Cyanohydrin Phosphonate Natural Product from <i>Streptomyces regensis</i>

Cioni, Joel P.; Doroghazi, James R.; Yu, Xiaomin; Evans, Bradley S.; Lee, Jaeheon; Metcalf, William W.

doi:10.1021/np400722m

Cited by 27 publications

(34 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Two other bioactive strains, Streptomyces sp. NRRL S-474 and NRRL S-481, belong to a group of seven strains with a pepM gene cluster similar, but not identical, to the one found in Streptomyces regensis NRRL WC-3744, the known producer of hydroxynitrilaphos (40) (Fig. 3A).…”

Section: Dereplication Of Phosphonate Biosynthetic Pathways and Produmentioning

confidence: 93%

See 1 more Smart Citation

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.

Self Cite

189

185

View full text Add to dashboard Cite

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

show abstract

Section: Dereplication Of Phosphonate Biosynthetic Pathways and Produmentioning

confidence: 93%

“…Including the eight additional molecules we recently reported elsewhere (24,38,40,45) (SI Appendix, Fig. S4), this program has yielded 19 new phosphonate natural products to date.…”

Section: Pepmentioning

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.

Self Cite

189

185

View full text Add to dashboard Cite

show abstract

“…NMR-guided fractionation was used in the isolation of three new compounds from S. regensis strain WC-3744 [9]. From this strain, N-acetyl-2AEP, N-acetyl-1-hydroxy-2AEP were purified along with cyanophos (cyano[hydroxyl]methyl phosphonic acid), a novel cyanohydrin compound.…”

Section: Recently Discovered Phosphonate Natural Productsmentioning

confidence: 99%

“…From this strain, N-acetyl-2AEP, N-acetyl-1-hydroxy-2AEP were purified along with cyanophos (cyano[hydroxyl]methyl phosphonic acid), a novel cyanohydrin compound. Analysis of the phosphonate gene clusters suggests that cyanophos may have origins from 2-AEP and is likely only an intermediate in the biosynthesis of a yet to be determined final product [9]. …”

Section: Recently Discovered Phosphonate Natural Productsmentioning

confidence: 99%

Genomics-enabled discovery of phosphonate natural products and their biosynthetic pathways

Doroghazi

Metcalf

2014

Journal of Industrial Microbiology and Biotechnology

Self Cite

View full text Add to dashboard Cite

Phosphonate natural products have proven to be a rich source of useful pharmaceutical, agricultural and biotechnology products, whereas study of their biosynthetic pathways has revealed numerous intriguing enzymes that catalyze unprecedented biochemistry. Here we review the history of phosphonate natural product discovery, highlighting technological advances that have played a key role in the recent advances in their discovery. Central to these developments has been the application of genomics, which allowed discovery and development of a global phosphonate metabolic framework to guide research efforts. This framework suggests that the future of phosphonate natural products remains bright, with many new compounds and pathways yet to be discovered.

show abstract

“…These studies demonstrated that enzymatic reactions could be studied in situ at low substrate concentrations without isotopic enrichment or purification. Other recent studies have employed 2D heteronuclear multiple bond correlation for the identification of C–P compounds and the elucidation of enzymatic activities …”

Section: Introductionmentioning

confidence: 99%

Investigation of enzymatic C–P bond formation using multiple quantum HCP nuclear magnetic resonance spectroscopy

Werner

Allen

et al. 2015

Magnetic Reson in Chemistry

View full text Add to dashboard Cite

The biochemical mechanism for the formation of the C–P–C bond sequence found in L-phosphinothricin, a natural product with antibiotic and herbicidal activity, remains unclear. To obtain further insight into the catalytic mechanism of PhpK, the P-methyltransferase responsible for the formation of the second C–P bond in L-phosphinothricin, we utilized a combination of stable isotopes and two-dimensional nuclear magnetic resonance spectroscopy. Exploiting the newly emerged Bruker QCI probe (Bruker Corp.), we specifically designed and ran a 13C-31P multiple quantum 1H-13C-31P (HCP) experiment in 1H-31P two-dimensional mode directly on a PhpK-catalyzed reaction mixture using 13CH3-labeled methylcobalamin as the methyl group donor. This method is particularly advantageous because minimal sample purification is needed to maximize product visualization. The observed 3:1:1:3 multiplet specifically and unequivocally illustrates direct bond formation between 13CH3 and 31P. Related nuclear magnetic resonance experiments based upon these principles may be designed for the study of enzymatic and/or synthetic chemical reaction mechanisms.

show abstract

Cyanohydrin Phosphonate Natural Product from Streptomyces regensis

Cited by 27 publications

References 52 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

Genomics-enabled discovery of phosphonate natural products and their biosynthetic pathways

Investigation of enzymatic C–P bond formation using multiple quantum HCP nuclear magnetic resonance spectroscopy

Contact Info

Product

Resources

About