Integrated multi-omics unveil the impact of H-phosphinic analogs of glutamate and α-ketoglutarate on Escherichia coli metabolism
Year: 2024
Type: article
Abstract: Desmethylphosphinothricin ( L -Glu-γ-P H ) is the H -phosphinic analog of glutamate with carbon-phosphorus-hydrogen (C-P-H) bonds. In L -Glu-γ-P H the phosphinic group acts as a bioisostere of the glutamate γ-carboxyl group allowing the molecule to be a substrate of Escherichia coli glutamate decarboxylase, a pyridoxal 5′-phosphate-dependent α-decarboxylase. In addition, the L -Glu-γ-P H decarboxylation product, GABA-P H , is further metabolized by bacterial GABA-transaminase, another pyridoxal 5′-phosphate-dependent enzyme, and succinic semialdehyde dehydrogenase, a NADP + -dependent enzyme. The product of these consecutive reactions, the so-called GABA shunt, is succinate-P H , the H -phosphinic analog of succinate, a tricarboxylic acid cycle intermediate. Notably, L -Glu-γ-P H displays antibacterial activity in the same concentration range of well-established antibiotics in E. coli . The dipeptide L-Leu-Glu-γ-P H was shown to display an even higher efficacy, likely as a consequence of an improved penetration into the bacteria. Herein, to further understand the intracellular effects of L-Glu-γ-P H , 1 H NMR-based metabolomics, and LC-MS-based shotgun proteomics were used. This study included also the keto-derivative of L-Glu-γ-P H, α-ketoglutarate-γ-P H (α-KG-γ-P H ), which also exhibits antimicrobial activity. L -Glu-γ-P H and α-KG-γ-P H are found to similarly impact bacterial metabolism, although the overall effect of α-KG-γ-P H is more pervasive. Notably, α-KG-γ-P H is converted intracellularly into L -Glu-γ-P H , but the opposite was not found. In general, both molecules impact the pathways where aspartate, glutamate, and glutamine are used as precursors for the biosynthesis of related metabolites, activate the acid stress response, and deprive cells of nitrogen. This work highlights the multi-target drug potential of L -Glu-γ-P H and α-KG-γ-P H and paves the way for their exploitation as antimicrobials.
Source: Journal of Biological Chemistry
Institutions: University of Namur, Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Sapienza University of Rome, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, Université Paris-Saclay, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement, Laboratoire Innovations Technologiques pour la Détection et le Diagnostic, CEA Paris-Saclay, Médicaments et Technologies pour la Santé, Russian Academy of Sciences, Engelhardt Institute of Molecular Biology
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: gold
Estimated APC paid: $2,800
Funders: Federation of European Microbiological Societies, European Cooperation in Science and Technology, Sapienza Università di Roma, Russian Science Foundation, National Institutes of Health, Fundação para a Ciência e a Tecnologia, Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, National Institute of Diabetes and Digestive and Kidney Diseases, Pacific Northwest National Laboratory
Awards: G1402700502, G1483381719, Carboxydotrophs for alkane production: from CO/CO2 to fuel, G1916712426, G229807030, G3111867497, G3309579038, G3340144160, G4046065984, G4152799573, G4169012886, G4504718640, G4941345466, Biomedical Data Commons Workbench (BDCW), G5268643033, Ciências da Vida para um Futuro Saudável e Sustentável, G5910569720, Microbiologia Molecular, Estrutural e Celular - – Instituto de Tecnologia Química e Biológica António Xavier, G6551364792, G6694557351, G6997658380, G7315488542, Microbiologia Molecular, Estrutural e Celular - – Instituto de Tecnologia Química e Biológica António Xavier, G7991599336, G886374, G9000048486
OpenAlex ID: W4402669200