Studies on new phosphonic acid antibiotics. I. FR-900098, isolation and characterization.

Okuhara, Masakuni; Kuroda, Yoshio; Goto, Toshio; Okamoto, Masanori; Terano, Hiroshi; Kohsaka, Masanobu; Aoki, Hatsuo; Imanaka, Hiroshi

doi:10.7164/antibiotics.33.13

Cited by 112 publications

(75 citation statements)

References 15 publications

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“…Blind PCR screening of this library identified 403 putative phosphonate producers. Subsequent draft genome sequencing of all candidate strains confirmed the presence of pepM in 278 strains, including 244 from the NRRL collection; 30 from our laboratory collection; and four additional strains specifically added to the study because of their known ability to produce phosphonothrixin (26), FR-900098 (27), and fosmidomycin (28) (SI Appendix, Table S1). The majority (87%) of the pepM + strains are Streptomyces, with the remainder scattered among 24 genera, a distribution that mirrors the composition of the strain collection.…”

Section: Resultsmentioning

confidence: 99%

Discovery of phosphonic acid natural products by mining the genomes of 10,000 actinomycetes

Gao

Doroghazi

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

189

185

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Although natural products have been a particularly rich source of human medicines, activity-based screening results in a very high rate of rediscovery of known molecules. Based on the large number of natural product biosynthetic genes in microbial genomes, many have proposed "genome mining" as an alternative approach for discovery efforts; however, this idea has yet to be performed experimentally on a large scale. Here, we demonstrate the feasibility of large-scale, high-throughput genome mining by screening a collection of over 10,000 actinomycetes for the genetic potential to make phosphonic acids, a class of natural products with diverse and useful bioactivities. Genome sequencing identified a diverse collection of phosphonate biosynthetic gene clusters within 278 strains. These clusters were classified into 64 distinct groups, of which 55 are likely to direct the synthesis of unknown compounds. Characterization of strains within five of these groups resulted in the discovery of a new archetypical pathway for phosphonate biosynthesis, the first (to our knowledge) dedicated pathway for H-phosphinates, and 11 previously undescribed phosphonic acid natural products. Among these compounds are argolaphos, a broad-spectrum antibacterial phosphonopeptide composed of aminomethylphosphonate in peptide linkage to a rare amino acid N 5 -hydroxyarginine; valinophos, an N-acetyl L-Val ester of 2,3-dihydroxypropylphosphonate; and phosphonocystoximate, an unusual thiohydroximate-containing molecule representing a new chemotype of sulfur-containing phosphonate natural products. Analysis of the genome sequences from the remaining strains suggests that the majority of the phosphonate biosynthetic repertoire of Actinobacteria has been captured at the gene level. This dereplicated strain collection now provides a reservoir of numerous, as yet undiscovered, phosphonate natural products.natural products | genome mining | phosphonic acid | antibiotic

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Section: Resultsmentioning

confidence: 99%

Discovery of phosphonic acid natural products by mining the genomes of 10,000 actinomycetes

Gao

Doroghazi

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

189

185

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“…Before use, the lactones of MV and MVA were converted to their open acid forms. Fos (Okuhara et al, 1980) was made available by Robert J. Eilers (Monsanto, St. Louis, MO). The peptidomimetic protein geranylgeranylation inhibitor GGti-2133 (Vasudevan et al, 1999) was purchased from Calbiochem (Merck).…”

Section: Chemicalsmentioning

confidence: 99%

The Plastidial 2-C-Methyl-d-Erythritol 4-Phosphate Pathway Provides the Isoprenyl Moiety for Protein Geranylgeranylation in Tobacco BY-2 Cells

et al. 2009

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Protein farnesylation and geranylgeranylation are important posttranslational modifications in eukaryotic cells. We visualized in transformed Nicotiana tabacum Bright Yellow-2 (BY-2) cells the geranylgeranylation and plasma membrane localization of GFP-BD-CVIL, which consists of green fluorescent protein (GFP) fused to the C-terminal polybasic domain (BD) and CVIL isoprenylation motif from the Oryza sativa calmodulin, CaM61. Treatment with fosmidomycin (Fos) or oxoclomazone (OC), inhibitors of the plastidial 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway, caused mislocalization of the protein to the nucleus, whereas treatment with mevinolin, an inhibitor of the cytosolic mevalonate pathway, did not. The nuclear localization of GFP-BD-CVIL in the presence of MEP pathway inhibitors was completely reversed by all-transgeranylgeraniol (GGol). Furthermore, 1-deoxy-D-xylulose (DX) reversed the effects of OC, but not Fos, consistent with the hypothesis that OC blocks 1-deoxy-D-xylulose 5-phosphate synthesis, whereas Fos inhibits its conversion to 2-C-methyl-Derythritol 4-phosphate. By contrast, GGol and DX did not rescue the nuclear mislocalization of GFP-BD-CVIL in the presence of a protein geranylgeranyltransferase type 1 inhibitor. Thus, the MEP pathway has an essential role in geranylgeranyl diphosphate (GGPP) biosynthesis and protein geranylgeranylation in BY-2 cells. GFP-BD-CVIL is a versatile tool for identifying pharmaceuticals and herbicides that interfere either with GGPP biosynthesis or with protein geranylgeranylation.

