly, nisin has been used in over eighty countries for more than forty years without development of resistance (14, 17, 18). It is used for a variety of commercial applications including the preservation of dairy products, canned vegetables, and toothpaste. This extensive use has resulted in a number of questions that have been the topic of recent research. Why has this compound enjoyed such a long lifetime as an effective agent compared to most other antibiotics? How is this large protein-like compound synthesized in nature? And how might nisin be developed into a more effective compound for human use? This article will present the mode of action of nisin as well as the manner in which it is synthesized in nature. In the course of the review, the meaning of the terms regio-, chemo-, and stereoselectivity are discussed. What Are Lantibiotics? The name lantibiotic was introduced in 1988 as an abbreviation for lanthionine-containing antibiotic peptide (19). Lanthionines are unusual cross-linked amino acids that contain thioether bridges (carbon–sulfur–carbon linkages) be-

tween the side chains of the amino acids D-alanine (red or bold in printed edition, Figure 4) and L-alanine (blue or gray in printed edition, Figure 4) (20). They were first discovered in wool after treatment with aqueous solutions of high pH, which has given lanthionines their names (lana is Latin for wool) (21). When these thioethers are present within peptides, they introduce cyclic structures as exemplified in Figure 3 for nisin. Discovered in 1928 (22, 23) at about the same time as penicillin (24), the compound is one of the oldest known antibacterial agents even though its structure was not determined until 1971 (25). In addition to the lanthionine motif, lantibiotics often contain methyl substituted lanthionines, dehydroalanines, and dehydrobutyrines as well as some other unusual amino acids (Figure 4). To date over 40 lantibiotics with distinct structures have been isolated from different bacteria, including nisin, mersacidin, lacticin 481, and cinnamycin (Figure 5) (26). These compounds are synthesized within the producing bacteria by a series of enzymes generally known as the Lan proteins. The enzymes are given specific names according to the particular lantibiotic they produce (i.e., the nisin-producing enzymes are NisA, NisB, NisC, etc.).

Figure 5. Structures of several lantibiotics using the shorthand notation introduced in Figure 4. The typical three letter abbreviations are used for the common amino acids. The ring designation is indicated in gray letters.

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Figure 6. Three-dimensional structure of nisin as determined by NMR spectroscopy (45). The atoms are color coded according to the CPK (Corey–Pauling–Koltun) system (46) (blue = N; red = O; gray = C; yellow = S).

The LanA peptide is first synthesized by the ribosome, a large molecular machine made up of RNA and proteins (27, 28). The ribosome performs the last step in decoding the information present in the DNA of the bacterium into the structure of proteins and peptides in a process termed translation. In the case of lantibiotics the ribosome produces

a pre-peptide. This pre-peptide is later modified by the Lan enzymes to yield the mature lantibiotic, and in this posttranslational modification process the unusual amino acids shown in Figure 4 are formed. The fact that the pre-peptide is encoded in the genome sets these antibiotics apart from other peptide-based structures like vancomycin (Figure 2) that are produced by multienzyme complexes known as nonribosomal peptide synthetases (29). Lantibiotics have been categorized into several groups based on their shapes and biosynthetic pathways. Type A lantibiotics, including nisin and lacticin 481 (Figure 5) have a net positive charge and have elongated structures varying in length from 20 to 34 amino acids (30) (see the 3D structure of nisin in Figure 6). The type A lantibiotics are further divided according to the enzymes involved in their biosynthesis; type AI compounds such as nisin are synthesized by two distinct enzymes (LanB and LanC) whereas type AII compounds such as lacticin 481 are synthesized by just one enzyme with the generic name LanM. The type B lantibiotics, including cinnamycin and mersacidin (Figure 5), have a more compact structure than their type A counterparts. These lantibiotics either have a net negative charge or are neutral under physiological conditions (pH ∼7). Mersacidin has great promise for the treatment of multi-drug resistant bacteria in-

