Determination of the Absolute Configuration of (−)‐Hydroxynitrilaphos and Related Biosynthetic Questions

Pallitsch, Katharina; Happl, Barbara; Stieger, Christian E.

doi:10.1002/chem.201702904

Cited by 6 publications

(8 citation statements)

References 51 publications

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“…The presence of an unusual aminophosphonate-(R)-2-amino-1-hydroxyethylphosphonic acid (compound 9) and its acetyl derivative has been determined in lipid fractions of Bacteriovorax stolpii [40,41]. Its configuration was elegantly determined by a combination of chemical synthesis and biochemical studies [42].…”

Section: Ciliatine (Aep 2-aminoethylphosphonic Acid)mentioning

confidence: 99%

Phosphonates: Their Natural Occurrence and Physiological Role

Kafarski¹

2020

Contemporary Topics About Phosphorus in Biology and Materials

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The first natural compound containing carbon-to-phosphorus bond-ciliatine was discovered 60 years ago, and for four decades, phosphonates were considered simply as a biological curiosity. Finding the importance of these compounds in biogeochemical phosphorus cycling, their role in methane production, as well as discovery of numerous phosphonates and phosphonopeptides of promising antibacterial and antifungal activities has stimulated the development of studies on this class of compounds, especially on their metabolism and biochemistry. These studies are driven by the use of 31 P NMR and by a clever combination of genomics and innovative chemistry by using the method of selective labeling of metabolites. These studies revealed unusual and interesting chemistry of these compounds.

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Section: Ciliatine (Aep 2-aminoethylphosphonic Acid)mentioning

confidence: 99%

Phosphonates: Their Natural Occurrence and Physiological Role

Kafarski¹

2020

Contemporary Topics About Phosphorus in Biology and Materials

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“…Oxime-forming N-oxidases single proton associated with each of the products, which we assigned as (E)-1 and (Z)-1 at 6.82 and 7.37 ppm, respectively. This assignment is supported by a recent report of the total synthesis of the phosphonocystoximic acids, which involves the synthesis of ethyl-protected aldoximes as intermediates (27).…”

Section: Table 2 Oxidation Of Nicotinamide Cofactors By Hpxl and Pcxlmentioning

confidence: 66%

“…The aldoxime protons for the protected (E)-isomer have a chemical shift of 6.82 ppm, whereas the aldoxime proton associated with the protected (Z)-isomer has a chemical shift of 7.41 ppm (27). Our assignment of the third product as 2-nitroethylphosphonic acid (2) is based on the observation of phosphoruscorrelated protons at 2.03 and 4.48 ppm, which is consistent with literature values of synthetically produced 2-nitroethylphosphonic acid (28).…”

Section: Table 2 Oxidation Of Nicotinamide Cofactors By Hpxl and Pcxlmentioning

confidence: 99%

PcxL and HpxL are flavin-dependent, oxime-forming N-oxidases in phosphonocystoximic acid biosynthesis in Streptomyces

Goettge

Cioni

Pallitsch

et al. 2018

Journal of Biological Chemistry

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Several oxime-containing small molecules have useful properties, including antimicrobial, insecticidal, anticancer, and immunosuppressive activities. Phosphonocystoximate and its hydroxylated congener, hydroxyphosphonocystoximate, are recently discovered oxime-containing natural products produced by sp. NRRL S-481 and NRRL WC-3744, respectively. The biosynthetic pathways for these two compounds are proposed to diverge at an early step in which 2-aminoethylphosphonate (2AEPn) is converted to ()-1-hydroxy-2-aminoethylphosphonate (()-1H2AEPn) in but not in sp. NRRL S-481). Subsequent installation of the oxime moiety into either 2AEPn or ()-1H2AEPn is predicted to be catalyzed by PcxL or HpxL from sp. NRRL S-481 and NRRL WC-3744, respectively, whose sequence and predicted structural characteristics suggest they are unusual -oxidases. Here, we show that recombinant PcxL and HpxL catalyze the FAD- and NADPH-dependent oxidation of 2AEPn and 1H2AEPn, producing a mixture of the respective aldoximes and nitrosylated phosphonic acid products. Measurements of catalytic efficiency indicated that PcxL has almost an equal preference for 2AEPn and ()-1H2AEPn. 2AEPn was turned over at a 10-fold higher rate than ()-1H2AEPn under saturating conditions, resulting in a similar but slightly lower / We observed that ()-1H2AEPn is a relatively poor substrate for PcxL but is clearly the preferred substrate for HpxL, consistent with the proposed biosynthetic pathway in HpxL also used both 2AEPn and ()-1H2AEPn, with the latter inhibiting HpxL at high concentrations. Bioinformatic analysis indicated that PcxL and HpxL are members of a new class of oxime-forming -oxidases that are broadly dispersed among bacteria.

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“…Special interest should be put on a small, but steadily growing group of low-molecular phosphonates of secondary metabolic origin, which have a commercialization rate that is far above the average for natural products in general. 41,48 The favorable properties of these biogenic phosphonates led to the use of both synthetic and biogenic phosphonates in clinics and agriculture. However, phosphonates were for a long time believed to have limited environmental importance.…”

Section: Discussionmentioning

confidence: 99%

“…Thus biogenic (-)-hydroxynitrilaphos could be clearly shown to be (S)-configured. 41 These investigations answered some of the pending structural questions concerning hydroxynitrilaphos and phosphonocystoximate. However, most of the steps involved in their biosynthesis are still unknown.…”

Section: Synpacts Syn Lettmentioning

confidence: 98%

Synthetic Phosphonic Acids as Potent Tools to Study Phosphonate Enzymology

Pallitsch

Kalina²,

Stanković³

2019

Synlett

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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

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Determination of the Absolute Configuration of (−)‐Hydroxynitrilaphos and Related Biosynthetic Questions

Cited by 6 publications

References 51 publications

Phosphonates: Their Natural Occurrence and Physiological Role

Phosphonates: Their Natural Occurrence and Physiological Role

PcxL and HpxL are flavin-dependent, oxime-forming N-oxidases in phosphonocystoximic acid biosynthesis in Streptomyces

Synthetic Phosphonic Acids as Potent Tools to Study Phosphonate Enzymology

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