Aspartyl Phosphonates and Phosphoramidates: The First Synthetic Inhibitors of Bacterial Aspartate-Semialdehyde Dehydrogenase

Cox, Russell J.; Gibson, Jennifer S.; Martin, Maria Belen Mayo

doi:10.1002/1439-7633(20020902)3:9<874::aid-cbic874>3.0.co;2-v

Cited by 45 publications

(37 citation statements)

References 30 publications

(49 reference statements)

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“…However, similar compounds have been chemically synthesized as potential inhibitors of D-alanine:D-alanine ligase 20, 23 and aspartate semi-aldehyde dehydrogenase. 24 Glutamine synthetase has also been demonstrated to catalyze the phosphorylation of L-methionine- S -sulfoximine on nitrogen. 25 The identity of L-glutamine phosphate was confirmed by 31 P NMR experiments, 15 N-labeling, and mass spectrometry.…”

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confidence: 99%

Discovery of a Glutamine Kinase Required for the Biosynthesis of the O-Methyl Phosphoramidate Modifications Found in the Capsular Polysaccharides of Campylobacter jejuni

et al. 2017

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Bacterial capsular polysaccharides (CPS) are complex carbohydrate structures that play a role in the overall fitness of the organism. Campylobacter jejuni, known for being a major cause of bacterial gastroenteritis worldwide, produces a CPS with a unique O-methyl phosphoramidate (MeOPN) modification on specific sugar residues. The formation of P-N bonds in nature is relatively rare and the pathway for the assembly of the phosphoramidate moiety in the CPS of C. jejuni is unknown. In this investigation we discovered that the initial transformation in the biosynthetic pathway for the MeOPN modification of the CPS involves the direct phosphorylation of the amide nitrogen of L-glutamine with ATP by the catalytic activity of Cj1418. The other two products are AMP and inorganic phosphate. The L-glutamine-phosphate product was characterized using 31P-NMR spectroscopy and mass spectrometry. We suggest that this newly discovered enzyme be named L-glutamine kinase.

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confidence: 99%

Discovery of a Glutamine Kinase Required for the Biosynthesis of the O-Methyl Phosphoramidate Modifications Found in the Capsular Polysaccharides of Campylobacter jejuni

et al. 2017

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“…For this reason, potent inhibitors of ASA‐DH could form a new class of antibacterial agents. We have previously reported the synthesis and properties of ASA‐DH inhibitors based on the structure of the substrate, aspartyl phosphate 1 4. We now report the design, synthesis and testing of compounds designed to act as covalent inactivators of ASA‐DH.…”

Section: Methodsmentioning

confidence: 99%

“…In previous work, we described the synthesis of analogues of 1 , in which the phosphate ester oxygen atom was replaced by CF 2 , CH 2 or NH (compounds 4 – 6 , respectively) 4. These compounds were designed to mimic the substrate 1 but be incapable of losing phosphate.…”

Section: Methodsmentioning

confidence: 99%

“…These compounds also allowed us to learn about substrate recognition in the active site of ASA‐DH. The phosphate p K

_{a_{2}}

should be around 7 or higher for optimal binding,4 so that the phosphate is mono‐ionised at physiological pH. For the difluorophosphonate 4 with a p K

_{a_{2}}

of about 4.5, initial binding was therefore poor, while the phosphonate 5 (p K

_{a_{2}}

≈6.1) and phosphoramidate 6 (p K

_{a_{2}}

≈6.3) bound progressively better.…”

Section: Methodsmentioning

confidence: 99%

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Design, Synthesis and Analysis of Inhibitors of Bacterial Aspartate Semialdehyde Dehydrogenase

2005

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Unsaturated and fluorinated analogues of aspartyl-beta-phosphate were synthesised as potential inhibitors of the bacterial enzyme aspartate semialdehyde dehydrogenase (ASA-DH). Acetylenic and Z-olefinic analogues showed competitive inhibition, but an E-olefinic analogue was inactive. A monofluoromethylene phosphonate competed poorly, but showed time-dependent inhibition of ASA-DH in the absence of phosphate. Simulated docking procedures were used to rationalise the results. These studies showed that substrate and inhibitor binding are mediated by interaction with two active-site arginine residues, and for likely covalent attachment to the active-site thiol group, electrophilic carbon atoms should be located 4.5 A, or less, from the thiol.

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“…8 The reported synthesis of βAFP involves more than 8 steps, leading to a low overall yield of the final product. 6,9 Our aim was to develop a more efficient synthesis of βAFP by finding an coupling reaction between the carbonyl group of the L-aspartate acid chloride and the difluoromethylene moiety of the phosphonate, thus affording the protected target in one step from the protected amino acid precursor. Lithio(difluoromethyl)-phosphonates have been used to react with methyl esters for the direct preparation of ketones.…”

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confidence: 99%

A Facile Synthesis of a DifluoromethyleneAnalog of β-Aspartyl Phosphate as an Inhibitor ofl-Aspartate-β-semialdehyde Dehydrogenase

Han¹,

Moore²,

Viola³

2003

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Aspartyl Phosphonates and Phosphoramidates: The First Synthetic Inhibitors of Bacterial Aspartate-Semialdehyde Dehydrogenase

Cited by 45 publications

References 30 publications

Discovery of a Glutamine Kinase Required for the Biosynthesis of the O-Methyl Phosphoramidate Modifications Found in the Capsular Polysaccharides of Campylobacter jejuni

Discovery of a Glutamine Kinase Required for the Biosynthesis of the O-Methyl Phosphoramidate Modifications Found in the Capsular Polysaccharides of Campylobacter jejuni

Design, Synthesis and Analysis of Inhibitors of Bacterial Aspartate Semialdehyde Dehydrogenase

A Facile Synthesis of a DifluoromethyleneAnalog of β-Aspartyl Phosphate as an Inhibitor ofl-Aspartate-β-semialdehyde Dehydrogenase

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