New Basic Water-Soluble Antibiotics Bd-12 and by-81. Ii

Ito, Yukio; Ohashi, Yoshitami; Sakurai, Yoshinori; Sakurazawa, Masaharu; Yoshida, H.; Awataguchi, Shigemi; Okuda, Tomoharu

doi:10.7164/antibiotics.21.307

Cited by 28 publications

(8 citation statements)

References 3 publications

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“…The first member of this group of compounds, ST-F, was isolated more than 70 years ago . These compounds consist of the amino sugar streptothrisamine 95 , composed of streptolidine lactam attached to carbamoylated d -gulosamine, linked to an l -β-Lys pseudopeptide (one to seven residues) by an amide bond in STs 96 , or to a glycyl derivative in ST-related compounds 97 – 101 − (Figure ). In these two classes of molecules, the d -gulosamine and the streptolidine lactam are conserved, but they can be tailored by various chemical modifications.…”

Section: Aa-trna-dependent Transferasesmentioning

confidence: 99%

Aminoacyl-tRNA-Utilizing Enzymes in Natural Product Biosynthesis

2017

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Aminoacyl-tRNAs were long thought to be involved solely in ribosome-dependent protein synthesis and essential primary metabolism processes, such as targeted protein degradation and peptidoglycan synthesis. About 10 years ago, an aminoacyl-tRNA-dependent enzyme involved in the biosynthesis of the antibiotic valanimycin was discovered in a Streptomyces strain. Far from being an isolated case, this discovery has been followed by the description of an increasing number of aminoacyl-tRNA-dependent enzymes involved in secondary metabolism. This review describes the three groups of aminoacyl-tRNA-dependent enzymes involved in the synthesis of natural products. Each group is characterized by a particular chemical reaction, and its members are predicted to share a specific fold. The three groups are cyclodipeptide synthases involved in diketopiperazine synthesis, LanB-like dehydratases involved in the posttranslational modification of ribosomal peptides, and transferases from various biosynthesis pathways.

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Section: Aa-trna-dependent Transferasesmentioning

confidence: 99%

Aminoacyl-tRNA-Utilizing Enzymes in Natural Product Biosynthesis

2017

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“…Other ST congeners with structural nuances exist, such as BD-12 (Fig. 1a , compound 2 ) which has an unusual N -formimidoylglycine in place of the β-Lys oligopeptide 3 – 5 , and glycinothricin (Fig. 1a , compound 1 ), which is similar to BD-12 but lacks the N -formimidoyl group (Fig.…”

Section: Introductionmentioning

confidence: 99%

N-Formimidoylation/-iminoacetylation modification in aminoglycosides requires FAD-dependent and ligand-protein NOS bridge dual chemistry

et al. 2023

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Oxidized cysteine residues are highly reactive and can form functional covalent conjugates, of which the allosteric redox switch formed by the lysine-cysteine NOS bridge is an example. Here, we report a noncanonical FAD-dependent enzyme Orf1 that adds a glycine-derived N-formimidoyl group to glycinothricin to form the antibiotic BD-12. X-ray crystallography was used to investigate this complex enzymatic process, which showed Orf1 has two substrate-binding sites that sit 13.5 Å apart unlike canonical FAD-dependent oxidoreductases. One site could accommodate glycine and the other glycinothricin or glycylthricin. Moreover, an intermediate-enzyme adduct with a NOS-covalent linkage was observed in the later site, where it acts as a two-scissile-bond linkage facilitating nucleophilic addition and cofactor-free decarboxylation. The chain length of nucleophilic acceptors vies with bond cleavage sites at either N–O or O–S accounting for N-formimidoylation or N-iminoacetylation. The resultant product is no longer sensitive to aminoglycoside-modifying enzymes, a strategy that antibiotic-producing species employ to counter drug resistance in competing species.

