Cinnamycin

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Cinnamycin
Cinnamycin.svg
Names
IUPAC name
(1S,4S,13S,16S,19R,22S,25S,28R,31S,37S,41R,44R,47S,50S,53R,56R,65S)-44-amino-37-(2-amino-2-oxoethyl)-50-(3-amino-3-oxopropyl)-4,16,22-tribenzyl-47-(3-carbamimidamidopropyl)-31-[(R)-carboxy(hydroxy)methyl]-41,70-dimethyl-2,5,8,14,17,20,23,26,29,32,35,38,45,48,51,54,57,67-octadecaoxo-25-propan-2-yl-42,69,72-trithia-3,6,9,15,18,21,24,27,30,33,36,39,46,49,52,55,58,60,66-nonadecazapentacyclo[38.18.9.319,56.328,53.09,13]triheptacontane-65-carboxylic acid
Other names
Lanthiopeptin; NSC-71936; Ro09-198
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
PubChem CID
UNII
  • InChI=1S/C89H125N25O25S3/c1-43(2)66-84(133)109-59-41-140-40-58-79(128)108-60-42-142-45(4)68(86(135)105-55(75(124)110-66)34-48-22-12-7-13-23-48)111-76(125)54(33-47-20-10-6-11-21-47)104-82(131)61-26-17-31-114(61)65(118)38-98-72(121)53(32-46-18-8-5-9-19-46)103-78(127)57(106-80(60)129)36-95-29-15-14-24-52(87(136)137)102-85(134)67(112-77(126)56(35-63(92)116)99-64(117)37-97-83(132)69(113-81(59)130)70(119)88(138)139)44(3)141-39-49(90)71(120)100-50(25-16-30-96-89(93)94)73(122)101-51(74(123)107-58)27-28-62(91)115/h5-13,18-23,43-45,49-61,66-70,95,119H,14-17,24-42,90H2,1-4H3,(H2,91,115)(H2,92,116)(H,97,132)(H,98,121)(H,99,117)(H,100,120)(H,101,122)(H,102,134)(H,103,127)(H,104,131)(H,105,135)(H,106,129)(H,107,123)(H,108,128)(H,109,133)(H,110,124)(H,111,125)(H,112,126)(H,113,130)(H,136,137)(H,138,139)(H4,93,94,96)/t44-,45?,49+,50+,51+,52+,53+,54+,55+,56+,57+,58+,59+,60+,61+,66+,67?,68+,69+,70-/m1/s1
    Key: QJDWKBINWOWJNZ-IDGBIKHQSA-N
  • C[C@@H]1C2C(=O)N[C@@H](CCCCNC[C@H]3C(=O)N[C@H](C(=O)NCC(=O)N4CCC[C@H]4C(=O)N[C@H](C(=O)N[C@H]5C(SC[C@@H](C(=O)N3)NC(=O)[C@H](CSC[C@@H](C(=O)N[C@H](C(=O)NCC(=O)N[C@H](C(=O)N2)CC(=O)N)[C@H](C(=O)O)O)NC(=O)[C@@H](NC(=O)[C@@H](NC5=O)CC6=CC=CC=C6)C(C)C)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CS1)N)CCCNC(=N)N)CCC(=O)N)C)CC7=CC=CC=C7)CC8=CC=CC=C8)C(=O)O
Properties
C89H125N25O25S3
Molar mass 2041.31 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Cinnamycin is a tetracyclic antibacterial peptide produced by Streptomyces cinnamoneus containing 19 amino acid residues including the unusual amino acids threo-3-methyl-lanthionine, meso-lanthionine, lysinoalanine, and 3-hydroxyaspartic acid.

Contents

Cinnamycin belongs to the class of molecules known as lantibiotics which belongs to ribosomally synthesized post-translationally modified peptides. The unique receptor for cinnamycin is phosphatidylethanolamine (PE) lipids which is a major compound present in many bacterial cell membranes.

