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Ceramida e ceramidase ácida: importância fisiopatológica e terapêutica
| Name: | Description: | Size: | Format: | |
|---|---|---|---|---|
| PPG_27803 | 1.1 MB | Adobe PDF |
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Abstract(s)
A ceramida é um esfingolípido tipicamente encontrado nas membranas das células eucarióticas. Para além da sua função estrutural, esta molécula lipídica tem também sido associada a funções reguladoras, nomeadamente no âmbito da apoptose onde atua como molécula pró-apoptótica. O metabolismo da ceramida é representado por uma complexa rede de reações inter-relacionadas que compreende três vias metabólicas: biossintética, catabólica e reciclagem. O catabolismo da ceramida em esfingosina e ácido gordo é assegurado por uma família de enzimas conhecidas por ceramidases. Estas enzimas atuam em diferentes compartimentos celulares sob condições fisiológicas distintas. A ceramidase ácida (aCDase) está localizada no lisossoma e é responsável pela produção da esfingosina lisossomal. Após a sua exportação para o citoplasma, a esfingosina pode ser fosforilada ou utilizada na via de reciclagem para a produção de ceramida. O balanço entre a ceramida e a esfingosina-1-fosfato pode ser utilizado como sensor de morte ou sobrevivência celular. Em virtude disso, as patologias caracterizadas por défice ou excesso de atividade enzimática de aCDase podem apresentar desequilíbrios da razão ceramida/esfingosina 1-fosfato. Por isso, essas doenças poderão ser revertidas, total ou parcialmente, através da reposição de uma quantidade adequada de aCDase funcionalmente ativa ou da inibição da expressão / atividade enzimática da aCDase, respetivamente. A potencialidade de modulação terapêutica da etapa do metabolismo catalisada pela aCDase tem sido explorada em várias áreas da Medicina, recorrendo quer a fármacos orfãos ou co-adjuvantes terapêuticos, e com resultados muito promissores.
The ceramide is a sphingolipid typically found in membranes of eukaryotic cells. Besides its structural function, this lipid molecule has also been associated to regulatory functions, namely as a pro-apoptotic molecule in the apoptosis process. The ceramide metabolism is represented by a complex inter-connected network of reactions comprising three metabolic pathways: biosynthetic, catabolic and recycling. The ceramide catabolism in sphingosine and fatty acid is catalysed by a family of enzymes known as ceramidases. These enzymes act in different cell compartments under distinct physiologic conditions. The acid ceramidase (aCDase) is located in the lysosome being responsible for the production of the lysosomal sphingosine. After its exportation to the cytoplasm, the sphingosine can be phosphorylated or used in the recycling pathway to the production of ceramide. The balance between ceramide and sphingosine-1-phosphate can be used as sensor of cell death or survival. Because of that, pathologies characterised by deficit or excess of aCDase enzymatic activity may present unbalances levels of the ratio ceramide/sphingosine 1-phosphate. Such diseases could be reverted, total or partially, in the presence of an adequate amount of functionally active aCDase or through the inhibition of aCDase expression / enzymatic activity, respectively. The potentiality of therapeutic modulation of the metabolic step catalysed by aCDase has been explored in distinct areas of Medicine, using either orphan drugs or co-adjuvant therapeutic agents, with promising results.
The ceramide is a sphingolipid typically found in membranes of eukaryotic cells. Besides its structural function, this lipid molecule has also been associated to regulatory functions, namely as a pro-apoptotic molecule in the apoptosis process. The ceramide metabolism is represented by a complex inter-connected network of reactions comprising three metabolic pathways: biosynthetic, catabolic and recycling. The ceramide catabolism in sphingosine and fatty acid is catalysed by a family of enzymes known as ceramidases. These enzymes act in different cell compartments under distinct physiologic conditions. The acid ceramidase (aCDase) is located in the lysosome being responsible for the production of the lysosomal sphingosine. After its exportation to the cytoplasm, the sphingosine can be phosphorylated or used in the recycling pathway to the production of ceramide. The balance between ceramide and sphingosine-1-phosphate can be used as sensor of cell death or survival. Because of that, pathologies characterised by deficit or excess of aCDase enzymatic activity may present unbalances levels of the ratio ceramide/sphingosine 1-phosphate. Such diseases could be reverted, total or partially, in the presence of an adequate amount of functionally active aCDase or through the inhibition of aCDase expression / enzymatic activity, respectively. The potentiality of therapeutic modulation of the metabolic step catalysed by aCDase has been explored in distinct areas of Medicine, using either orphan drugs or co-adjuvant therapeutic agents, with promising results.
Description
Keywords
Cancro Ceramida Ceramidase ácida Esfingolipidoses Metabolismo Acid ceramidase Cancer Ceramide Sphingolipidoses Metabolism