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“…Although STs have been used effectively as selective agents for recombinant DNA work in some of these organisms, STs are not currently used therapeutically due to their inherent toxicity. In addition to the STs, it has been reported that Streptomyces strains produce ST analogues that possess a glycinederived side chain rather than the ␤-Lys residue: 15), citromycin (16,17), glycinothricin (18), A-269A (19), and A-269A= (19) (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

tRNA-Dependent Aminoacylation of an Amino Sugar Intermediate in the Biosynthesis of a Streptothricin-Related Antibiotic

Maruyama

Niikura

Izumikawa

et al. 2016

Appl Environ Microbiol

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The antibiotic streptothricin (ST) possesses an amino sugar bound to an L-␤-lysine (␤-Lys) residue via a peptide bond. The peptide bond formation has been shown to be catalyzed by a nonribosomal peptide synthetase (NRPS) during ST biosynthesis. The focus of this study is the closely related ST analogue BD-12, which carries a glycine-derived side chain rather than a ␤-Lys residue. Here, in Streptomyces luteocolor NBRC13826, we describe our biosynthetic studies of BD-12, which revealed that the peptide bond between the amino sugar and the glycine residue is catalyzed by a Fem-like enzyme (Orf11) in a tRNA-dependent manner rather than by an NRPS. Although there have been several reports of peptide bond-forming tRNA-dependent enzymes, to our knowledge, Orf11 is the first enzyme that can accept an amino sugar as a substrate. Our findings clearly demonstrate that the structural diversity of the side chains of ST-type compounds in nature is generated in an unusual manner via two distinct peptide bond-forming mechanisms. Moreover, the identification and functional analysis of Orf11 resulted in not only the production of new ST-related compounds, but also the provision of new insights into the structure-activity relationship of the ST-related antibiotics. (1), STs with an oligo(␤-Lys) consisting of two to seven residues have been identified (Fig. 1). ST-F inhibits protein biosynthesis in prokaryotic cells (2), and STs carrying the longer oligo(␤-Lys) side chains show higher levels of antibacterial activity. Moreover, STs strongly inhibit the growth of eukaryotes, such as yeasts (3-5), fungi (6), protozoa (7), insects (8), plants (9), and mammals (10-13). Although STs have been used effectively as selective agents for recombinant DNA work in some of these organisms, STs are not currently used therapeutically due to their inherent toxicity. In addition to the STs, it has been reported that Streptomyces strains produce ST analogues that possess a glycinederived side chain rather than the ␤-Lys residue: 15), citromycin (16,17), glycinothricin (18), A-269A (19), and A-269A= (19) (Fig. 1). These analogues display potent antibacterial activities, although their molecular targets remain unclear. Also, like the STs, the ST analogues are not used clinically due to their toxicity.We previously identified the ST-biosynthetic gene cluster (accession no. AB684619) in Streptomyces rochei NBRC 12908 (Fig. 2) and elucidated the biosynthetic mechanisms of the oligo(␤-Lys) side chains (20). Nonribosomal peptide synthetases (NRPSs) are known to catalyze the assembly of a myriad of structurally complex peptide natural products (21). However, in the previous study, we identified three unique stand-alone NRPSs among the ST-biosynthetic enzymes and showed that they assembled the structurally simple peptide oligo(␤-Lys) (Fig. 3A). The biosynthesis is initiated by adenylation of ␤-Lys in Orf5 (stand-alone adenylation [A] domain), and the resulting L-␤-lysyl-O-AMP is loaded

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New Basic Water-Soluble Antibiotics Bd-12 and by-81. Ii

Cited by 28 publications

References 3 publications

Aminoacyl-tRNA-Utilizing Enzymes in Natural Product Biosynthesis

Aminoacyl-tRNA-Utilizing Enzymes in Natural Product Biosynthesis

N-Formimidoylation/-iminoacetylation modification in aminoglycosides requires FAD-dependent and ligand-protein NOS bridge dual chemistry

tRNA-Dependent Aminoacylation of an Amino Sugar Intermediate in the Biosynthesis of a Streptothricin-Related Antibiotic

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