Reevaluation of the Final Steps in the Biosynthesis of Blasticidin S by Streptomyces griseochromogenes and Identification of a Novel Self-Resistance Mechanism

Zhang, Qibo; Cone, Martha C.; Gould, Steven J.; Zabriskie, T. Mark

doi:10.1016/s0040-4020(99)01060-1

Cited by 20 publications

(36 citation statements)

References 35 publications

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“…3 Comparative analysis of the biosynthetic pathways of arginomycin and blasticidin S. (i) Genes responsible for the generation of cytosinine. Cytosinine was previously isolated as an intermediate during blasticidin S biosynthesis (11,12) and postulated to be a common precursor for arginomycin and blasticidin S, given their structural similarity. Based on the BS biosynthetic pathway, four pairs of homologous counterparts, BlsM/ ArgD, BlsD/ArgE, BlsH/ArgH, and BlsE/ArgF (13) (see Table S2 in the supplemental material), are assumed to be involved in the biosynthesis of this intermediate.…”

Section: Resultsmentioning

confidence: 99%

“…Both blsI and blsK are essential to BS biosynthesis (9), which involves the formation of two amide bonds. As leucylblasticidin S (LBS) was proved to be the penultimate compound in the blasticidin S biosynthetic pathway (12), two enzymes were required to activate and attach leucine and ␤-arginine/or leucyl-␤-arginine to BS. Given that ArgJ and ArgK are homologous to BlsI and BlsK, respectively, it is proposed that there also exists a leucylation of the ␣-amino group of the ␤-methylarginine in arginomycin biosynthesis (Fig.…”

Section: Resultsmentioning

confidence: 99%

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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%

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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“…Several segments of S. griseochromogenes chromosomal DNA cloned in the pOJ446 vector produced intermediates of blasticidin S biosynthesis when expressed in S. lividans. 17, 18 One cosmid, cos9 (Figure 1 A and B), produced late intermediates, including leucylblasticidin S (LBS), and was selected for DNA sequencing. Sequence analysis of the 36.7‐kb cos9 insert with the Frameplot program29 identified 28 open reading frames (ORFs) organized into three groups based on transcriptional direction (Figure 1 C).…”

Section: Resultsmentioning

confidence: 99%

“…Biochemical studies on blasticidin S have included purification and characterization of a unique glucuronosyltransferase that forms the cytosylglucuronic acid intermediate 15. Work performed in crude cell‐free systems detected activities for an aminosugar tautomerase and acetyl and methyltransferases and an unusual self‐resistance mechanism 16, 17. Previously, we identified and cloned the blasticidin S gene cluster from Streptomyces griseochromogenes and expressed the pathway in S. lividans.…”

Section: Introductionmentioning

confidence: 99%

“…To further our investigations into the biosynthesis of 1 , we identified a 36‐kb DNA fragment from an S. griseochromogenes genomic library in pOJ446 that contains the blasticidin S gene cluster and demonstrates heterologous production of CGA and other intermediates in the biosynthetic pathway in S. lividans. 18 We later revised the biosynthetic pathway to include leucylblasticidin S (LBS) as the penultimate compound in the pathway (Scheme ) 17. Here we report the complete nucleotide sequence and organization of the blasticidin S biosynthesis gene cluster and describe the initial characterization of individual gene products.…”

Section: Introductionmentioning

confidence: 99%

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The Blasticidin S Biosynthesis Gene Cluster from Streptomyces griseochromogenes: Sequence Analysis, Organization, and Initial Characterization

et al. 2003

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Blasticidin S is a potent antifungal and cytotoxic peptidyl nucleoside antibiotic from Streptomyces griseochromogenes. The mixed biosynthesis of the compound is evident from the three distinct structural components: a cytosine base, an amino deoxyglucuronic acid, and N-methyl beta-arginine. The blasticidin S biosynthesis gene cluster was cloned from S. griseochromogenes and the pathway heterologously expressed in S. lividans from a cosmid harboring a 36.7-kb fragment of S. griseochromogenes DNA. The complete DNA sequence of this insert has now been determined and evidence suggests a contiguous 20-kb section defines the blasticidin S biosynthesis cluster. The predicted functions of several open reading frames are consistent with the expected biochemistry and include an arginine 2,3-aminomutase, a cytosylglucuronic acid synthase, and a guanidino N-methyltransferase. Insight into other steps in the assembly of blasticidin S was evident from sequence homology with proteins of known function and heterologous expression of fragments of the cluster. Additionally, the gene that directs the production of free cytosine, blsM, was subcloned and expressed in Escherichia coli. Characterization of BlsM revealed that cytidine monophosphate serves as the precursor to cytosine.

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Pyrimidine as Constituent of Natural Biologically Active Compounds

Lagoja

2005

C&B

478

178

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This review describes the various manifestations of the pyrimidine system (alkylated, glycosylated, benzo-annelated.). These comprise pyrimidine nucleosides as well as alkaloids and antibiotics--some of them have been discovered and isolated from natural sources already long time ago, others have been reported very recently. A short overview on pyrimidine syntheses (prebiotic synthesis, biosynthesis, and metabolism) is given. The biological activities of most of the pyrimidine analogs are briefly described, and, in some cases, syntheses are formulated.

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Reevaluation of the Final Steps in the Biosynthesis of Blasticidin S by Streptomyces griseochromogenes and Identification of a Novel Self-Resistance Mechanism

Cited by 20 publications

References 35 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

The Blasticidin S Biosynthesis Gene Cluster from Streptomyces griseochromogenes: Sequence Analysis, Organization, and Initial Characterization

Pyrimidine as Constituent of Natural Biologically Active Compounds

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