Figure 7. Representative example of the post-translational maturation process of lantibiotics. Amino acids are represented using the oneletter code (39) except for dehydroalanine (Dha) and dehydrobutyrine (Dhb). In this code, S = Ser, T = Thr, and C = Cys. The prepeptide NisA is ribosomally synthesized, followed by NisB catalyzed dehydration of underlined Ser and Thr residues in the C-terminal region of NisA (see Scheme I for the details of the dehydration). NisC catalyzes the addition of Cys residues in a regio-, chemo-, and stereoselective manner to five of the Dha (red) and Dhb (blue) residues to generate five cyclic thioethers: one lanthionine (A-ring) and four methyllanthionines (B–-E rings). After dehydration and cyclization is complete, the leader peptide is proteolytically removed by the protease NisP. In the final structure, three letter code is used for the common amino acids.

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cluding vancomycin-resistant strains (31), and cinnamycin has received attention as a potential anti-inflammatory compound (32). Biosynthesis of lantibiotics The thioethers in lantibiotics are formed in a two-step process carried out by the biosynthetic enzymes (Figure 7). In the first step water is eliminated from specific serine (Ser) and threonine (Thr) residues in the pre-peptide LanA to give carbon–carbon double bonds. The residues resulting from this dehydration are known as dehydroalanine (Dha, formed from serine) and dehydrobutyrine (Dhb, formed from threonine; for structures see Figure 4). This reaction is carried out by the LanB enzymes, which are therefore classified as dehydratases. As discussed below for the LanM enzymes, the dehydration step actually involves first addition of a phosphate group to the alcohol functionalities of Ser and Thr and then elimination of these phosphates to produce the Dha and Dhb residues (Scheme I). The LanC cyclases subsequently catalyze the addition of cysteine thiols to these dehydro amino acid residues to give cyclic products (Scheme I). For certain lantibiotics, a single enzyme LanM carries out both the dehydration and cyclization reactions. All lantibiotic precursor

peptides undergo these modifications only in their C-terminal region. The N-terminal part of LanA is known as the leader peptide and remains unaffected while the biosynthetic enzymes are processing the peptide. This leader peptide is later removed by a protease (Figure 7). Because amino acids in the structural region are modified while similar amino acids in the leader region are not acted upon, the LanB and LanM enzymes are regioselective. It may seem odd that LanA contains a leader peptide when it does not undergo modification and is not present in the mature antibiotic. The exact function of the leader region is still unknown, but several roles have been suggested. For example, it may serve as a scaffold that is recognized by the modification enzymes. Alternatively, the leader peptide may provide a signal for secretion of the final lantibiotic product from the cell in order to kill its neighbors. Finally, lantibiotics do not display antibiotic activity until the leader peptide has been removed. Therefore the leader peptide may protect the producing strain by rendering the lantibiotic inactive while it is still inside the cell. In all, the synthesis of lantibiotics from the constituent amino acids utilizes just four consecutive biocatalysts: the ribosome makes the pre-peptide, the dehydratase introduces the dehydro amino acids, the cyclase catalyzes ring forma-

Scheme I. Use of the phosphate group in the dehydration step.

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tion, and a protease cleaves off the leader peptide. This is a very impressive example of the power of nature to make complex natural products. For comparison, the group of Shiba and coworkers in Japan spent more than 6 years to achieve the landmark total synthesis of nisin utilizing a total of more than 60 chemical steps (33, 34).

Figure 8. The post-translational maturation process of lacticin 481. Amino acids are shown in one-letter code (39), except for the final structure in which three-letter code is used. LctM catalyzes the dehydration of the underlined Ser and Thr residues in the C-terminal region of LctA. The leader peptide sequence is MKEQNSFNLLQEVTESELDLILGA. The substrate used for in vitro reconstitution of the maturation process (35) had an additional N-terminal peptide attached with the sequence GSSHHHHHHSSGLVPRGSH. LctM also catalyzes the addition of three Cys residues to three of the Dha and Dhb residues to generate three cyclic thioethers, one methyllanthionine (blue) and two lanthionines (red). The leader peptide is proteolytically removed by the protease domain of the LctT transporter that excretes the final product.

