Studies on the Biodegradation of Fosfomycin: Synthesis of <sup>13</sup>C‐Labeled Intermediates, Feeding Experiments with <i>Rhizobium huakuii</i> PMY1, and Isolation of Labeled Amino Acids from Cell Mass by HPLC

McGrath, John W.; Hammerschmidt, Friedrich; Kählig, Hanspeter; Wuggenig, Frank; Lamprecht, Günther; Quinn, John P.

doi:10.1002/chem.201100725

Cited by 4 publications

(7 citation statements)

References 29 publications

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“…The catabolic reaction sequence involved has been further elucidated (McGrath et al, 2009, 2011), and although the enzyme responsible for the C–P bond cleavage step has not yet been fully described its substrate is likely to be (R)-1-hydroxy-2-oxopropylphosphonic acid. Given that S. huakuii cells release essentially quantitative levels of Pi when using fosfomycin as a sole C source, expression of the C–P cleavage enzyme is clearly Pho-independent.…”

Section: Enzymes Of Phosphonate Catabolism In Microorganismsmentioning

confidence: 99%

The genes and enzymes of phosphonate metabolism by bacteria, and their distribution in the marine environment

2012

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Phosphonates are compounds that contain the chemically stable carbon–phosphorus (C–P) bond. They are widely distributed amongst more primitive life forms including many marine invertebrates and constitute a significant component of the dissolved organic phosphorus reservoir in the oceans. Virtually all biogenic C–P compounds are synthesized by a pathway in which the key step is the intramolecular rearrangement of phosphoenolpyruvate to phosphonopyruvate. However C–P bond cleavage by degradative microorganisms is catalyzed by a number of enzymes – C–P lyases, C–P hydrolases, and others of as-yet-uncharacterized mechanism. Expression of some of the pathways of phosphonate catabolism is controlled by ambient levels of inorganic P (Pi) but for others it is Pi-independent. In this report we review the enzymology of C–P bond metabolism in bacteria, and also present the results of an in silico investigation of the distribution of the genes that encode the pathways responsible, in both bacterial genomes and in marine metagenomic libraries, and their likely modes of regulation. Interrogation of currently available whole-genome bacterial sequences indicates that some 10% contain genes encoding putative pathways of phosphonate biosynthesis while ∼40% encode one or more pathways of phosphonate catabolism. Analysis of metagenomic data from the global ocean survey suggests that some 10 and 30%, respectively, of bacterial genomes across the sites sampled encode these pathways. Catabolic routes involving phosphonoacetate hydrolase, C–P lyase(s), and an uncharacterized 2-aminoethylphosphonate degradative sequence were predominant, and it is likely that both substrate-inducible and Pi-repressible mechanisms are involved in their regulation. The data we present indicate the likely importance of phosphonate-P in global biogeochemical P cycling, and by extension its role in marine productivity and in carbon and nitrogen dynamics in the oceans.

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Section: Enzymes Of Phosphonate Catabolism In Microorganismsmentioning

confidence: 99%

The genes and enzymes of phosphonate metabolism by bacteria, and their distribution in the marine environment

2012

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“…Based on the findings from the above described studies, 13,14 we suggest a hypothetical biodegradation route for fosfomycin in Rhizobium huakuii PMY1 (Scheme 1) following a hydrolytic mechanism. We assume that dihydroxypropylphosphonic acid (R,R)-4 is formed by opening of the epoxide ring by an NAD + dependent dehydrogenase to give (R)-1-hydroxy-2-oxopropylphosphonic acid [(R)-5].…”

Section: Proposed Biodegradation Pathway For Fosfomycinmentioning

confidence: 81%

“…1 Some biogenic phosphonates of agricultural and medicinal importance. † Electronic supplementary information (ESI) available: 1 H, 13 C and 31 P NMR spectra of the synthesised compounds, X-ray data. CCDC 1522706 for 25b.…”

Section: Introductionmentioning

confidence: 99%

“…12 To unravel the stepwise mineralisation of fosfomycin, they prepared putative intermediates of the catabolic pathway, among those also some isotopically labelled compounds. 13,14 The synthesised compounds were tested as phosphorus/carbon source for the bacterium. Furthermore, cell lysates were incubated with the compounds.…”

