Biosynthesis of 2-Hydroxyethylphosphonate, an Unexpected Intermediate Common to Multiple Phosphonate Biosynthetic Pathways

Shao, Zengyi; Blodgett, Joshua A. V.; Circello, Benjamin T.; Eliot, Andrew C.; Woodyer, Ryan D.; Li, Gongyong; Donk, Wilfred A. van der; Metcalf, William W.; Zhao, Huimin

doi:10.1074/jbc.m801788200

Cited by 45 publications

(54 citation statements)

References 25 publications

(30 reference statements)

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“…2A, group 3). Interestingly, the nearly identical cluster found in Bacteroides eggerthii DSM 20697 has replaced the gene needed to make AEP from phosphonoacetaldehyde with a gene that produces hydroxyethylphosphonate (HEP) from the same substrate (46). Thus, we conclude that some Bacteroides strains produce a similar capsular polysaccharide decorated with HEP instead of AEP.…”

Section: Ability To Synthesize Phosphonates Is Relatively Common Andmentioning

confidence: 95%

Diversity and abundance of phosphonate biosynthetic genes in nature

Doroghazi

Janga

et al. 2013

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

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Phosphonates, molecules containing direct carbon-phosphorus bonds, compose a structurally diverse class of natural products with interesting and useful biological properties. Although their synthesis in protozoa was discovered more than 50 y ago, the extent and diversity of phosphonate production in nature remains poorly characterized. The rearrangement of phosphoenolpyruvate (PEP) to phosphonopyruvate, catalyzed by the enzyme PEP mutase (PepM), is shared by the vast majority of known phosphonate biosynthetic pathways. Thus, the pepM gene can be used as a molecular marker to examine the occurrence and abundance of phosphonate-producing organisms. Based on the presence of this gene, phosphonate biosynthesis is common in microbes, with ∼5% of sequenced bacterial genomes and 7% of genome equivalents in metagenomic datasets carrying pepM homologs. Similarly, we detected the pepM gene in ∼5% of random actinomycete isolates. The pepM-containing gene neighborhoods from 25 of these isolates were cloned, sequenced, and compared with those found in sequenced genomes. PEP mutase sequence conservation is strongly correlated with conservation of other nearby genes, suggesting that the diversity of phosphonate biosynthetic pathways can be predicted by examining PEP mutase diversity. We used this approach to estimate the range of phosphonate biosynthetic pathways in nature, revealing dozens of discrete groups in pepM amplicons from local soils, whereas hundreds were observed in metagenomic datasets. Collectively, our analyses show that phosphonate biosynthesis is both diverse and relatively common in nature, suggesting that the role of phosphonate molecules in the biosphere may be more important than is often recognized.

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Section: Ability To Synthesize Phosphonates Is Relatively Common Andmentioning

confidence: 95%

Diversity and abundance of phosphonate biosynthetic genes in nature

Doroghazi

Janga

et al. 2013

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

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148

204

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“…Frankia alni ACN contains two additional biosynthetic gene clusters (FA31 and FA29) related to cetoniacytone A, an aminocyclitol antitumor agent from the endosymbiont Actinomyces sp. strain Lu 9419 (58), and the antibiotic and herbicidal phosphinothricin tripeptide from Streptomyces viridochromogenes (49). In cluster FA29, a conserved set of six genes encodes the biosynthesis of the phosphinothricin intermediate phosphonoformate.…”

Section: Resultsmentioning

confidence: 99%

Significant Natural Product Biosynthetic Potential of Actinorhizal Symbionts of the Genus Frankia, as Revealed by Comparative Genomic and Proteomic Analyses

