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.

Expansion of the structural diversity of peptide antibiotics was performed through two different methods. Supplementation-based incorporation (SPI) and stop-codon suppression (SCS) approaches were used for co-translational incorporation of isostructural and orthogonal noncanonical amino acids (ncAAs) into the lasso peptide capistruin. Two ncAAs were employed for the SPI method and five for the SCS method; each of them probing the incorporation of ncAAs in strategic positions of the molecule. Evaluation of the assembly by HR-ESI-MS proved more successful for the SCS method. Bio-orthogonal chemistry was used for post-biosynthetic modification of capistruin congener Cap_Alk10 containing the ncAA Alk (Nε-Alloc-L-lysine) instead of Ala. A second-generation Hoveyda-Grubbs catalyst was used for an in vitro metathesis reaction with Cap_Alk10 and an allyl alcohol, which offers options for post-biosynthetic modifications. The use of synthetic biology allows for the in vivo production of new peptide-based antibiotics from an expanded amino acid repertoire.

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