Cinnamycin was first isolated in 1952 and some other compounds with similar sequence and structure were found later. [1]

Structure

Cinnamycin has a compact globular structure and composed of following general amino acid sequence: [2]

Ala-Arg-Gln-Ala-Ala-Ala-Phe-Gly-Pro-Phe-Abu-Phe-Val-Ala-Asp-Gly-Asn-Abu-Lys

The backbone amino acid residues are linked through four bridges including one mesolanthionine (Lan), two (2S,3S,6R)-3-methyllanthionines (MeLan) and one (2S,8S)-lysinoalanine (LysAla) bridge. Side chain crosslinking of serine and threonine with cysteine yields mesolanthionine(Lan) and  methyllanthionine (MeLan) respectively. The presence of these thiol bridges along with lysinoalanine bridge makes cinnamycin one of the smallest peptides with a well-organized three dimensional structure. Based on NMR experiments, the binding pocket of cinnamycin consists of 7-14 amino acid residues which can accommodate the substrate phosphatidylethanolamine (PE). This smaller size of the binding pocket makes cinnamycin specific for its receptor (PE). However the function of erytho-3-hydroxy-L-aspartic acid (HyAsp) at residue 15, is not very pronounced. [3]

The peptides duramycin and ancovenin can also be considered to belong to the family of cinnamycin. These peptides also consist of a similar structure to cinnamycin as globular 19 aa peptides with one Lan, two MeLan and an unusual lysinoalanine bridge between Lys-19 and Ser-6. They also exhibit a modification in position 15, an aspartate hydroxylation yielding the erythro-3-hydroxy-aspartic acid. Among the cinnamycin group, ancovenin is the most different variant since it does not possess the aspartate 15 modification and the lysine-alanine bridge. [3] [4]

Receptor–molecule interactions

Cinnamycin selectively binds to its receptor phosphatidylethanolamine (PE) which resides in the inner layer of the plasma membrane with a 1:1 stoichiometry. Based on NMR studies, it has been suggested that this selectivity of cinnamycin for PE is due to the binding of the primary ammonium group of the PE head group into a small binding pocket on the peptide surface that cannot accommodate larger head groups such as that of e.g., phosphatidylcholine. [3]

Cinamycin mainly interacts with PE through the hydrogen-bonding network formed between the lipid ammonium and the backbone carbonyl of Phe7 and Val13. The PE ammonium group also interacts with the hydroxyl and the carboxylate groups of HyAsp15. Beside this ammonium-binding site, the backbone amide hydrogens of residues 10−13 are also critical in binding the lipid phosphate.

It has also been reported that Duramycin and cinnamycin promote membrane binding by inducing transbilayer lipid movement and alter the curvature of PE present membrane upon binding since cinnamycin preferably binds to highly curved lipid membranes. [5] [6]

Cinnamycin gene cluster – Cin

The genetics studies have revealed that the four genes cinA, cinM, cinX and cinorf7 play an important role in the biosynthesis of cinnamycin. cinA encodes the cinnamycin precursor peptide. The LanM family proteins encoded by the cinM gene are responsible for the dehydration of serine and threonine residues in the propeptide followed by the subsequent formation of lanthionine bridges. CinX encodes the protein that catalyzes the hydroxylation of aspartate at position 15. Furthermore cinorf7 is indicated to be crucial in the formation of lysinoalanine bridge. [7]

Biosynthesis

Lantibiotics are a group of ribosomally synthesized, post-translationally modified antimicrobial peptides with characteristic lanthionine(Lan) and methyllanthionine (MeLan) thioether crosslinks. The biosynthesis of cinnamycin is encoded by the cin biosynthetic gene cluster and the synthesis is initiated when the structural gene lanA encodes the precursor peptide which carries an N-terminal extension called "leader peptide" which is 59 amino acid residues long is recognized by various enzymes to process the C-terminal propeptide which is 19 amino acid residues long and will be transformed into cinnamycin through post-translational modifications. The first step in the formation of Lan/MeLan bridges is the dehydration of serine and threonine residues to yield dehydroalanine (Dha) and dehydrobutyrine (Dhb) respectively. These undergo through intramolecular Michael addition with neighbouring cysteine residues to form thioether bridges. Cinnamycin belongs to class II lantibiotics in which, both dehydration and cyclization are catalyzed by a bifunctional enzyme called LanM. After the core peptide is processed, the leader peptide is proteolytically cleaved from the mature peptide. [8]

The post-translational modifications of cinnamycin include the formation of lanthionine bridges, the formation lysinoalanine (Lal) bridge between lysine 19 and serine 6 and the hydroxylation of L-aspartate at position 15.

In most of the class II lantibiotics GG or GA protease cleavage motif  is  present whereas in cinnamycin an AXA motif is present between the leader sequence and the core region of CinA.

