Follow the leader: the use of leader peptides to guide natural product biosynthesis

Abstract

The avalanche of genomic information in the past decade has revealed that natural product biosynthesis using the ribosomal machinery is much more widespread than originally anticipated. Nearly all of these compounds are crafted through posttranslational modifications of a larger precursor peptide that often contains the marching orders for the biosynthetic enzymes. We review here the available information for how the peptide sequences in the precursors govern the posttranslational tailoring processes for several classes of natural products. In addition, we highlight the great potential these leader peptide directed biosynthetic systems offer for engineering conformationally restrained and pharmacophore-rich products with structural diversity that greatly expands the proteinogenic repertoire.

Cysteine S -glycosylation, a new post-translational modification found in glycopeptide bacteriocins

“…Cysteine thiols are precursors for conformationally-constraining post-translational modifications such as disulfide bonds, cyclic thioethers and thiazole heterocycles found in a diverse ensemble of antimicrobial peptides including defensins, lantibiotics and thiopeptide antibiotics [5,6]. The sulfur to a-carbon bridges of subtilosin A [26] and thuricin CD [27] are further testament to the versatility of cysteine thiols as substrates for post-translational modification enzymes.…”

“…Some bacteriocins exhibit unusual post-translational modifications [5,6], for example the C-terminal glycosyl ester linkage in microcin E492m [7], but there are no confirmed reports of bacteriocins with glycosylated sidechains.…”

Molecular basis for the broad substrate selectivity of a peptide prenyltransferase

“…A significant subset of cyanobactins is modified by either forward or reverse isoprenylation on Ser, Thr, or Tyr residues of the macrocycles, or in some cases on the terminal nitrogen of linear peptides (7). The basis of relaxed substrate specificity has been examined for a series of RiPP modification enzymes, revealing that conserved recognition sequences within the leader region of the precursor peptide enable modification of hypervariable core peptides (8)(9)(10)(11).…”

Evolution of lanthipeptide synthetases

“…The nonribosomal peptide synthetases are responsible for the biosynthesis of many clinically important antibiotics (1,2). A different strategy involves posttranslational modifications of linear ribosomally synthesized peptides (3,4). This biosynthetic strategy is also widely distributed and found in all three domains of life.…”

“…Many lanthipeptides, such as the commercially used food preservative nisin, have potent antimicrobial activity and are termed lantibiotics. Maturation of lanthipeptides involves posttranslational modifications of a C-terminal core region of a precursor peptide and subsequent proteolytic removal of an N-terminal leader sequence that is not modified (3). Their thioether bridges are installed by the initial dehydration of Ser and Thr residues, followed by stereoselective intramolecular Michael-type addition of Cys thiols to the newly formed dehydroamino acids (Fig.…”