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Tyrocidine

Page history last edited by Mike Burkart 11 years, 7 months ago

Tyrocidine

 

 

 

Tyrocidine is a cyclic decapeptide antibiotic that is produced by Bacillus brevis, a Gram-positive aerobic spore-forming bacillus commonly found in soil, air, water, and decaying matter. Tyrocidine is in fact a mixture of four cyclic decapeptides, tyrocidines A, B, C, and D. Tyrocidine is a constituent of tyrothricin, a mixture of polypeptide antibiotics.

 

 

 

 

 

Contents:

 

1. History

 

2. Structure

 

3. Biosynthesis

 

4. Mechanism of action

 

5. Clinical use

 

6. References

 

 

 

History

 


Tyrocidine is a constituent of tyrothricin. In 1939 the American microbiologist René Dubos demonstrated that a soil bacterium was capable of decomposing the starchlike capsule of the pneumococcus bacterium, without which the pneumococcus is harmless and does not cause pneumonia. Dubos then found in the soil a microbe, Bacillus brevis, from which he obtained a product, tyrothricin, that was highly toxic to a wide range of bacteria.

 

 

 

Structure

 


 

                                                                                             Figure 1: Structures of the four different forms of tyrocidine

 

The four forms of tyrocine differ in amino acid composition at their 3rd, 4th, and 7th amino acid position (beginning with D-Phe as the "1st" amino acid).

 

 

 

Biosynthesis

 


Since the biosynthesis of all four tyrocidine compouds are similar, tyrocidine A is used as an example that can be applied to the other 3 compounds.

 

 

                                        Figure 2 : Tyrocidine A

 

The cyclic decapeptide antibiotic tyrocidine is produced by Bacillus brevis on an enzyme complex comprising three peptide synthetases, TycA, TycB, and TycC (tyrocidine synthetases 1, 2, and 3), via the nonribosomal pathway. Nonribosomal pathways are characterized by substrates that are not restricted to the 20 proteinogenic amino acids; that is to say, the amino acids that are found in proteins and that are coded for in the standard genetic code. Products synthesized using this pathway can incorporate nonproteinogenic amino acids, such as hydroxy-, D-, and N-methylated amino acids.

 

Tyrocidine synthase 1 incorporates the first amino acid, Tyrocidine synthase 2 incorporates the next 3, and Tyrocidine synthase 3 incorporates the final 6 amino acids.

 

 

 

  

                                        Figure 3: Activation of amino acids

 

 

 

The amino acid constituents are activated as aminoacyl adenylate at the expense of ATP and are thioesterified on the thiol moiety of an enzyme-attached cofactor, 4'phosphopantetheine.

 

 

 

 

 

Each module is defined to harbor all catalytic activities to incorporate a single amino acid residue into the peptide product. The modules coincide in number with the number of incorporated

amino acids.

 

 

 

                                                                                                                                             Figure 4: Modules of the enzyme complex

 

                                                                     

 

 

In the above figure: A, adenylation (catalyses amino-acid activation); PCP, peptidyl carrier protein; C, condensation (catalyses peptide-bond formation); TE, (thioesterase) releases the completed polypeptide chain from the final module, and catalyzes the cyclization of the molecule.

 

Activated amino acids are condensed stepwise in an amino-to carboxy-terminal direction. Nucleophilic attack by the amino group of the neighboring aminoacyl thioester is catalysed by the C domain and results in amide (peptide) bond formation. As well as activating the amino acids and catalyzing the formation of the peptide linkages, the enzyme may possess other domains that are responsible for epimerizing L-amino acids to D-amino acids. A terminal thioesterase domain is responsible for terminating chain extension and releasing the peptide from the enzyme. Cyclization occurs when the amino acids at the two termini of a linear peptide link up to form another peptide bond.

 

 

 

 

Mechanism of action

 


 

 

Tyrocidine kills bacteria by interacting with their cytoplasmic membranes and causing leakage of their intracellular content. It also affects intracellular membranes such as those of mitochondria. Tyrocidine inhibits RNA synthesis in an in-vitro transcriptional system by forming a complex with the DNA. Bacillus brevis, under conditions of severe nitrogen starvation brought about by nutritional shift-down, is unable to induce sporulation (process of becoming a spore) unless supplemented with the peptide antibiotic tyrocidine.

 

 

 

Clinical use

 


Tyrocidines are too toxic for therapeutic use on their own, but are incorporated into lozenges for relief of throat infections. They are also found to be toxic to red blood and reproductive cells in humans but can be used to good effect when applied as an ointment on body surfaces, and are active against many Gram-positive bacteria. 

 

 

 

References

 


1. http://www.infoplease.com/ce6/sci/A0856640.html

 

2. Henning D. Mootz, Mohamed A. Marahiel, “The Tyrocidine Biosynthesis Operon of Bacillus brevis: Complete Nucleotide Sequence and Biochemical Characterization of Functional Internal Adenylation Domains”, Journal of Bacteriology, Nov. 1997, p. 6843-6850

 

3. Paul M Dewick, “Medicinal Natural Products – A Biosynthetic Approach”, Second Edition, John Wiley & Sons, LTD

 

 

 

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