Modelling the variable incorporation of aromatic amino acids in the tyrocidines and analogous cyclodecapeptides

J. A. Vosloo, J. L. Snoep, M. Rautenbach*

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

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Aims: A mathematical model of the nonribosomal synthesis of tyrocidines and analogues by Brevibacillus parabrevis was constructed using a competitive binding mechanism (CBM) for the incorporation of the three variable aromatic amino acid (Aaa) residues in their sequence. These antimicrobial peptides have a conserved structure (D-Phe1-Pro2-Aaa3-D-Aaa4-Asn5-Gln6-Aaa7-Val8-Orn9-Leu10), apart from the Aaa in positions 3, 4 and 7 containing either Phe, Trp or Tyr. 

Methods and Results: Ultra-performance liquid chromatography linked mass spectrometry was used to profile peptides from extracts of cultures grown in media with various Phe : Trp ratios. The CBM model describes the production of peptides as a function of growth medium Aaa concentration. The model accounts for variable Aaa incorporation by simultaneously considering the influence of maximal incorporation rate and cooperativity, despite similar KM’s of synthetase modules. 

Conclusions: Our CBM model can be utilized to predict the Aaa composition of produced peptides from the concentration of Aaas in the growth medium. 

Significance and Impact of the Study: Subtly exploiting the inherent promiscuity of the nontemplate coded peptide synthesis allows for external control of peptide identity, without using genetic manipulation. Such versatility is exploitable in the production of targeted peptide complexes and rare peptides where production processes are reliant on nonribosomal synthesis.

Original languageEnglish
Pages (from-to)1665-1676
Number of pages12
JournalJournal of Applied Microbiology
Issue number6
Early online date1 Dec 2019
Publication statusPublished - 1 Dec 2019


This research was funded by the BIOPEP TM Peptide Fund, Department of Biochemistry, Stellenbosch University, Stellenbosch, South Africa. BIOPEP TM produces peptides for industrial applications. JLS acknowledges funding from the DST/NRF, particularly for funding the SARCHI initiative (NRF‐SARCHI‐82813).

FundersFunder number
Universiteit Stellenbosch
Department of Science and Technology, Republic of South AfricaNRF‐SARCHI‐82813
Department of Biochemistry


    • antibiotic
    • computational modelling
    • manipulation
    • peptide production
    • tyrocidine


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