Udwary

Gontang

Jones

et al. 2011

Appl Environ Microbiol

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Bacteria of the genus Frankia are mycelium-forming actinomycetes that are found as nitrogen-fixing facultative symbionts of actinorhizal plants. Although soil-dwelling actinomycetes are well-known producers of bioactive compounds, the genus Frankia has largely gone uninvestigated for this potential. Bioinformatic analysis of the genome sequences of Frankia strains ACN14a, CcI3, and EAN1pec revealed an unexpected number of secondary metabolic biosynthesis gene clusters. Our analysis led to the identification of at least 65 biosynthetic gene clusters, the vast majority of which appear to be unique and for which products have not been observed or characterized. More than 25 secondary metabolite structures or structure fragments were predicted, and these are expected to include cyclic peptides, siderophores, pigments, signaling molecules, and specialized lipids. Outside the hopanoid gene locus, no cluster could be convincingly demonstrated to be responsible for the few secondary metabolites previously isolated from other Frankia strains. Few clusters were shared among the three species, demonstrating species-specific biosynthetic diversity. Proteomic analysis of Frankia sp. strains CcI3 and EAN1pec showed that significant and diverse secondary metabolic activity was expressed in laboratory cultures. In addition, several prominent signals in the mass range of peptide natural products were observed in Frankia sp. CcI3 by intact-cell matrix-assisted laser desorption-ionization mass spectrometry (MALDI-MS). This work supports the value of bioinformatic investigation in natural products biosynthesis using genomic information and presents a clear roadmap for natural products discovery in the Frankia genus.

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“…Other members mimic carboxyl groups or the tetrahedral intermediates formed during enzymatic metabolism of these moieties. Recent studies have started to reveal nature's biosynthetic strategies toward several of these compounds, including the clinically used antibiotic fosfomycin (2)(3)(4), the antimalaria clinical candidate FR900098 (5,6), the antifungal tripeptide rhizocticin (7), and the widely used herbicide phosphinothricin (8)(9)(10)(11)(12) (Fig. 1A).…”

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confidence: 99%

Characterization and structure of DhpI, a phosphonate O -methyltransferase involved in dehydrophos biosynthesis

Lee

Bae

Kuemin

et al. 2010

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

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Phosphonate natural products possess a range of biological activities as a consequence of their ability to mimic phosphate esters or tetrahedral intermediates formed in enzymatic reactions involved in carboxyl group metabolism. The dianionic form of these compounds at pH 7 poses a drawback with respect to their ability to mimic carboxylates and tetrahedral intermediates. Microorganisms producing phosphonates have evolved two solutions to overcome this hurdle: biosynthesis of monoanionic phosphinates containing two P-C bonds or esterification of the phosphonate group. The latter solution was first discovered for the antibiotic dehydrophos that contains a methyl ester of a phosphonodehydroalanine group. We report here the expression, purification, substrate scope, and structure of the O-methyltransferase from the dehydrophos biosynthetic gene cluster. The enzyme utilizes S-adenosylmethionine to methylate a variety of phosphonates including 1-hydroxyethylphosphonate, 1,2-dihydroxyethylphosphonate, and acetyl-1-aminoethylphosphonate. Kinetic analysis showed that the best substrates are tripeptides containing as C-terminal residue a phosphonate analog of alanine suggesting the enzyme acts late in the biosynthesis of dehydrophos. These conclusions are corroborated by the X-ray structure that reveals an active site that can accommodate a tripeptide substrate. Furthermore, the structural studies demonstrate a conformational change brought about by substrate or product binding. Interestingly, the enzyme has low substrate specificity and was used to methylate the clinical antibiotic fosfomycin and the antimalaria clinical candidate fosmidomycin, showing its promise for applications in bioengineering.antibiotics | bioengineering | conformational change | X-ray crystallography | domain-swap

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Biosynthesis of 2-Hydroxyethylphosphonate, an Unexpected Intermediate Common to Multiple Phosphonate Biosynthetic Pathways

Cited by 45 publications

References 25 publications

Diversity and abundance of phosphonate biosynthetic genes in nature

Diversity and abundance of phosphonate biosynthetic genes in nature

Significant Natural Product Biosynthetic Potential of Actinorhizal Symbionts of the Genus Frankia, as Revealed by Comparative Genomic and Proteomic Analyses

Characterization and structure of DhpI, a phosphonate O -methyltransferase involved in dehydrophos biosynthesis

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