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Sirtuínas: funções e alvos terapêuticos
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As sirtuínas são uma família de sete enzimas (SIRT1-SIRT7) de propriedades e características únicas que desempenham um papel crucial na homeostase metabólica celular. A SIRT1 e SIRT3 regulam a ativação/inibição de várias proteínas alvo, através da remoção de grupos “acetilo”, processo denominado desacetilação, e utilizam o NAD+ como cofactor sendo, por isso, sensíveis à sua concentração e disponibilidade. As concentrações do sistema redox NAD/NADH são reflexo do estado metabólico das células e, assim, estas enzimas, fundamentalmente a SIRT1, são encaradas como sensores metabólicos. Sendo o envelhecimento, uma condição que interfere com o estado metabólico das células, também o seu efeito sobre as sirtuínas será determinante.
O presente trabalho pretende rever as principais características e localização das diferentes sirtuínas, bem como as funções que as distinguem no metabolismo celular, focando-se nas sirtuínas 1, 3 e 4. Esta revisão sublinha as principais evidências científicas que sustentam o conhecimento atual, e pretende-se perceber como poderemos modular a atividade enzimática das sirtuínas, na pesquisa de novas estratégias farmacológicas em patologias relevantes. Neste contexto, serão revistos os principais inibidores ou ativadores da atividade enzimática das sirtuínas e de que forma podem existir efeitos específicos e diferentes entre cada proteína. Uma estratégia para induzir a atividade enzimática de certas sirtuínas inclui modificações na dieta, quer pela restrição calórica, quer pelo jejum. A ação destas enzimas pode ser crucial no contexto das doenças metabólicas ou outras patologias relacionadas com o envelhecimento celular. Desta forma, o seu papel na Diabetes Mellitus tipo II, Doenças Cardiovasculares e Neurodegenerativas, bem como em vários órgãos e processos chave, será abordado e aprofundado. A modulação da atividade das sirtuínas representa um tópico emergente de investigação científica com reconhecidas potencialidades terapêuticas.
Sirtuins are a family of seven enzymes (SIRT1-SIRT7) with unique properties and characteristics that play a crucial role in cellular metabolic homeostasis. Both SIRT1 and SIRT3 regulate the activation/inhibition of several target proteins, by removing acetyl groups, a process called deacetylation, and use NAD+ as a cofactor and are therefore sensitive to its concentration and availability. The concentrations of the redox system NAD/NADH reflect the metabolic state of the cells and, in this way, these enzymes, mainly SIRT1, can be considered as metabolic sensors. Since aging is a condition that interferes with the metabolic state of cells, its effect on sirtuins will also be decisive. The present review will approach the main characteristics and localization of the different sirtuins, as well as the functions that distinguish them in cellular metabolism, focusing on sirtuins 1, 3 and 4. This work aims to underline the main scientific evidences that support the current knowledge, and to understand how we can modulate the enzymatic activity of sirtuins, in the search for new pharmacological strategies in relevant pathologies. In this context, the main inhibitors or activators of the enzymatic activity of sirtuins will be reviewed and how specific and different effects may exist for each protein. A strategy to induce a potential increased activity of specific sirtuins involves the diet modification, either by calorie restriction, or by fasting. The action of these enzymes can be crucial in the context of metabolic diseases or other pathologies related to cell aging. Thus, their role in type II Diabetes Mellitus, Cardiovascular and Neurodegenerative Diseases, as well as in several organs and key processes, will be further addressed and developed. The modulation of the activity of sirtuins represents an emerging topic of scientific research with recognized therapeutic potential.
Sirtuins are a family of seven enzymes (SIRT1-SIRT7) with unique properties and characteristics that play a crucial role in cellular metabolic homeostasis. Both SIRT1 and SIRT3 regulate the activation/inhibition of several target proteins, by removing acetyl groups, a process called deacetylation, and use NAD+ as a cofactor and are therefore sensitive to its concentration and availability. The concentrations of the redox system NAD/NADH reflect the metabolic state of the cells and, in this way, these enzymes, mainly SIRT1, can be considered as metabolic sensors. Since aging is a condition that interferes with the metabolic state of cells, its effect on sirtuins will also be decisive. The present review will approach the main characteristics and localization of the different sirtuins, as well as the functions that distinguish them in cellular metabolism, focusing on sirtuins 1, 3 and 4. This work aims to underline the main scientific evidences that support the current knowledge, and to understand how we can modulate the enzymatic activity of sirtuins, in the search for new pharmacological strategies in relevant pathologies. In this context, the main inhibitors or activators of the enzymatic activity of sirtuins will be reviewed and how specific and different effects may exist for each protein. A strategy to induce a potential increased activity of specific sirtuins involves the diet modification, either by calorie restriction, or by fasting. The action of these enzymes can be crucial in the context of metabolic diseases or other pathologies related to cell aging. Thus, their role in type II Diabetes Mellitus, Cardiovascular and Neurodegenerative Diseases, as well as in several organs and key processes, will be further addressed and developed. The modulation of the activity of sirtuins represents an emerging topic of scientific research with recognized therapeutic potential.
Descrição
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2020, Universidade de Lisboa, Faculdade de Farmácia.
Palavras-chave
SIRT1 SIRT3 Restrição calórica Stress oxidativo Mestrado integrado - 2020