A natural prodrug activation mechanism in the biosynthesis of nonribosomal peptides

Abstract

Highlight describes the recently discovered prodrug activation mechanism found in the biosynthesis of nonribosomally produced peptides and peptide/polyketide hybrids as well as related mechanisms.

The Microbes inside Us and the Race for Colibactin

“…[8] Therefore,i nhibition of ClbP by small molecules could confer protection against colibactininduced colorectal cancers. [9] Thei dentification of similar prodrug activation mechanisms in other natural products derived from NRPS and PKS/ NRPS hybrids revealed aw idespread occurrence of such am echanism, [10] which was originally identified for the antibiotic xenocoumacin from Xenorhabdus nematophila. [11] There,i tw as shown that acylated prexenocoumacins are cleaved after ac onserved d-asparagine upon secretion from the cell, which results in the active antibiotic xenocoumacin 1.…”

Low-Molecular-Weight Metabolites Secreted by Paenibacillus larvae as Potential Virulence Factors of American Foulbrood

“…Similar NRPS have been shown to be involved in the biosynthesis of piperazines or terphenylquinones from fungi (48,49). The largest gene cluster (cluster 4) encodes an NRPS-PKS hybrid with all structural features of the prodrug activation mechanism previously identified in the biosynthesis of xenocoumacin, zwittermicin, and colibactin (39,(50)(51)(52). Additionally, a putatively incomplete NRPS-PKS hybrid gene cluster (cluster 5 in Fig.…”

Catalysis of Extracellular Deamination by a FAD‐Linked Oxidoreductase after Prodrug Maturation in the Biosynthesis of Saframycin A

“…[3] This reaction requires ac ryptic fatty acyl chain for substrate recognition ( Figure 1). [4] Analogously,i ti se xpected that am aturating step is required in the biosynthesis of SFM-A from Streptomyces lavendulae;h owever the corresponding enzymatic reaction is obscure.T he cleavage of the fatty acyl chain releases af ree amino group at C25, and further deamination is needed to afford the C25 keto group in SFM-S (2; Figure 1). [4] Analogously,i ti se xpected that am aturating step is required in the biosynthesis of SFM-A from Streptomyces lavendulae;h owever the corresponding enzymatic reaction is obscure.T he cleavage of the fatty acyl chain releases af ree amino group at C25, and further deamination is needed to afford the C25 keto group in SFM-S (2; Figure 1).…”

“…Given that all known prodrug-maturation processes occur outside the cell membrane, [4,6] then ext deamination step is most probably performed extracellularly by as ecreted enzyme containing an N-terminal signal peptide.G uided by this information, we searched for as ecreted enzyme,w hose function remained unverified, among the proteins encoded by the sfm gene cluster.SfmCy2 was found to harbor a27amino acid, N-terminal signal-peptide sequence corresponding to af amily of twin-arginine translocation (Tat) signal peptides with conserved aR R-AXA sequence (see Figure S3). [9] Importantly,t he Tats ystem has been proven to be am ajor general route for protein export in Streptomyces.…”

“…[3] Recently,t his sort of process was defined as an atural prodrug activation mechanism, in which final peptide products undergo enzymatic hydrolytic maturation from the precursors. [4] Analogously,i ti se xpected that am aturating step is required in the biosynthesis of SFM-A from Streptomyces lavendulae;h owever the corresponding enzymatic reaction is obscure.T he cleavage of the fatty acyl chain releases af ree amino group at C25, and further deamination is needed to afford the C25 keto group in SFM-S (2; Figure 1). Previously,SFM-Y3 (6, Figure 1), aC25 amino derivative containing ac yano group at C21 instead of the hydroxy group,w as isolated from the SFM-A producer strain.…”