Dehydroamino acid residues in bioactive natural products

Abstract

In this review, we will discuss recent advances in the biosynthesis of peptidyl NPs containing unusual dhAA residues and cryptic dhAA residues. The proposed biosynthetic pathways of these natural products will also be discussed.

Efficient synthetic methods for α,β-dehydroamino acids as useful and environmentally benign building blocks in biological and materials science

“…Although α,β-dehydroamino acids, including dehydroalanine, are not part of the 20 natural proteinogenic amino acids, their structures are frequently found in natural peptides. 8 It is known that dehydroalanine units in these natural peptides are produced through the dehydration of serine moieties. 9 In light of these findings, researchers have also developed an artificial method for synthesizing dehydroalanines from natural amino acids such as serine and cysteine.…”

PEARL-Catalyzed Peptide Bond Formation after Chain Reversal by Ureido-Forming Condensation Domains

“…A small subset of NRPSs are encoded in biosynthetic gene clusters (BGCs) with enzymes annotated as class I lantibiotic dehydratases. , These enzymes are composed of two domains: an N-terminal glutamylation domain (protein family PF04738) and a C-terminal elimination domain (protein family PF14028). They generate the dehydroamino acids of ribosomally synthesized and post-translationally modified peptides (RiPPs), including lanthipeptides (called lantibiotics if they display antibiotic activity) and thiopeptides . The dehydration reaction involves the glutamylation of serine and threonine hydroxyl groups using glutamyl-tRNA Glu catalyzed by the N-terminal domain of the enzyme, and subsequent elimination of glutamate by the C-terminal domain to generate peptidyl dehydroamino acids (Figure C ). , Enzymes frequently mis-annotated as lantibiotic dehydratases are peptide aminoacyl-tRNA ligases (PEARLs). − PEARLs share sequence homology with the glutamylation domain of lantibiotic dehydratases, but catalyze peptide bond formation at the C-terminus of a carrier peptide using adenosine-5′-triphosphate (ATP) and aminoacyl-tRNA (Figure C ) .…”

“… 21 , 22 These enzymes are composed of two domains: an N-terminal glutamylation domain (protein family PF04738) and a C-terminal elimination domain (protein family PF14028). They generate the dehydroamino acids 23 of ribosomally synthesized and post-translationally modified peptides (RiPPs), 24 including lanthipeptides 22 (called lantibiotics if they display antibiotic activity) and thiopeptides. 25 The dehydration reaction involves the glutamylation of serine and threonine hydroxyl groups using glutamyl-tRNA Glu catalyzed by the N-terminal domain of the enzyme, and subsequent elimination of glutamate by the C-terminal domain to generate peptidyl dehydroamino acids ( Figure 1 C ).…”

Michael Addition Reaction between Dehydroalanines and Phosphites Enabled the Introduction of Phosphonates into Oligopeptides

“…3−5 Inspired by the significance of phosphorylation in living organism, phosphopeptides are frequently studied, with most approaches relying on serine, threonine, or tyrosine phosphorylation via the construction of P−O bonds, while peptide phosphorylation on other amino acids has been less explored. 6−9 Dehydroalanine (Dha) is a unique amino acid that exists in nature 10,11 and has been involved in a variety of chemical transformations for peptide and protein late-stage modifications. 12−16 Specifically, its distinctive structure as a 1,4-unsaturated carbonyl compound makes it a potential site for peptide phosphorylation via Michael addition.…”

“…Phosphorus-containing compounds not only are crucial and prevalent in living organisms , but also are encountered in highly significant drugs, being extensively applied across various fields. − Inspired by the significance of phosphorylation in living organism, phosphopeptides are frequently studied, with most approaches relying on serine, threonine, or tyrosine phosphorylation via the construction of P–O bonds, while peptide phosphorylation on other amino acids has been less explored. − Dehydroalanine (Dha) is a unique amino acid that exists in nature , and has been involved in a variety of chemical transformations for peptide and protein late-stage modifications. − Specifically, its distinctive structure as a 1,4-unsaturated carbonyl compound makes it a potential site for peptide phosphorylation via Michael addition. Davis and co-workers , and Liu and co-workers have independently done pioneering work on late-stage protein modification on Dha to mimic post-translational modification of proteins to identify their functions through the construction of C–S bonds (Scheme A).…”