Tyrocidinetyrocidine a, tyrocidine
18S,21S,24S,27R,32aS -9-2-amino-2-oxoethyl- 21-3-aminopropyl- 3,6,27-tribenzyl-15- 4-hydroxybenzyl-24-isobutyl- 18-isopropyl- 1,4,7,10,13,16,19,22,25,28- decaoxodotriacontahydropyrrolo decaazacyclotriacontin- 12-ylpropanamide
- 8011-61-8 Y
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 See figure 1 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 sporulationFigure 1: a Amino acid sequence of tyrocidine A b Sequence changes for the 4 types of tyrocidine
Tyrocidines A, B, and C are cyclic decapeptides The biosynthesis of tyrocidine involves three enzymes Parts of its sequence are identical to gramicidin S
- 1 History
- 2 Mechanism of action
- 3 Biosynthesis
- 4 Chemoenzymatic strategies
- 5 References
- 6 External links
In 1939, the American microbiologist René Dubos discovered the soil microbe Bacillus brevis He observed the ability of the microbe to decompose the capsule of pneumococcus bacterium, rendering it harmless From the soil microbe B brevis, he isolated tyrothricin, which had a high toxicity to a large range of bacteria Tyrothricin was later found to be a mixture of the peptides gramicidin and tyrocidine These were observed to have toxic effects in red blood cells and reproductive cells in humans, however, if applied externally as an ointment tyrocidine could also be used as a potent antimicrobial agent Dubos's discovery helped revive interest in research on penicillin
Mechanism of action
Tyrocidine has a unique mode of action in which it disrupts the cell membrane function, making it a favorable target for engineering derivatives Tyrocidine appears to perturb the lipid bilayer of a microbe’s inner membrane by permeating the lipid phase of the membrane The exact affinity and location of tyrocidine within the phospholipid bilayer is not yet known
The biosynthesis of Tyrocidine is similar to Gramicidin S, and is achieved through the use of nonribosomal protein synthetases NRPSs Its biosynthesis is via an enzymatic assembly consisting of 3 peptide synthetase proteins, TycA, TycB, and TycC, which contain 10 modules The different tyrocidine analogues A–D are not produced by different enzymes, but rather by an enzyme system that is capable of incorporating different amino acids of structural similarity at specified sites The amino acid sequence is determined by the organization of the enzyme and not by any RNA templateFigure 2: The tyrocidine operon
The tyrocine synthetases TycA, TycB, and TycC are encoded on the tyrocine operon This consists of the three genes encoding for the three synthetases as well as three additional open reading frames ORFs These ORFs, labeled as TycD, TycE, and TycF are downstream of the three synthetase genes see figure 2 TycD &TycE have the highest similarity to members of the ATP-binding cassette ABC transporter family which aid in the transport of substrates across a membrane It has been suggested that the tandem transporters play a role in conferring resistance in the producer cell through tyrocidine secretion TycF has been identified as a thioesterase TE and is similar to other TEs in bacterial operons used for encoding peptide synthetases However, the precise function of these TEs remains unknown The size of the peptide synthetases corresponds to the amount of activation they carry out TycA is the smallest and activates a single amino acid from one module, TycB is intermediate in size and activates 3 amino acids with 3 modules, and TycC is the largest and activates 6 amino acids with 6 modules See figure 3Figure 3: Modules and Domains for Tyrocidine biosynthesis
Each module performs all the catalytic reactions necessary to incorporate a single amino acid onto the peptide chain This is accomplished through the subdomains for adenylation A, peptityl carrier protein PCP, condensation C, and depending on the amino acid position, an epimerization E The adenylation subdomain is used in activating the specific amino acid Each module uses one molecule of the selected substrate amino acid with one molecule of ATP to give an aminoacyl adenylate enzyme complex and pyrophosphate The activated amino acid can then be transferred to the enzyme bound 4'-phosphopantetheine of the carrier protein with the expulsion of AMP from the system The carrier protein uses the 4'-phosphopantetheine prosthetic group for loading of the growing peptide and their monomer precursors Elongation of the peptide