A cinnamycin specific-protease is absent in the gene cluster and hence the sequence is recognized by type I signal peptidase of the general secretory (sec) pathway. The enzymes responsible for Asp hydroxylation and Lal bridge formation are yet to be discovered. [9]

Immunity mechanism

A unique immunity mechanism is present in the producing strain Streptomyces cinnamoneus against the inhibitory actions from its own product. In general Cinnamycin performs its antimicrobial activity by binding to phosphatidylethanolamine which is a major membrane lipid in streptomycetes. To protect the producing strain, the cinorf10 gene encodes a PE monomethyltransferase which catalyzes the PE methylation reaction. This transcription by cinorf10 begins at very low levels of cinnamycin to ensure a considerable amount of PE is methylated prior to high-level production of cinnamycin. Based on the structure of cinnamycin-PE complex, monomethylated PE will not fit into the binding pocket of cinnamycin and the inhibitory action will no longer be supported. [10]

Cinnamycin-like compounds

Based on the classification by Jung in 1991 there are two types of lantibiotics as type A and type B. Type A lantibiotics are elongated, flexible, rod like molecules that are positively charged and act on bacterial membranes by the formation of pores. In contrast type B lantibiotics have an inflexible globular structure due to the presence of characteristic head-to-tail crosslinkage. This group of molecules carries a negative charge or no net charge and interfere with various enzymes involved in cell wall biosynthesis. [8]

Cinnamycin is closely related to type B lantibiotics duramycin, duramycin B, duramycin C, and ancovenin. These compounds are all derived from 19-aa propeptides and have one Lan, two MeLan and an unusual lysinoalanine bridge between Lys-19 and Ser-6 and an erythro-3-hydroxy-L-aspartic acid at position 15 which mediates the interaction between cinnamycin and its biological target phosphatidylethanolamine and hence important for their antimicrobial activity. They are all produced by actinomycetes, the duramycins and cinnamycin exclusively by streptomycetes. [7]

Biological activities

In addition to the antimicrobial properties, cinnamycin-like peptides exhibit inhibitory actions against the  angiotensin-converting enzyme, the activity of phospholipase A2, proliferation of herpes simplex virus, prostaglandin, and leucotriene biosynthesis. Further it inhibits the growth of Bacillus subtilis, anaerobic bacteria, fungi and yeasts (although less intensely). [7] [11]

These peptides are also capable in treating the blood pressure regulation, inflammation and viral infection. These molecules consist of a well-defined pocket set up by the four cyclization events and recognizes phosphatidylethanolamine (PE) with a high affinity and selectivity. This ability to selectively bind to PE lipids makes cinnamycin an ideal probe for detecting the location of PE containing membranes such as cancer cells and to disrupt them. [3]

The compounds like duramycin and cinnamycin which disrupt PE association with phosphatidylserine receptors necessary for entry of many enveloped viruses is a promising strategy for broad-spectrum antiviral activity. [12] Cinnamycin binds to the substrate of phospholipase A2, the phosphatidylethanolamine (PE) with a high specificity at a 1:1 ratio and this binding alters the operation of ion channels. This feature is utilized in pharmaceutical industry for cystic fibrosis treatment. Furthermore, PLA2 catalyzes the reaction for liberating arachidonic acid from phospholipids in the cell membranes, which is a precursor for the synthesis of eicosanoids, which are associated with inflammation. Such lantibiotics can also be used in regulation of inflammatory processes. The inhibition of PLA2 is also associated with treatments for some diseases such as atherosclerosis, diabetes and cancer. [9] [11]

Related Research Articles

<span class="mw-page-title-main">Amino acid</span> Organic compounds containing amine and carboxylic groups

Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the α-amino acids, from which proteins are composed. Only 22 α-amino acids appear in the genetic code of all life.

<span class="mw-page-title-main">Protein primary structure</span> Linear sequence of amino acids in a peptide or protein

Protein primary structure is the linear sequence of amino acids in a peptide or protein. By convention, the primary structure of a protein is reported starting from the amino-terminal (N) end to the carboxyl-terminal (C) end. Protein biosynthesis is most commonly performed by ribosomes in cells. Peptides can also be synthesized in the laboratory. Protein primary structures can be directly sequenced, or inferred from DNA sequencess.

<span class="mw-page-title-main">Post-translational modification</span> Biological processes

Post-translational modification (PTM) is the covalent and generally enzymatic modification of proteins following protein biosynthesis. This process often occurs in the endoplasmic reticulum and the golgi apparatus. Proteins are synthesized by ribosomes translating mRNA into polypeptide chains, which may then undergo PTM to form the mature protein product. PTMs are important components in cell signaling, as for example when prohormones are converted to hormones.