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How Do the Lan Enzymes Work? The only synthetic enzyme whose activity has been studied in purified form is LctM (35), which is responsible for modifying LctA to the lantibiotic lacticin 481 (Figure 8). The LctM enzyme was purified from bacterial cells using chromatographic techniques and it was shown to require both Mg2+ and adenosine triphosphate (ATP) to carry out the dehydration and cyclization steps. This finding suggests that serine and threonine hydroxyl groups on LctA are first phosphorylated with ATP to achieve dehydration (Scheme I) (36). This strategy is nature’s way of turning the poor leaving group of an alcohol into a good leaving group for elimination. This reaction is analogous to transforming an alcohol to a sulfonate (tosylate, mesylate) in synthetic organic chemistry. The LctM enzyme also controls the positions at which these modifications take place. This is a truly remarkable example of the selectivity of enzymes as LctM seeks out 4 serine and threonine residues out of 15 such amino acids in the LctA substrate that was used in these studies (Figure 8, note that not all Ser and Thr are shown, see figure legend). During this process, a single enzyme cleaves 8 chemical bonds and makes 6 new chemical bonds. The lantibiotic biosynthetic enzymes perform these reactions in a manner that cannot be easily reproduced nonenzymatically. A dehydroalanine is a much more reactive amino acid than a dehydrobutyrine, and hence it usually reacts with cysteine much faster than the dehydrobutyrine. Such propensity of one chemical group to react more rapidly than another under a given set of conditions is called chemoselectivity. An example in which this chemoselectivity poses a problem for synthetic approaches towards lantibiotics is shown in Figure 9. A segment of the nisin pre-peptide containing Dha and Dhb residues was synthesized chemically (37). This peptide was used to investigate whether a similar cyclization as that catalyzed by the NisC protein to make nisin’s A- and B-rings would take place without the enzyme. Unfortunately, both cysteine residues were found to attack a dehydroalanine, rather than a dehydrobutyrine residue. The enzyme on the other hand is able to overcome the much lower reactivity of the dehydrobutyrine residue and forces one of the cysteines to attack one particular Dhb to make the Bring (Figure 9). Finally, these proteins exert one more level of control. The ribosome can only accept amino acids with the L-stereochemistry (Figure 10A). Hence, at first glance it appears inconsistent that lantibiotics are synthesized ribosomally because the lanthionines and methyllanthionines contain a Damino acid functionality (Figure 10B). The biosynthetic pathway depicted in Scheme I resolves this apparent contradiction, because the D-stereochemistry of the lanthionine is introduced after ribosomal synthesis during the protonation of intermediate A (an enolate) in the cyclization reaction. The LanC and LanM enzymes that carry out this transformation therefore must control the face of the delivery of the proton, an example of stereoselectivity. In summary, the LanB, LanC, and LanM enzymes carry out their chemical reactions with an impressive level of regio-, stereo-, and chemoselectivity.


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Figure 9. Attempted biomimetic synthesis of the A- and B-rings of nisin. After reduction of the disulfide bond in peptide 1, the cysteine at position 7 does form the A-ring, but the cysteine at position 11 does not attack the dehydrobutyrine at position 8 to generate the B-ring (dashed arrow) but rather adds to dehydroalanine 5 (solid arrow) (37).

Engineering of Lantibiotics Although natural products are great leads for drugs, they often suffer from unwanted side effects, poor solubility, or difficulties in delivering the compound to the diseased cells within the patient. The capability to use synthetic organic chemistry for the preparation of derivatives of natural products has been at the heart of the spectacular success of the pharmaceutical industry in developing drugs against a wide range of human ailments. If the use of biosynthetic methods is to rival the synthetic organic approach, they need to be capable of making analogs to improve the pharmacological properties. Hence, in the past decade much effort has focused on engineering of biosynthetic pathways and their enzymes. In the area of the lantibiotics, many analogs have been prepared simply by changing the DNA sequence that encodes for the pre-peptide in the producing organism (in vivo). These studies have shown that the biosynthetic enzymes have a very relaxed substrate specificity and 55 different analogs of nisin have been prepared by changing the sequence of the pre-peptide (26).

