Structural aspects of phenylglycines, their biosynthesis and occurrence in peptide natural products

Abstract

Phenylglycine-type amino acids occur in a wide variety of peptide natural products, including glycopeptide antibiotics and biologically active linear and cyclic peptides. Sequencing of biosynthesis gene clusters of chloroeremomycin, balhimycin and pristinamycin paved the way for intensive investigations on the biosynthesis of 4-hydroxyphenylglycine (Hpg), 3,5-dihydroxyphenylglycine (Dpg) and phenylglycine (Phg) in recent years. The significance and importance of this type of unusual non-proteinogenic aromatic amino acids also for medicinal chemistry has drawn the attention of many research groups and pharmaceutical companies. Herein structures and properties of phenylglycine containing natural products as well as the biosynthetic origin and incorporation of phenylglycines are discussed.

A route to diastereomerically pure phenylglycine thioester peptides: crucial intermediates for investigating glycopeptide antibiotic biosynthesis

“…[1][2][3][4] Due to the modular structure of nonribosomal peptide synthetases (NRPSs) -comprising repeating domains performing specific catalytic functions -and their non-dependence on the ribosome, NRPS assembly lines are able to synthesise peptides from a wide range of amino acids. 1,3 This feature, combined with the extensive incorporation of (D)-amino acids and large range of further structural modifications, contribute to the extensive diversity of natural NRPS-peptides. 1,2 Given the complexity of many of these compounds that are of medical interest -such as the glycopeptide antibiotics ( Fig.…”

“…Our synthetic strategy will also prove highly useful for the investigation of the many novel NRPS and NRPS/ PKS systems that produce important phenylglycine containing peptide products. 3,[26][27][28] Open Access funding provided by the Max Planck Society.…”

“…However, the diversity of amino acid monomers utilised by NRPS machineries can now present serious problems for such syntheses, with no better example found than the phenylglycine residues that form the majority of residues in the peptide core of GPAs such as teicoplanin. 3 Phenylglycine residues, by virtue of their structure, are highly epimerisation prone residues, especially under the basic conditions required for Fmoc-based solid phase peptide synthesis (SPPS) strategies. 3 Through the careful selection of activation and coupling conditions, it is possible to generate peptides (such as GPA precursor peptides) using Fmoc synthesis.…”

“…3 Phenylglycine residues, by virtue of their structure, are highly epimerisation prone residues, especially under the basic conditions required for Fmoc-based solid phase peptide synthesis (SPPS) strategies. 3 Through the careful selection of activation and coupling conditions, it is possible to generate peptides (such as GPA precursor peptides) using Fmoc synthesis. [9][10][11] However, the requirement to synthesise peptide CoA species for PCP loading adds a further complication, as the generation of the C-terminal thioester necessitates either activation and coupling or thioester exchange, both of which have high potential to racemise the C-terminal residue.…”

Total synthesis of feglymycin based on a linear/convergent hybrid approach using micro-flow amide bond formation

“…Phenylglycine (Phg), 4-hydroxyphenylglycine (Hpg) and 3,5-dihydroxyphenylglycine (Dpg) are the most important representatives of the arylglycines because they can be found in various biologically active natural products such as formadicin, ramoplanin, vancomycin and teicoplanin4. These arylglycines significantly contribute to the biological activity of these natural products4.…”