<span class="mw-page-title-main">Phenylalanine hydroxylase</span> Mammalian protein found in Homo sapiens

Phenylalanine hydroxylase. (PAH) (EC 1.14.16.1) is an enzyme that catalyzes the hydroxylation of the aromatic side-chain of phenylalanine to generate tyrosine. PAH is one of three members of the biopterin-dependent aromatic amino acid hydroxylases, a class of monooxygenase that uses tetrahydrobiopterin (BH4, a pteridine cofactor) and a non-heme iron for catalysis. During the reaction, molecular oxygen is heterolytically cleaved with sequential incorporation of one oxygen atom into BH4 and phenylalanine substrate. In humans, mutations in its encoding gene, PAH, can lead to the metabolic disorder phenylketonuria.

<span class="mw-page-title-main">Lanthionine</span> Chemical compound

Lanthionine is a nonproteinogenic amino acid with the chemical formula (HOOC-CH(NH2)-CH2-S-CH2-CH(NH2)-COOH). It is typically formed by a cysteine residue and a dehydrated serine residue. Despite its name, lanthionine does not contain the element lanthanum.

<span class="mw-page-title-main">Nisin</span> Chemical compound

Nisin is a polycyclic antibacterial peptide produced by the bacterium Lactococcus lactis that is used as a food preservative. It has 34 amino acid residues, including the uncommon amino acids lanthionine (Lan), methyllanthionine (MeLan), didehydroalanine (Dha), and didehydroaminobutyric acid (Dhb). These unusual amino acids are introduced by posttranslational modification of the precursor peptide. In these reactions a ribosomally synthesized 57-mer is converted to the final peptide. The unsaturated amino acids originate from serine and threonine, and the enzyme-catalysed addition of cysteine residues to the didehydro amino acids result in the multiple (5) thioether bridges.

<span class="mw-page-title-main">Dehydroalanine</span> Chemical compound

Dehydroalanine is a dehydroamino acid. It does not exist in its free form, but it occurs naturally as a residue found in peptides of microbial origin. As an amino acid residue, it is unusual because it has an unsaturated backbone.

Lantibiotics are a class of polycyclic peptide antibiotics that contain the characteristic thioether amino acids lanthionine or methyllanthionine, as well as the unsaturated amino acids dehydroalanine, and 2-aminoisobutyric acid. They belong to ribosomally synthesized and post-translationally modified peptides.

<span class="mw-page-title-main">Phalloidin</span> Chemical compound

Phalloidin belongs to a class of toxins called phallotoxins, which are found in the death cap mushroom (Amanita phalloides). It is a rigid bicyclic heptapeptide that is lethal after a few days when injected into the bloodstream. The major symptom of phalloidin poisoning is acute hunger due to the destruction of liver cells. It functions by binding and stabilizing filamentous actin (F-actin) and effectively prevents the depolymerization of actin fibers. Due to its tight and selective binding to F-actin, derivatives of phalloidin containing fluorescent tags are used widely in microscopy to visualize F-actin in biomedical research.

<span class="mw-page-title-main">Polymyxin</span>

Polymyxins are antibiotics. Polymyxins B and E are used in the treatment of Gram-negative bacterial infections. They work mostly by breaking up the bacterial cell membrane. They are part of a broader class of molecules called nonribosomal peptides.

<span class="mw-page-title-main">Teicoplanin</span> Pharmaceutical drug

Teicoplanin is an antibiotic used in the prophylaxis and treatment of serious infections caused by Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus and Enterococcus faecalis. It is a semisynthetic glycopeptide antibiotic with a spectrum of activity similar to vancomycin. Its mechanism of action is to inhibit bacterial cell wall synthesis.

Biosynthesis is a multi-step, enzyme-catalyzed process where substrates are converted into more complex products in living organisms. In biosynthesis, simple compounds are modified, converted into other compounds, or joined to form macromolecules. This process often consists of metabolic pathways. Some of these biosynthetic pathways are located within a single cellular organelle, while others involve enzymes that are located within multiple cellular organelles. Examples of these biosynthetic pathways include the production of lipid membrane components and nucleotides. Biosynthesis is usually synonymous with anabolism.