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For example, additional dehydro amino acids have been introduced by inserting additional Ser or Thr residues (38). The resulting lantibiotic analog can then be isolated from the bacterial medium and analyzed for bactericidal activity and structural features. A convenient method for establishing antibiotic activity is the agar diffusion assay depicted in

Figure 10. (A) Stereochemistry of L-amino acids that are found in all proteins that are synthesized by the ribosome. (B) Stereochemistry of the lanthionine showing one L-amino acid and one D-amino acid moiety.


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Figure 11. Typical bioassay to determine the antibiotic activity of a compound. The picture shows a Petri dish filled with agar on which a layer (a “lawn”) of bacteria is grown. A compound to be tested was applied at the center of each quadrant. If the compound has antibiotic activity, a region is observed within which all bacteria have died (called a zone or halo of clearance).

Figure 11. Nisin analogs (mutants) have also been instrumental in deciphering which parts of the lantibiotic structure are essential for antibiotic activity (26). In addition to the in vivo method, the recent success in preparing lacticin 481 in vitro (i.e., in the test tube) has opened the door for accessing greater functional and structural diversity of lantibiotic analogs. In the in vivo approach, mutations are made to the DNA but these can introduce only a limited number of amino acids (the 20 proteinogenic amino acids) (39) at the various positions. The in vitro method al-

Figure 13. Three dimensional structure of the lipid II-nisin complex showing the complementary shapes of the two molecules at their binding surface (42). The color coding for lipid II is the same as in Figure 12, and Nisin is shown in the yellow.

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Figure 12. Structure of lipid II, the essential intermediate for cell wall biosynthesis. In the box is the diphosphate (pyrophosphate) fragment that is recognized by the amide backbones of the A- and B-rings of nisin.

lows a hybrid between the organic synthesis and biosynthetic pathways via chemical incorporation of non-proteinogenic amino acids into the LanA peptide. These unnatural peptides are then treated with purified enzymes to provide lantibiotic analogs that are not accessible in vivo. This strategy has so far only been reported with the lacticin synthetase system (35). Mode of Action of Lantibiotics Most commonly used antibiotics function by inhibiting a specific target that is necessary for survival of the organism. These targets are often involved in bacterial cell-wall synthesis, in protein biosynthesis, or in DNA replication (1). To prevent toxicity of the antibiotic to patients, the target proteins are either absent in humans or have a sufficiently different structure in people compared to bacteria that the corresponding human enzymes are not inhibited. Cell-wall biosynthesis has been a particularly popular target since the cell wall is essential to prevent a bacterium from literally bursting open and because human cells do not contain a cell wall. For instance, penicillins, cephalosporins, and vancomycin (Figures 1 and 2) all target the enzymes that assemble the cell wall. Until recently, lantibiotics were primarily known for their permeabilization of bacterial cell membranes via pore formation (40). Once pores are present in a target cell membrane, materials that are essential for survival of the bacterium escape. Pore formation is a fairly common mode of action for


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Figure 14. Schematic representation of the make-up of pores formed by the 2:1 nisin–lipid II complex. The view is perpendicular to the membrane.

peptide-based antibiotics, but recent studies indicate that lantibiotics are lethal at much lower concentrations than other pore formers, suggesting that they may have a second mode of action. In the late 1990s this additional mechanism was identified (12, 41). Several lantibiotics including nisin and mersacidin interact in a highly specific manner with a biosynthetic intermediate involved in cell-wall formation known as lipid II (Figure 12). The cell wall is formed by cross-linking many lipid II molecules with each other to generate a netlike structure that envelops the cell. By binding to lipid II, nisin prevents this cross-linking, thereby disrupting the formation of a sturdy cell wall. The structure of nisin bound to lipid II was recently reported revealing that the amide backbone of rings A and B of nisin (Figure 3) surround the diphosphate group of lipid II like a tight-fitting glove (Figure 13) (42). Coincidentally, lipid II is also the target of vancomycin, which binds to the D-Ala-D-Ala moiety of lipid II. What sets nisin apart from vancomycin and a few other compounds that have been shown to bind to lipid II (43) is that nisin not only sequesters lipid II to prevent cellwall biosynthesis, it also hijacks these molecules to create pores in the membrane. These are made up of nisin bound to lipid II (Figure 14) (44). This double-edged sword may have contributed to the absence of widespread resistance despite nisin’s ubiquitous worldwide use. Furthermore, since nisin binds to a biosynthetic intermediate rather than a single enzyme, it may be a formidable challenge for a bacterium to change the structure of lipid II as a potential

