A New Cytosine Glycoside from <i>Streptomyces </i><i>griseochromogenes </i>Produced by the Use in Vivo of Enzyme Inhibitors

Zhang, Q; Sj, Gould; Tm, Zabriskie

doi:10.1021/np970468o

Cited by 6 publications

(1 citation statement)

References 28 publications

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“…This observation reflects the possibility that the oxidation of 4=-hydroxyl CGA involves versatile biochemistry. In addition, BlsH, a degT dnrJ eryC1 strS aminotransferase homolo- gous to ArgH, was proposed to be responsible for conversion of the 4=-keto CGA to 4=-amino CGA (15).…”

Section: Resultsmentioning

confidence: 99%

Biosynthesis of the β-Methylarginine Residue of Peptidyl Nucleoside Arginomycin in Streptomyces arginensis NRRL 15941

Feng

Gao

et al. 2014

Appl Environ Microbiol

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bThe peptidyl nucleoside arginomycin is active against Gram-positive bacteria and fungi but displays much lower toxicity to mice than its analog blasticidin S. It features a rare amino acid, ␤-methylarginine, which is attached to the deoxyhexose moiety via a 4=-aminoacyl bond. We here report cloning of the complete biosynthetic gene cluster for arginomycin from Streptomyces arginensis NRRL 15941. Among the 14 putative essential open reading frames, argM, encoding an aspartate aminotransferase (AAT), and adjacent argN, encoding an S-adenosyl methionine (SAM)-dependent methyltransferase, are coupled to catalyze arginine and yield ␤-methylarginine in Escherichia coli. Purified ArgM can transfer the ␣-amino group of L-arginine to ␣-ketoglutaric acid to give glutamate and thereby converts L-arginine to 5-guanidino-2-oxopentanoic acid, which is methylated at the C-3 position by ArgN to form 5-guanidino-3-methyl-2-oxopentanoic acid. Iteratively, ArgM specifically catalyzes transamination from the donor L-aspartate to the resulting 5-guanidino-3-methyl-2-oxopentanoic acid, generating ␤-methylarginine. The complete and concise biosynthetic pathway for the rare and bioactive amino acid revealed by this study may pave the way for the production of ␤-methylarginine either by enzymatic conversion or by engineered living cells.A rginomycin (Fig. 1) is a peptidyl nucleoside antibiotic isolated from Streptomyces arginensis NRRL 15941 that shows bioactivity against Gram-positive bacteria and fungi, such as Micrococcus luteus and Penicillium oxalicum (1). Although the overall skeleton of arginomycin is highly similar to that of blasticidin S (BS) (Fig. 1), a representative peptidyl nucleoside antibiotic exhibiting strong inhibitory activity against rice blast caused by Pyricularia oryzae Cavara (2), arginomycin showed much lower toxicity to mice (1). They differ from each other only in the modification of the L-arginine-derived guanidino side chain (Fig. 1). A feeding experiment indicated that ␤-arginine in BS is derived from an intramolecular amino migration of ␣-arginine (3). BlsG, an arginine 2,3-aminomutase homologous to lysine 2,3-aminomutase (4), was assumed to govern this migration in the BS biosynthesis pathway. In contrast, ␦-N-methylation was demonstrated to be the ultrabiosynthetic step, as the conversion of demethylblasticidin S to BS was observed in a cell extract of the BS producer Streptomyces griseochromogenes supplied with radiolabeled S-adenosyl-L-methionine (SAM) (5). Likewise, ␦-N-methylation of the guanidyl group of arginomycin should also occur after attachment of the guanidino side chain to the nucleoside core moiety. In addition to this, arginomycin bears at the relatively unreactive ␤ position of arginine the ␤-methylarginine moiety for which ␤-methylation is a commitment step and is of considerable interest to this study in uncovering new enzymology. There are two possibilities for the timing of the ␤-methylation of arginine: (i) L-arginine is first converted to free ␤-methylarginine and is coupled with ...

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Section: Resultsmentioning

confidence: 99%

Biosynthesis of the β-Methylarginine Residue of Peptidyl Nucleoside Arginomycin in Streptomyces arginensis NRRL 15941

Feng

Gao

et al. 2014

Appl Environ Microbiol

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Analysis of the Mildiomycin Biosynthesis Gene Cluster in Streptoverticillum remofaciens ZJU5119 and Characterization of MilC, a Hydroxymethyl cytosyl‐glucuronic Acid Synthase

Deng

et al. 2012

ChemBioChem

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Mildiomycin (MIL) is a peptidyl‐nucleoside antibiotic produced by Streptoverticillum remofaciens ZJU5119 that exhibits strong inhibitory activity against powdery mildew. The entire MIL biosynthesis gene cluster was cloned and expressed in Streptomyces lividans 1326. Systematic gene disruptions narrowed down the cluster to 16 functional ORFs and identified the boundaries of the gene cluster. A putative cytosylglucuronic acid (CGA) synthase gene, milC, was disrupted in Sv. remofaciens and heterologously expressed in E. coli. An in vitro assay revealed that purified MilC could utilize either cytosine or hydroxymethylcytosine as substrate to yield CGA or hydroxymethyl‐CGA (HM‐CGA), respectively. MilG is believed to be a key enzyme in the MIL biosynthesis pathway and contains the CXXXCXXC motif characteristic of members of the radical S‐adenosyl methionine (SAM) superfamily. Disruption of milG leads to accumulation of HM‐CGA. Labeling experiments with 13C6‐L‐arginine indicated that decarboxylation at C5 of the pyranoside ring was coupled with the attachment of 5‐guanidino‐2,4‐dihydroxyvalerate side chain through CC bond formation. In contrast, exogenous 13C6‐labeled 4‐hydroxy‐L‐arginine was not incorporated into the MIL structure. Comparative analysis of the 16 MIL ORFs with counterparts involved in the biosynthesis of the structurally similar compound blasticidin S, along with the results above, provide insight into the complete MIL biosynthetic pathway.

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Natural Products from Actinobacteria for Drug Discovery

Nair

Abraham

2020

Advances in Pharmaceutical Biotechnology

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A New Cytosine Glycoside from Streptomyces griseochromogenes Produced by the Use in Vivo of Enzyme Inhibitors

Cited by 6 publications

References 28 publications

Biosynthesis of the β-Methylarginine Residue of Peptidyl Nucleoside Arginomycin in Streptomyces arginensis NRRL 15941

Biosynthesis of the β-Methylarginine Residue of Peptidyl Nucleoside Arginomycin in Streptomyces arginensis NRRL 15941

Analysis of the Mildiomycin Biosynthesis Gene Cluster in Streptoverticillum remofaciens ZJU5119 and Characterization of MilC, a Hydroxymethyl cytosyl‐glucuronic Acid Synthase

Natural Products from Actinobacteria for Drug Discovery

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