<span class="mw-page-title-main">Tyrocidine</span> Chemical compound

Tyrocidine is a mixture of cyclic decapeptides produced by the bacteria Bacillus brevis found in soil. It can be composed of 4 different amino acid sequences, giving tyrocidine A–D. Tyrocidine is the major constituent of tyrothricin, which also contains gramicidin. Tyrocidine was the first commercially available antibiotic, but has been found to be toxic toward human blood and reproductive cells. The function of tyrocidine within its host B. brevis is thought to be regulation of sporulation.

<span class="mw-page-title-main">Amino acid synthesis</span> The set of biochemical processes by which amino acids are produced

Amino acid synthesis is the set of biochemical processes by which the amino acids are produced. The substrates for these processes are various compounds in the organism's diet or growth media. Not all organisms are able to synthesize all amino acids. For example, humans can synthesize 11 of the 20 standard amino acids. These 11 are called the non-essential amino acids).

<span class="mw-page-title-main">Phosphatidylethanolamine N-methyltransferase</span> Protein-coding gene in the species Homo sapiens

Phosphatidylethanolamine N-methyltransferase is a transferase enzyme which converts phosphatidylethanolamine (PE) to phosphatidylcholine (PC) in the liver. In humans it is encoded by the PEMT gene within the Smith–Magenis syndrome region on chromosome 17.

<span class="mw-page-title-main">Diphosphomevalonate decarboxylase</span> InterPro Family

Diphosphomevalonate decarboxylase (EC 4.1.1.33), most commonly referred to in scientific literature as mevalonate diphosphate decarboxylase, is an enzyme that catalyzes the chemical reaction

N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD) is an enzyme that catalyzes the release of N-acylethanolamine (NAE) from N-acyl-phosphatidylethanolamine (NAPE). This is a major part of the process that converts ordinary lipids into chemical signals like anandamide and oleoylethanolamine. In humans, the NAPE-PLD protein is encoded by the NAPEPLD gene.

<span class="mw-page-title-main">Non-proteinogenic amino acids</span> Are not naturally encoded in the genome

In biochemistry, non-coded or non-proteinogenic amino acids are distinct from the 22 proteinogenic amino acids which are naturally encoded in the genome of organisms for the assembly of proteins. However, over 140 non-proteinogenic amino acids occur naturally in proteins and thousands more may occur in nature or be synthesized in the laboratory. Chemically synthesized amino acids can be called unnatural amino acids. Unnatural amino acids can be synthetically prepared from their native analogs via modifications such as amine alkylation, side chain substitution, structural bond extension cyclization, and isosteric replacements within the amino acid backbone. Many non-proteinogenic amino acids are important:

Ribosomally synthesized and post-translationally modified peptides (RiPPs), also known as ribosomal natural products, are a diverse class of natural products of ribosomal origin. Consisting of more than 20 sub-classes, RiPPs are produced by a variety of organisms, including prokaryotes, eukaryotes, and archaea, and they possess a wide range of biological functions.

<span class="mw-page-title-main">Lipid II</span> Chemical compound

Lipid II is a precursor molecule in the synthesis of the cell wall of bacteria. It is a peptidoglycan, which is amphipathic and named for its bactoprenol hydrocarbon chain, which acts as a lipid anchor, embedding itself in the bacterial cell membrane. Lipid II must translocate across the cell membrane to deliver and incorporate its disaccharide-pentapeptide "building block" into the peptidoglycan mesh. Lipid II is the target of several antibiotics.