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mechanism of resistance because it takes several enzymes to prepare lipid II. Conclusion The biogenesis and mode of action of lantibiotics have attracted much attention in the last decade and a great deal of insight has been gained. These peptide-derived compounds are especially interesting because they have been used as bactericidal agents for an extended period with very little bacterial resistance. With the development of peptide engineering methods, the mechanism by which lantibiotics are produced in bacteria can be better understood, allowing for the development of new and more potent analogs. Acknowledgments Our work on lantibiotics has been supported by the National Institutes of Health (GM 58822). We thank Champak Chatterjee for help with preparation of Figure 14. Literature Cited 1. Walsh, C. T. Antibiotics: Actions, Origins, Resistance; ASM Press: Washington DC, 2003. 2. Lowy, F. D. N. Engl. J. Med. 1998, 339, 520–532. 3. Levy, S. B.; Marshall, B. Nat. Med. 2004, 10, S122–129. 4. Woodyer, R.; Chen, W.; Zhao, H. J. Chem. Educ. 2004, 81, 126–133.


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Chemistry for Everyone 5. Roberts, S. M. J. Chem. Educ. 2000, 77, 344–348. 6. Held, M.; Schmid, A.; van Beilen, J. B.; Witholt, B. Pure Appl. Chem. 2000, 72, 1337–1343. 7. Schmid, A.; Dordick, J. S.; Hauer, B.; Kiener, A.; Wubbolts, M.; Witholt, B. Nature 2001, 409, 258–268. 8. Schoemaker, H. E.; Mink, D.; Wubbolts, M. G. Science 2003, 299, 1694–1697. 9. Panke, S.; Held, M.; Wubbolts, M. Curr. Opin. Biotechnol. 2004, 15, 272–279. 10. Cane, D. E.; Walsh, C. T.; Khosla, C. Science 1998, 282, 63– 68. 11. Cane, D. E. Biotechnology 1995, 28, 633–655. 12. Breukink, E.; Wiedemann, I.; van Kraaij, C.; Kuipers, O. P.; Sahl, H.; de Kruijff, B. Science 1999, 286, 2361–2364. 13. Benkerroum, N.; Sandine, W. E. J. Dairy Sci. 1988, 71, 3237– 3245. 14. Delves–Broughton, J.; Blackburn, P.; Evans, R. J.; Hugenholtz, J. Antonie van Leeuwenhoek 1996, 69, 193–202. 15. Mead, P. S.; Slutsker, L.; Dietz, V.; McCaig, L. F.; Bresee, J. S.; Shapiro, C.; Griffin, P. M.; Tauxe, R. V. Emerg. Infect. Dis. 1999, 5, 607–625. 16. Buzby, J. C.; Roberts, T. World Health Stat. Q 1997, 50, 57–66. 17. Hurst, A. Adv. Appl. Microbiol. 1981, 27, 85–123. 18. Rayman, M. K.; Aris, B.; Hurst, A. Appl. Environ. Microbiol. 1981, 41, 375–380. 19. Schnell, N.; Entian, K. D.; Schneider, U.; Gotz, F.; Zahner, H.; Kellner, R.; Jung, G. Nature 1988, 333, 276–278. 20. Xie, L.; van der Donk, W. A. Curr. Opin. Chem. Biol. 2004, 8, 498–507. 21. Horn, M. J.; Jones, D. B.; Ringel, S. J. J. Biol. Chem. 1941, 138, 141–149. 22. Rogers, L. A. J. Bacteriol. 1928, 16, 321–325. 23. Rogers, L. A.; Whittier, E. O. J. Bacteriol. 1928, 16, 211–229. 24. Fleming, A. Brit. J. Exp. Path. 1929, 10, 226–236. 25. Gross, E.; Morell, J. L. J. Am. Chem. Soc. 1971, 93, 4634– 4635. 26. Chatterjee, C.; Paul, M.; Xie, L.; van der Donk, W. A. Chem. Rev. 2005, 105, 633–684. 27. Ban, N.; Nissen, P.; Hansen, J.; Moore, P. B.; Steitz, T. A. Science 2000, 289, 905–920.