chain is achieved through condensation of the upstream PCP onto an adjacent downstream PCP-bound monomer In certain domains you will find modification subdomains, such as the E subdomain seen in domains 1 and 4 in tyrocidine, which will generate the D-configured amino acid On the final module is the TE domain used as a catalyst for cyclization or product release The release of the product from the carrier protein is achieved through acylation of the active site serine of TE in which the decapeptide is transferred from the thiol ether to the serine residue Deacylation can then occur through intramolecular cyclization or through hydrolysis to give the cyclic or linear product respectively See figure 4Figure 4: Proposed cyclization reaction catalyzed by thioesterase
In the case of tyrocidine, ring closure has been shown to be highly favorable due to 4 H-bonds helping the decapeptide backbone to adopt a stable conformation See figure 5 This intramolecular cyclization occurs in a head-to-tail fashion involving the N-terminus of the D-Phe1 and the C-terminus of the L-Leu10 See figure 4Figure 5: Hydrogen-bonding illustrating stabilizing effects of cyclization
There is no general chemical solution for macrocyclization of a peptide chain Isolated tyrocidine Tyc TE domains can be used to cyclize chemically derived peptidyl-thioester substrates, providing a powerful route to new cyclic compounds In order for this macrocyclization to occur, the peptide chain must be activated at its C-terminus with an N-acethylcysteamine SNAC leaving group An alanine scan through the 10 positions of tyrocidine shows that only the D-Phe and L-Orn are required for sufficient cyclization
Tyc TE can also be used biomimetically in which it mimics the environment created by the TE domain with the substrate’s PCP through use of a synthetic tether linked to a polyethylene glycol PEG amide resin Use of this resin bound to a desired substrate with isolated TE can allow for catalytic release of the resin as well as macrocyclization of the substrate See figure 6 Use of solid phase peptide synthesis SPPS allowed the incorporation of a diverse array of monomers into the peptide chain Later studies used the high tolerance of Tyc TE in order to modify the peptide backbone post-synthetically This also allowed for glycosylation of the tyrosine or serine residues to be incorporated Use of these methods has led to many promising new therapeutic agentsFigure 6: Biomimetic macrocyle synthesis
- ^ Pubchem: Tyrocidine and Tyrothricin"PubChem Compound Result"
- ^ a b c Mootz HD, Marahiel MA November 1997 "The tyrocidine biosynthesis operon of Bacillus brevis: complete nucleotide sequence and biochemical characterization of functional internal adenylation domains" J Bacteriol 179 21: 6843–50 PMC 179617 PMID 9352938
- ^ "Antibiotics" The Columbia Electronic Encyclopedia 6th ed Columbia University Press 2007 pp online Check date values in: |access-date= help; |access-date= requires |url= help
- ^ a b Qin C, Bu X, Wu X, Guo Z 2003 "A chemical approach to generate molecular diversity based on the scaffold of cyclic decapeptide antibiotic tyrocidine A" J Comb Chem 5 4: 353–5 doi:101021/cc0300255 PMID 12857101
- ^ Prenner EJ, Lewis RN, McElhaney RN December 1999 "The interaction of the antimicrobial peptide gramicidin S with lipid bilayer model and biological membranes" Biochim Biophys Acta 1462 1–2: 201–21 doi:101016/S0005-27369900207-2 PMID 10590309
- ^ a b c d Kopp F, Marahiel MA August 2007 "Macrocyclization strategies in polyketide and nonribosomal peptide biosynthesis" Nat Prod Rep 24 4: 735–49 doi:101039/b613652b PMID 17653357
- ^ Roskoski R, Gevers W, Kleinkauf H, Lipmann F December 1970 "Tyrocidine biosynthesis by three complementary fractions from Bacillus brevis ATCC 8185" Biochemistry 9 25: 4839–45 doi:101021/bi00827a002 PMID 4320358
- ^ a b c d Kohli RM, Walsh CT, Burkart MD August 2002 "Biomimetic synthesis and optimization of cyclic peptide antibiotics" Nature 418 6898: 658–61 doi:101038/nature00907 PMID 12167866
- ^ Trauger JW, Kohli RM, Mootz HD, Marahiel MA, Walsh CT September 2000 "Peptide cyclization catalysed by the thioesterase domain of tyrocidine synthetase" Nature 407 6801: 215–8 doi:101038/35025116 PMID 11001063
- Tyrocidine at the US National Library of Medicine Medical Subject Headings MeSH
tyrocidine, tyrocidine, tyrocidine a, tyrocidine a
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