References

  1. ↑ Wang, Xiaoqi; Gu, Qing; Breukink, Eefjan (2020-08-01). "Non-lipid II targeting lantibiotics". Biochimica et Biophysica Acta (BBA) - Biomembranes. MEMBRANE EFFECTORS AND ACTUATORS. 1862 (8): 183244. doi: 10.1016/j.bbamem.2020.183244 . ISSN   0005-2736. PMID   32126235. S2CID   212406013.
  2. ↑ Kessler, Horst; Steuernagel, Stefan; Will, Martin; Jung, Günther; Kellner, Roland; Gillessen, Dieter; Kamiyama, Tsutomu (1988). "The Structure of the Polycyclic Nonadecapeptide Ro 09-0198". Helvetica Chimica Acta. 71 (8): 1924–1929. doi:10.1002/hlca.19880710811. ISSN   1522-2675.
  3. 1 2 3 4 Vestergaard, Mikkel; Berglund, Nils Anton; Hsu, Pin-Chia; Song, Chen; Koldsø, Heidi; Schiøtt, Birgit; Sansom, Mark S. P. (2019-11-12). "Structure and Dynamics of Cinnamycin–Lipid Complexes: Mechanisms of Selectivity for Phosphatidylethanolamine Lipids". ACS Omega. 4 (20): 18889–18899. doi:10.1021/acsomega.9b02949. PMC   6854821 . PMID   31737850.
  4. ↑ Gomes, Karen Machado; Duarte, Rafael Silva; de Freire Bastos, Maria do Carmo (2017-02-01). "Lantibiotics produced by Actinobacteria and their potential applications (a review)". Microbiology. 163 (2): 109–121. doi: 10.1099/mic.0.000397 . ISSN   1350-0872. PMID   28270262.
  5. ↑ Makino, Asami; Baba, Takeshi; Fujimoto, Kazushi; Iwamoto, Kunihiko; Yano, Yoshiaki; Terada, Nobuo; Ohno, Shinichi; Sato, Satoshi B.; Ohta, Akinori; Umeda, Masato; Matsuzaki, Katsumi (January 2003). "Cinnamycin (Ro 09-0198) Promotes Cell Binding and Toxicity by Inducing Transbilayer Lipid Movement". Journal of Biological Chemistry. 278 (5): 3204–3209. doi: 10.1074/jbc.M210347200 . PMID   12446685.
  6. ↑ Iwamoto, Kunihiko; Hayakawa, Tomohiro; Murate, Motohide; Makino, Asami; Ito, Kazuki; Fujisawa, Tetsuro; Kobayashi, Toshihide (September 2007). "Curvature-Dependent Recognition of Ethanolamine Phospholipids by Duramycin and Cinnamycin". Biophysical Journal. 93 (5): 1608–1619. Bibcode:2007BpJ....93.1608I. doi:10.1529/biophysj.106.101584. PMC   1948045 . PMID   17483159.
  7. 1 2 3 Widdick, D. A.; Dodd, H. M.; Barraille, P.; White, J.; Stein, T. H.; Chater, K. F.; Gasson, M. J.; Bibb, M. J. (2003-04-01). "Cloning and engineering of the cinnamycin biosynthetic gene cluster from Streptomyces cinnamoneus cinnamoneus DSM 40005". Proceedings of the National Academy of Sciences. 100 (7): 4316–4321. Bibcode:2003PNAS..100.4316W. doi: 10.1073/pnas.0230516100 . ISSN   0027-8424. PMC   153090 . PMID   12642677.
  8. 1 2 McAuliffe, Olivia; Ross, R. Paul; Hill, Colin (May 2001). "Lantibiotics: structure, biosynthesis and mode of action". FEMS Microbiology Reviews. 25 (3): 285–308. doi: 10.1111/j.1574-6976.2001.tb00579.x . ISSN   1574-6976. PMID   11348686.
  9. 1 2 Ökesli, Ayşe; Cooper, Lisa E.; Fogle, Emily J.; van der Donk, Wilfred A. (2011-08-31). "Nine Post-translational Modifications during the Biosynthesis of Cinnamycin". Journal of the American Chemical Society. 133 (34): 13753–13760. doi:10.1021/ja205783f. ISSN   0002-7863. PMC   3163434 . PMID   21770392.
  10. ↑ Repka, Lindsay M.; Chekan, Jonathan R.; Nair, Satish K.; van der Donk, Wilfred A. (2017-04-26). "Mechanistic Understanding of Lanthipeptide Biosynthetic Enzymes". Chemical Reviews. 117 (8): 5457–5520. doi:10.1021/acs.chemrev.6b00591. ISSN   0009-2665. PMC   5408752 . PMID   28135077.
  11. 1 2 Gomes, Karen Machado; Duarte, Rafael Silva; de Freire Bastos, Maria do Carmo (2017-02-01). "Lantibiotics produced by Actinobacteria and their potential applications (a review)". Microbiology. 163 (2): 109–121. doi: 10.1099/mic.0.000397 . ISSN   1350-0872. PMID   28270262.
  12. ↑ Kodani, Shinya; Komaki, Hisayuki; Ishimura, Sho; Hemmi, Hikaru; Ohnishi-Kameyama, Mayumi (2016-08-01). "Isolation and structure determination of a new lantibiotic cinnamycin B from Actinomadura atramentaria based on genome mining". Journal of Industrial Microbiology and Biotechnology. 43 (8): 1159–1165. doi:10.1007/s10295-016-1788-9. hdl: 10297/10284 . ISSN   1476-5535. PMID   27255974. S2CID   18281351.
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