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Cyclisation mechanisms in the biosynthesis of ribosomally synthesised and post-translationally modified peptides

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ABSTRACT

Ribosomally synthesised and post-translationally modified peptides (RiPPs) are a large class of natural products that are remarkably chemically diverse given an intrinsic requirement to be assembled from proteinogenic amino acids. The vast chemical space occupied by RiPPs means that they possess a wide variety of biological activities, and the class includes antibiotics, co-factors, signalling molecules, anticancer and anti-HIV compounds, and toxins. A considerable amount of RiPP chemical diversity is generated from cyclisation reactions, and the current mechanistic understanding of these reactions will be discussed here. These cyclisations involve a diverse array of chemical reactions, including 1,4-nucleophilic additions, [4 + 2] cycloadditions, ATP-dependent heterocyclisation to form thiazolines or oxazolines, and radical-mediated reactions between unactivated carbons. Future prospects for RiPP pathway discovery and characterisation will also be highlighted.

No MeSH data available.


Related in: MedlinePlus

Structure of autoinducing peptide AIP-I from Staphylococcus aureus and the sequence of the corresponding precursor peptide AgrD.
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Figure 9: Structure of autoinducing peptide AIP-I from Staphylococcus aureus and the sequence of the corresponding precursor peptide AgrD.

Mentions: A cysteine protease-like cyclase is proposed in the biosynthesis of autoinducing peptide [120] (AIP). However, its function differs from the above pathways as a thiolactone is generated in AIP biosynthesis (Fig. 9). Autoinducing peptides are secreted molecules that form part of a quorum-sensing system in Staphylococcus [121]. Heterologous expression in E. coli showed that only AgrD (precursor peptide) and AgrB (peptidase) are required for AIP biosynthesis, although AgrD contains an N-terminal signal peptide that is cleaved by an endogenous peptidase [120]. Unlike other macrocyclisation peptidases, AgrB does not belong to a well-characterised peptidase family, but mutagenesis experiments on Cys86 infer that a cysteine protease-like mechanism acts to generate a thioester acyl–enzyme intermediate that is then attacked by Cys28 of AgrD to generate a 16-membered thiolactone [120] (Fig. 9).


Cyclisation mechanisms in the biosynthesis of ribosomally synthesised and post-translationally modified peptides
Structure of autoinducing peptide AIP-I from Staphylococcus aureus and the sequence of the corresponding precursor peptide AgrD.
© Copyright Policy - Beilstein
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4979651&req=5

Figure 9: Structure of autoinducing peptide AIP-I from Staphylococcus aureus and the sequence of the corresponding precursor peptide AgrD.
Mentions: A cysteine protease-like cyclase is proposed in the biosynthesis of autoinducing peptide [120] (AIP). However, its function differs from the above pathways as a thiolactone is generated in AIP biosynthesis (Fig. 9). Autoinducing peptides are secreted molecules that form part of a quorum-sensing system in Staphylococcus [121]. Heterologous expression in E. coli showed that only AgrD (precursor peptide) and AgrB (peptidase) are required for AIP biosynthesis, although AgrD contains an N-terminal signal peptide that is cleaved by an endogenous peptidase [120]. Unlike other macrocyclisation peptidases, AgrB does not belong to a well-characterised peptidase family, but mutagenesis experiments on Cys86 infer that a cysteine protease-like mechanism acts to generate a thioester acyl–enzyme intermediate that is then attacked by Cys28 of AgrD to generate a 16-membered thiolactone [120] (Fig. 9).

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Ribosomally synthesised and post-translationally modified peptides (RiPPs) are a large class of natural products that are remarkably chemically diverse given an intrinsic requirement to be assembled from proteinogenic amino acids. The vast chemical space occupied by RiPPs means that they possess a wide variety of biological activities, and the class includes antibiotics, co-factors, signalling molecules, anticancer and anti-HIV compounds, and toxins. A considerable amount of RiPP chemical diversity is generated from cyclisation reactions, and the current mechanistic understanding of these reactions will be discussed here. These cyclisations involve a diverse array of chemical reactions, including 1,4-nucleophilic additions, [4 + 2] cycloadditions, ATP-dependent heterocyclisation to form thiazolines or oxazolines, and radical-mediated reactions between unactivated carbons. Future prospects for RiPP pathway discovery and characterisation will also be highlighted.

No MeSH data available.


Related in: MedlinePlus