Methylphosphonic acid is synthesized by marine bacteria and is a prominent component of dissolved organic phosphorus. Consequently, methylphosphonic acid also serves as a source of inorganic phosphate (Pi) for marine bacteria that are starved of this nutrient. Conversion of methylphosphonic acid into Pi is currently only known to occur through the carbon−phosphorus lyase pathway, yielding methane as a byproduct. In this work, we describe an oxidative pathway for the catabolism of methylphosphonic acid in Gimesia maris DSM8797. G. maris can use methylphosphonic acid as Pi sources despite lacking a phn operon encoding a carbon−phosphorus lyase pathway. Instead, the genome contains a locus encoding homologues of the non-heme Fe(II) dependent oxygenases HF130PhnY* and HF130PhnZ, which were previously shown to convert 2-aminoethylphosphonic acid into glycine and Pi. GmPhnY* and GmPhnZ1 were produced in E. coli and purified for characterization in vitro. The substrate specificities of the enzymes were evaluated with a panel of synthetic phosphonates. Via 31 P NMR spectroscopy, it is demonstrated that the GmPhnY* converts methylphosphonic acid to hydroxymethylphosphonic acid, which in turn is oxidized by GmPhnZ1 to produce formic acid and Pi. In contrast, 2-aminoethylphosphonic acid is not a substrate for GmPhnY* and is therefore not a substrate for this pathway. These results thus reveal a new metabolic fate for methylphosphonic acid.

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Phosphonic acids are highly stable phosphorus-containing compounds, which have been proposed as important intermediates in the global phosphorus cycle. Biogenic phosphonates as well as their synthetic analogues play an important role as potential enzyme inhibitor drugs and as alternative phosphorus source for microbes. Despite these properties, their metabolism is still poorly understood. New degradative pathways and unknown compounds are identified at fast pace. However, most of these pathways include a variety of unique enzymatic transformations, which are difficult to characterize – especially without sufficient amounts of the potential substrates and intermediates of the postulated transformations in hands. Thus, there is a great need for the development of synthetic methodologies to access phosphonic acids in high yields and in enantiomerically pure form for the use in enzymatic studies and in studies on the biological activity of newly isolated natural products, which are often only obtained in low yields. In this Synpacts article we aim at highlighting our recent contributions to this field.1 Introduction2 Phosphonates as Alternative Phosphorus Source3 The Application of Phosphonates in Enzymatic Studies4 Conclusion

Aim: Dysregulated levels of the translocator protein TSPO 18 KDa have been reported in several disorders, particularly neurodegenerative diseases. This makes TSPO an interesting target for the development of diagnostic biomarkers. Even though several radioligands have already been developed for in vivo TSPO imaging, the ideal TSPO radiotracer has still not been found. Results: Here, we report the chemical synthesis of a set of new TSPO ligands designed for future application in positron emission tomography, together with the determination of their biological activity and applied 11C-labeling strategy. Conclusion: The lead compound of our series, (R)-[11C]Me@NEBIQUINIDE, showed very promising results and is therefore proposed to be further evaluated under in vivo settings.

Racemic 1-hydroxy-3-butenyl-, 3-chloro-1-hydroxypropyl-, and 3-bromo-1-hydroxypropylphosphonate and the corresponding ( S )-enantiomers obtained by lipase-catalyzed resolution of the respective racemic chloroacetates were subjected to functional group manipulations. These comprised ozonolysis, Mitsunobu reactions with hydrazoic acid and N -hydroxyphthalimide, alkylation of hydrazine derivative, removal of phthaloyl group followed by intramolecular substitution, and global deprotection to deliver the racemates and ( R )-enantiomers (ee 92–99% by chiral high-performance liquid chromatography) of pyrrolidin-2-yl-, oxazolidin-3-yl-, oxazolidin-5-yl-, pyrazolidin-3-yl-, and 1,2-oxazinan-3-ylphosphonic acids. These phosphonic acids were evaluated as analogues of proline and proline analogues for the ability to inhibit γ-glutamyl kinase, δ 1 -pyrroline-5-carboxylate synthetase, and δ 1 -pyrroline-5-carboxylate reductase. Only the latter enzyme was inhibited by two of them at concentrations exceeding 1 mM.