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Enzymatic Metabolic Switches of Astrocyte Response to Lipotoxicity as Potential Therapeutic Targets for Nervous System Diseases.
Angarita-Rodríguez, Andrea; Matiz-González, J Manuel; Pinzón, Andrés; Aristizabal, Andrés Felipe; Ramírez, David; Barreto, George E; González, Janneth.
Affiliation
  • Angarita-Rodríguez A; Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá 110231, Colombia.
  • Matiz-González JM; Laboratorio de Bioinformática y Biología de Sistemas, Universidad Nacional de Colombia, Bogotá 111321, Colombia.
  • Pinzón A; Molecular Genetics and Antimicrobial Resistance Unit, Universidad El Bosque, Bogotá 110121, Colombia.
  • Aristizabal AF; Laboratorio de Bioinformática y Biología de Sistemas, Universidad Nacional de Colombia, Bogotá 111321, Colombia.
  • Ramírez D; Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá 110231, Colombia.
  • Barreto GE; Departamento de Farmacología, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción 4030000, Chile.
  • González J; Department of Biological Sciences, University of Limerick, V94 T9PX Limerick, Ireland.
Pharmaceuticals (Basel) ; 17(5)2024 May 16.
Article in En | MEDLINE | ID: mdl-38794218
ABSTRACT
Astrocytes play a pivotal role in maintaining brain homeostasis. Recent research has highlighted the significance of palmitic acid (PA) in triggering pro-inflammatory pathways contributing to neurotoxicity. Furthermore, Genomic-scale metabolic models and control theory have revealed that metabolic switches (MSs) are metabolic pathway regulators by potentially exacerbating neurotoxicity, thereby offering promising therapeutic targets. Herein, we characterized these enzymatic MSs in silico as potential therapeutic targets, employing protein-protein and drug-protein interaction networks alongside structural characterization techniques. Our findings indicate that five MSs (P00558, P04406, Q08426, P09110, and O76062) were functionally linked to nervous system drug targets and may be indirectly regulated by specific neurological drugs, some of which exhibit polypharmacological potential (e.g., Trifluperidol, Trifluoperazine, Disulfiram, and Haloperidol). Furthermore, four MSs (P00558, P04406, Q08426, and P09110) feature ligand-binding or allosteric cavities with druggable potential. Our results advocate for a focused exploration of P00558 (phosphoglycerate kinase 1), P04406 (glyceraldehyde-3-phosphate dehydrogenase), Q08426 (peroxisomal bifunctional enzyme, enoyl-CoA hydratase, and 3-hydroxyacyl CoA dehydrogenase), P09110 (peroxisomal 3-ketoacyl-CoA thiolase), and O76062 (Delta(14)-sterol reductase) as promising targets for the development or repurposing of pharmacological compounds, which could have the potential to modulate lipotoxic-altered metabolic pathways, offering new avenues for the treatment of related human diseases such as neurological diseases.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Language: En Journal: Pharmaceuticals (Basel) Year: 2024 Document type: Article Affiliation country: Colombia Country of publication: Switzerland

Full text: 1 Collection: 01-internacional Database: MEDLINE Language: En Journal: Pharmaceuticals (Basel) Year: 2024 Document type: Article Affiliation country: Colombia Country of publication: Switzerland