Section: Introductionmentioning

confidence: 99%

“…14 The experiments with the labelled compounds support the hypothesis that 4 is oxidised to the corresponding 2-oxo compound 5. 13 As it has a carbonyl group in the β-position to the phosphonic group, a hydrolytic mechanism for the cleavage of the C-P bond is indicated. 7 This hypothesis forms the basis of our synthetic experiments.…”

Section: Introductionmentioning

confidence: 99%

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Towards the biodegradation pathway of fosfomycin

Pallitsch

Schweifer²,

Roller

et al. 2017

Org. Biomol. Chem.

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Three functionalised propylphosphonic acids were synthesised to study C-P bond cleavage in R. huakuii PMY1. (R)-1-Hydroxy-2-oxopropylphosphonic acid [(R)-5] was prepared by chiral resolution of (±)-dimethyl 1-hydroxy-2-methylallyllphosphonate [(±)-12], followed by ozonolysis and deprotection. The N-(l-alanyl)-substituted (1R,2R)-2-amino-1-hydroxypropylphosphonic acid 10, a potential precursor for 2-oxopropylphosphonic acid (5) in cells, was obtained by coupling the aminophosphonic acid with benzotriazole-activated Z-l-alanine and hydrogenolytic deprotection. (1R*,2R*)-1,2-Dihydroxy-3,3,3-trifluoropropylphosphonic acid, a potential inhibitor of C-P bond cleavage after conversion into its 2-oxo derivative in the cell, was accessed from trifluoroacetaldehyde hydrate via hydroxypropanenitrile 21, which was silylated and reduced to the aldehyde (±)-23. Diastereoselective addition of diethyl trimethylsilyl phosphite furnished diastereomeric α-siloxyphosphonates. The less polar one was converted to the desired racemic phosphonic acid (±)-(1R*,2R*)-9 as its ammonium salt.

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Organophosphonates revealed: new insights into the microbial metabolism of ancient molecules

McGrath¹,

Chin²,

2013

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Organophosphonates are ancient molecules that contain the chemically stable C-P bond, which is considered a relic of the reducing atmosphere on primitive earth. Synthetic phosphonates now have a wide range of applications in the agricultural, chemical and pharmaceutical industries. However, the existence of C-P compounds as contemporary biogenic molecules was not discovered until 1959, with the identification of 2-aminoethylphosphonic acid in rumen protozoa. Here, we review advances in our understanding of the biochemistry and genetics of microbial phosphonate metabolism, and discuss the role of these compounds and of the organisms engaged in their turnover within the P cycle.

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Studies on the Biodegradation of Fosfomycin: Synthesis of ¹³C‐Labeled Intermediates, Feeding Experiments with Rhizobium huakuii PMY1, and Isolation of Labeled Amino Acids from Cell Mass by HPLC

Cited by 4 publications

References 29 publications

The genes and enzymes of phosphonate metabolism by bacteria, and their distribution in the marine environment

The genes and enzymes of phosphonate metabolism by bacteria, and their distribution in the marine environment

Towards the biodegradation pathway of fosfomycin

Organophosphonates revealed: new insights into the microbial metabolism of ancient molecules

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Studies on the Biodegradation of Fosfomycin: Synthesis of 13C‐Labeled Intermediates, Feeding Experiments with Rhizobium huakuii PMY1, and Isolation of Labeled Amino Acids from Cell Mass by HPLC

Cited by 4 publications

References 29 publications

The genes and enzymes of phosphonate metabolism by bacteria, and their distribution in the marine environment

The genes and enzymes of phosphonate metabolism by bacteria, and their distribution in the marine environment

Towards the biodegradation pathway of fosfomycin

Organophosphonates revealed: new insights into the microbial metabolism of ancient molecules

Contact Info

Product

Resources

About

Studies on the Biodegradation of Fosfomycin: Synthesis of ¹³C‐Labeled Intermediates, Feeding Experiments with Rhizobium huakuii PMY1, and Isolation of Labeled Amino Acids from Cell Mass by HPLC