Escherichia coli glutamate decarboxylase (EcGadB), a pyridoxal 5’-phosphate (PLP)-dependent enzyme, is highly specific for L-glutamate and was demonstrated to be effectively immobilised for the production of γ-aminobutyric acid (GABA), its decarboxylation product. Herein we show that EcGadB quantitatively decarboxylates the L-isomer of D,L-2-amino-4-(hydroxyphosphinyl)butyric acid (D,L-Glu-γ-PH), a phosphinic analogue of glutamate containing C-P-H bonds. This yields 3-aminopropylphosphinic acid (GABA-PH), a known GABAB receptor agonist and provides previously unknown D-Glu-γ-PH, allowing us to demonstrate that L-Glu-γ-PH, but not D-Glu-γ-PH, is responsible for D,L-Glu-γ-PH antibacterial activity. Furthermore, using GABase, a preparation of GABA-transaminase and succinic semialdehyde dehydrogenase, we show that GABA-PH is converted to 3-(hydroxyphosphinyl)propionic acid (Succinate-PH). Hence, PLP-dependent and NADP+-dependent enzymes are herein shown to recognise and metabolise phosphinic compounds, leaving unaffected the P-H bond. We therefore suggest that the phosphinic group is a bioisostere of the carboxyl group and the metabolic transformations of phosphinic compounds may offer a ground for prodrug design.

Enzymatic kinetic resolution of desmethylphosphinothricin indicates that phosphinic group is a bioisostere of carboxyl group / De Biase, Daniela; Cappadocio, Francesca; Pennacchietti, Eugenia; Giovannercole, Fabio; Coluccia, Antonio; Vepsäläinen, Jouko; Khomutov, Alex. - In: COMMUNICATIONS CHEMISTRY. - ISSN 2399-3669. - 3:1(2020). [10.1038/s42004-020-00368-z]

Enzymatic kinetic resolution of desmethylphosphinothricin indicates that phosphinic group is a bioisostere of carboxyl group

De Biase, Daniela
;
Giovannercole, Fabio;Coluccia, Antonio;
2020

Abstract

Escherichia coli glutamate decarboxylase (EcGadB), a pyridoxal 5’-phosphate (PLP)-dependent enzyme, is highly specific for L-glutamate and was demonstrated to be effectively immobilised for the production of γ-aminobutyric acid (GABA), its decarboxylation product. Herein we show that EcGadB quantitatively decarboxylates the L-isomer of D,L-2-amino-4-(hydroxyphosphinyl)butyric acid (D,L-Glu-γ-PH), a phosphinic analogue of glutamate containing C-P-H bonds. This yields 3-aminopropylphosphinic acid (GABA-PH), a known GABAB receptor agonist and provides previously unknown D-Glu-γ-PH, allowing us to demonstrate that L-Glu-γ-PH, but not D-Glu-γ-PH, is responsible for D,L-Glu-γ-PH antibacterial activity. Furthermore, using GABase, a preparation of GABA-transaminase and succinic semialdehyde dehydrogenase, we show that GABA-PH is converted to 3-(hydroxyphosphinyl)propionic acid (Succinate-PH). Hence, PLP-dependent and NADP+-dependent enzymes are herein shown to recognise and metabolise phosphinic compounds, leaving unaffected the P-H bond. We therefore suggest that the phosphinic group is a bioisostere of the carboxyl group and the metabolic transformations of phosphinic compounds may offer a ground for prodrug design.
2020
Escherichia coli; glutamate decarboxylase; bioisoster; phosphinic amino acids; enantiomers; antibiotic; 3-aminopropylphosphinic and 3-(hydroxyphosphinyl)propionic acids; 1H 13C 31P NMR.
01 Pubblicazione su rivista::01a Articolo in rivista
Enzymatic kinetic resolution of desmethylphosphinothricin indicates that phosphinic group is a bioisostere of carboxyl group / De Biase, Daniela; Cappadocio, Francesca; Pennacchietti, Eugenia; Giovannercole, Fabio; Coluccia, Antonio; Vepsäläinen, Jouko; Khomutov, Alex. - In: COMMUNICATIONS CHEMISTRY. - ISSN 2399-3669. - 3:1(2020). [10.1038/s42004-020-00368-z]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1436346
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