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•

28. 29. 30. 31.

32. 33. 34.

35. 36.

37. 38. 39. 40. 41. 42.

43. 44.

45.

46.

Moore, P. B.; Steitz, T. A. Nature 2002, 418, 229–235. Walsh, C. T. Science 2004, 303, 1805–1810. Jung, G. Angew. Chem., Intl. Ed. Engl. 1991, 30, 1051–1068. Kruszewska, D.; Sahl, H. G.; Bierbaum, G.; Pag, U.; Hynes, S. O.; Ljungh, A. J. Antimicrob. Chemother. 2004, 54, 648– 653. Märki, F.; Hanni, E.; Fredenhagen, A.; van Oostrum, J. Biochem. Pharmacol. 1991, 42, 2027–2035. Wakamiya, T.; Shimbo, K.; Shiba, T.; Nakajima, K.; Neya, M.; Okawa, K. Bull. Chem. Soc. Jpn. 1982, 55, 3878–3881. Fukase, K.; Kitazawa, M.; Akihiko, S.; Shimbo, K.; Fujita, H.; Horimoto, S.; Wakamiya, T.; Shiba, T. Tetrahedron Lett. 1988, 29, 795–798. Xie, L.; Miller, L. M.; Chatterjee, C.; Averin, O.; Kelleher, N. L.; van der Donk, W. A. Science 2004, 303, 679–681. Chatterjee, C.; Miller, L. M.; Leung, Y. L.; Xie, L.; Yi, M.; Kelleher, N. L.; van der Donk, W. A. 2005, 127, 15332– 15333. Zhu, Y.; Gieselman, M.; Zhou, H.; Averin, O.; van der Donk, W. A. Org. Biomol. Chem. 2003, 1, 3304–3315. Kuipers, O. P.; Rollema, H. S.; Yap, W. M.; Boot, H. J.; Siezen, R. J.; de Vos, W. M. J. Biol. Chem. 1992, 267, 24340–24346. Berg, J. M.; Tymoczko, J. L.; Stryer, L. Biochemistry, 5th ed.; W. H. Freeman: New York, 2002. Ruhr, E.; Sahl, H. G. Antimicrob. Agents Chemother. 1985, 27, 841–845. Brötz, H.; Bierbaum, G.; Leopold, K.; Reynolds, P. E.; Sahl, H. G. Antimicrob. Agents Chemother. 1998, 42, 154–160. Hsu, S. T.; Breukink, E.; Tischenko, E.; Lutters, M. A.; De Kruijff, B.; Kaptein, R.; Bonvin, A. M.; Van Nuland, N. A. Nat. Struct. Mol. Biol. 2004, 11, 963–967. Walker, S.; Chen, L.; Hu, Y.; Rew, Y.; Shin, D.; Boger, D. L. Chem. Rev. 2005, 105, 449–476. Breukink, E.; van Heusden, H. E.; Vollmerhaus, P. J.; Swiezewska, E.; Brunner, L.; Walker, S.; Heck, A. J.; de Kruijff, B. J. Biol. Chem. 2003, 278, 19898–19903. Van den Hooven, H. W.; Doeland, C. C.; Van de Kamp, M.; Konings, R. N.; Hilbers, C. W.; Van de Ven, F. J. M. Eur. J. Biochem. 1996, 235, 382–393. Koltun, W. L. Biopolymers 1965, 3, 665–679.


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Nature's Way To Make the Lantibiotics - Journal of Chemical

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