Identification and analysis of the resorcinomycin biosynthetic gene cluster

Abstract

Resorcinomycin (1) is composed of a nonproteinogenic amino acid, (S)-2-(3,5-dihydroxy-4-isopropylphenyl)-2-guanidinoacetic acid (2), and glycine. A biosynthetic gene cluster was identified in a genome database of Streptoverticillium roseoverticillatum by searching for orthologs of the genes responsible for biosynthesis of pheganomycin (3), which possesses a (2)-derivative at its N-terminus. The cluster contained a gene encoding an ATP-grasp-ligase (res5), which was suggested to catalyze the peptide bond formation between 2 and glycine. A res5-deletion mutant lost 1 productivity but accumulated 2 in the culture broth. However, recombinant RES5 did not show catalytic activity to form 1 with 2 and glycine as substrates. Moreover, heterologous expression of the cluster resulted in accumulation of only 2 and no production of 1 was observed. These results suggested that a peptide with glycine at its N-terminus may be used as a nucleophile and then maturated by a peptidase encoded by a gene outside of the cluster.

Mechanism of Action of Ribosomally Synthesized and Post-Translationally Modified Peptides

“…The pheganomycins (PGMs, 125 – 129 ) were first isolated in the late 1980s from Streptomyces cirratus (Figure ). The amidinotides are hybrid NRPS/PKS-RiPP products owing to the presence of the nonproteinogenic ( S )-2-amino-2-(3,5-dihydroxy-phenyl)­acetic acid moiety. , An ATP-grasp ligase links a precursor peptide with this nonproteinogenic amino acid to yield the final product. Although the related compounds resorcinomycins A and B also possess the phenyl-2-guanidinoacetic acid moiety, they are not true RiPPs, as they contain a single Gly residue instead of a ribosomally synthesized peptide.…”

Exploring Peptide Ligase Orthologs in Actinobacteria—Discovery of Pseudopeptide Natural Products, Ketomemicins

“…As a first step, we examined the function of a PGM1 ortholog responsible for biosynthesis of resorcinomycin, which also has a phenyl glycine derivative (( S )-2-(3,5-dihydroxy-4-isopropylphenyl)-2-guanidinoacetic acid) at its N -terminus followed by glycine (Figure ). , Gene disruption of the PGM1 ortholog gene and heterologous expression of the gene cluster suggested that machinery similar to that of pheganomycin biosynthesis was utilized for resorcinomycin biosynthesis …”

“…2,3 Gene disruption of the PGM1 ortholog gene and heterologous expression of the gene cluster suggested that machinery similar to that of pheganomycin biosynthesis was utilized for resorcinomycin biosynthesis. 4 In this study, we studied PGM1 orthologs found in actinobacteria, which constitute clusters of genes unrelated to pheganomycin and resorcinomycin biosynthesis. Because of the increasing availability of genome sequences, we identified many PGM1 orthologs in many different bacterial strains, mainly in actinobacteria.…”

Biosynthesis of the β‐Lactone Proteasome Inhibitors Belactosin and Cystargolide

“…[20] Recently,Dairi and coworkers reported an amide bond formation by ATP-grasp enzymes in resorcinomycin and pheganomycin biogenesis. [21] Furthermore,wepostulate that the subsequent transfer of the b-lactone building block to the dipeptide might be catalyzed by the conserved putative AMP-dependent synthetases CysF and BelH.…”