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“…We have succeeded in the first cloning and overexpression of the gene (dxr, formerly yaeM) encoding the DXP reductoisomerase from E. coli and have shown that the recombinant enzyme catalyzed the formation of MEP from DXP in a single step in the presence of both NADPH and a divalent cation, such as Mn 2ϩ , Mg 2ϩ , or Co 2ϩ (10,11). Additionally, we have demonstrated that the enzyme activity is strongly and specifically inhibited by fosmidomycin (FR-31564) (12), an antibiotic possessing the formyl and phosphonate functions in the molecule (13)(14)(15)(16) (Fig. 1).…”

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confidence: 94%

“…Thus, it is evident that the analyses of these mutants provide important information on critical amino acid residues in catalysis and/or structural integrity. DNA sequencing analysis revealed the point mutations of the amino acids, Gly 14 to Asp 14 and from Glu 231 to Lys 231 in the E. coli dxr-deficient mutants. These amino acid residues, Gly and Glu, were found in all the DXP reductoisomerase sequences from nine organisms (Fig.…”

mentioning

confidence: 99%

Characterization of 1-Deoxy-d-xylulose 5-Phosphate Reductoisomerase, an Enzyme Involved in Isopentenyl Diphosphate Biosynthesis, and Identification of Its Catalytic Amino Acid Residues

Kuzuyama¹,

Takahashi²,

Takagi

et al. 2000

Journal of Biological Chemistry

106

104

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1-Deoxy-D-xylulose 5-phosphate (DXP) reductoisomerase, which simultaneously catalyzes the intramolecular rearrangement and reduction of DXP to form 2-C-methyl-D-erythritol 4-phosphate, constitutes a key enzyme of an alternative mevalonate-independent pathway for isopentenyl diphosphate biosynthesis. The dxr gene encoding this enzyme from Escherichia coli was overexpressed as a histidine-tagged protein and characterized in detail. DNA sequencing analysis of the dxr genes from 10 E. coli dxr-deficient mutants revealed base substitution mutations at four points: two nonsense mutations and two amino acid substitutions (Gly 14 to Asp 14 and Glu 231 to Lys 231 ). Diethyl pyrocarbonate treatment inactivated DXP reductoisomerase, and subsequent hydroxylamine treatment restored the activity of the diethyl pyrocarbonate-treated enzyme. To characterize these defects, we overexpressed the mutant enzymes G14D, E231K, H153Q, H209Q, and H257Q. All of these mutant enzymes except for G14D were obtained as soluble proteins. Although the purified enzyme E231K had wildtype K m values for DXP and NADPH, the mutant enzyme had less than a 0.24% wild-type k cat value. K m values of H153Q, H209Q, and H257Q for DXP increased to 3.5-, 7.6-, and 19-fold the wild-type value, respectively. These results indicate that Glu 231 of E. coli DXP reductoisomerase plays an important role(s) in the conversion of DXP to 2-C-methyl-D-erythritol 4-phosphate, and that His 153

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Studies on new phosphonic acid antibiotics. I. FR-900098, isolation and characterization.

Abstract: A strain of Streptomyces, isolated from a soil sample and identified as Streptomyces rubelloinurinus sp. nov., has been found to produce FR-900098, an interesting new antibiotic

Cited by 112 publications

References 15 publications

Discovery of phosphonic acid natural products by mining the genomes of 10,000 actinomycetes

Discovery of phosphonic acid natural products by mining the genomes of 10,000 actinomycetes

The Plastidial 2-C-Methyl-d-Erythritol 4-Phosphate Pathway Provides the Isoprenyl Moiety for Protein Geranylgeranylation in Tobacco BY-2 Cells

Characterization of 1-Deoxy-d-xylulose 5-Phosphate Reductoisomerase, an Enzyme Involved in Isopentenyl Diphosphate Biosynthesis, and Identification of Its Catalytic Amino Acid Residues

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