Evolutionary and functional analysis of an NRPS condensation domain integrates β-lactam, ᴅ-amino acid, and dehydroamino acid synthesis

Nonribosomal peptide synthetases (NRPSs) are large, multidomain biosynthetic enzymes involved in the assembly-line–like synthesis of numerous peptide natural products. Among these are clinically useful antibiotics including three classes of β-lactams: the penicillins/cephalosporins, the monobactams, and the monocyclic nocardicins, as well as the vancomycin family of glycopeptides and the depsipeptide daptomycin. During NRPS synthesis, peptide bond formation is catalyzed by condensation (C) domains, which couple the nascent peptide with the next programmed amino acid of the sequence. A growing number of additional functions are linked to the activity of C domains. In the biosynthesis of the nocardicins, a specialized C domain prepares the embedded β-lactam ring from a serine residue. Here, we examine the evolutionary descent of this unique β-lactam–synthesizing C domain. Guided by its ancestry, we predict and demonstrate in vitro that this C domain alternatively performs peptide bond formation when a single stereochemical change is introduced into its peptide starting material. Remarkably, the function of the downstream thioesterase (TE) domain also changes. Natively, the TE directs C terminus epimerization prior to hydrolysis when the β-lactam is made but catalyzes immediate release of the alternative peptide. In addition, we investigate the roles of C-domain histidine residues in light of clade-specific sequence motifs, refining earlier mechanistic proposals of both β-lactam formation and canonical peptide synthesis. Finally, expanded phylogenetic analysis reveals unifying connections between β-lactam synthesis and allied C domains associated with the appearance of ᴅ-amino acid and dehydroamino acid residues in other NRPS-derived natural products.

Enantioselective Hydrogenation of Cyclic Tetrasubstituted-Olefinic Dehydroamino Acid Derivatives

Efficient asymmetric hydrogenation of cyclic tetrasubstituted-olefinic dehydroamino acid derivatives have been achieved with a Rh-ArcPhos catalyst, affording a series of α-acylamino-β-alkyl tetrahydropyranones with two contiguous chiral centers in up to...

Dehydroamino acid chemical biology: an example of functional group interconversion on proteins

The chemical biology of dehydroalanine and dehydrobutyrine in proteins is summarized and new concepts are presented.

“In situ immobilization” of a multicomponent chiral catalyst (MCC) via non-covalent interactions for heterogeneous asymmetric hydrogenation reactions

Novel hybrid catalysts that resulted from the anchoring of pyrene-tagged Rh(i) complexes onto graphene materials via π–π stacking interactions show excellent catalytic activity towards the hydrogenation of dehydroamino acid.