SIRT1 - Sirtuin 1 | Elisa - Clia - Antibody - Protein

Bachground:

Sirtuin 1, also referred to as NAD-dependent deacetylase sirtuin-1, is a protein encoded by the SIRT1 gene in humans. The name SIRT1 originates from its homologous counterpart, Sir2, found in yeast (Saccharomyces cerevisiae), indicating its evolutionary conservation. Positioned predominantly within the cell nucleus, SIRT1 acts as an enzyme that deacetylates transcription factors, thereby contributing to cellular regulation, particularly in response to stressors and in processes related to longevity. Belonging to the sirtuin family of proteins, which are homologs of the Sir2 gene in yeast, SIRT1 shares a sirtuin core domain and is categorized into class I of the sirtuin family. While the precise functions of human sirtuins remain under investigation, yeast sirtuin proteins are known to regulate epigenetic gene silencing and suppress recombination of rDNA. Sirtuin 1 expression is diminished in cells exhibiting high insulin resistance. Additionally, research has shown that SIRT1 can de-acetylate and modulate the activity of key members of the PGC1-alpha/ERR-alpha complex, crucial transcription factors involved in metabolic regulation.

Protein Structure:

• Composition: SIRT1 is a 747-amino acid protein.
• Domains:
• N-terminal Domain: Involved in substrate binding and interaction with other proteins.
• Catalytic Core: Contains the NAD+-binding site and deacetylase domain, essential for its enzymatic activity.
• C-terminal Domain: Important for the protein's stability and regulation.
• Post-translational Modifications: SIRT1 is subject to various post-translational modifications, including phosphorylation, sumoylation, and acetylation, which regulate its activity and stability.

Classification and Subtypes:

• Family: SIRT1 is part of the sirtuin family, which includes seven members (SIRT1-7) in mammals.
• Subtypes: There are no subtypes of SIRT1, but its functions overlap with other sirtuins, particularly SIRT2 and SIRT3, which also have roles in cellular metabolism and stress responses.

Function and Biological Significance:

• Deacetylation: SIRT1 removes acetyl groups from various protein substrates, including histones, transcription factors, and enzymes, thereby modulating their activity, stability, and interactions.
• Metabolic Regulation: SIRT1 plays a crucial role in regulating glucose and lipid metabolism. It activates key metabolic regulators such as PGC-1α, FOXO1, and PPAR-γ, influencing processes like gluconeogenesis, fatty acid oxidation, and mitochondrial biogenesis.
• Stress Response: SIRT1 enhances cellular stress resistance by deacetylating and activating stress response proteins like p53, FOXO3, and heat shock factor 1 (HSF1). This activity promotes cell survival under conditions of oxidative stress, DNA damage, and nutrient deprivation.
• Aging and Longevity: SIRT1 has been implicated in extending lifespan in model organisms. It mediates the beneficial effects of caloric restriction by enhancing metabolic efficiency, reducing oxidative stress, and improving DNA repair mechanisms.
• Inflammation: SIRT1 negatively regulates inflammation by deacetylating and inhibiting the activity of NF-κB, a key transcription factor involved in the inflammatory response.

Interactions:

• Transcription Factors: SIRT1 interacts with and deacetylates various transcription factors, including p53, FOXO1, PGC-1α, and NF-κB, modulating their activity and the expression of their target genes.
• Enzymes: It regulates the activity of enzymes involved in metabolism and stress responses, such as AMP-activated protein kinase (AMPK) and acetyl-CoA synthetase.
• Nuclear Receptors: SIRT1 modulates the activity of nuclear receptors like PPAR-γ and LXR, influencing lipid metabolism and inflammation.

Clinical Issues:

• Metabolic Disorders: Dysregulation of SIRT1 activity is associated with metabolic disorders, including obesity, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD). Enhancing SIRT1 activity has been proposed as a therapeutic strategy for these conditions.
• Cardiovascular Diseases: SIRT1 has protective roles in cardiovascular health by improving endothelial function, reducing inflammation, and preventing atherosclerosis. Reduced SIRT1 activity is linked to hypertension and cardiovascular disease.
• Neurodegenerative Diseases: SIRT1 is involved in neuroprotection and cognitive function. It has been studied in the context of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS), where it may help mitigate neurodegeneration and improve neuronal survival.
• Cancer: SIRT1's role in cancer is complex and context-dependent. It can act as a tumor suppressor by deacetylating p53 and inhibiting cell proliferation. However, in some cancers, SIRT1 may promote tumorigenesis by enhancing cell survival and metabolic adaptation.

Summary:

Sirtuin 1 (SIRT1) is a versatile NAD+-dependent deacetylase involved in regulating metabolism, stress responses, aging, and inflammation. It deacetylates various protein substrates, including transcription factors, enzymes, and nuclear receptors, thereby modulating their function. SIRT1 plays critical roles in metabolic regulation, promoting glucose and lipid homeostasis, enhancing cellular stress resistance, and influencing lifespan and aging processes. Clinically, SIRT1 is implicated in metabolic disorders, cardiovascular diseases, neurodegenerative diseases, and cancer. As a key regulator of numerous cellular pathways, SIRT1 is a promising therapeutic target for various diseases associated with metabolic dysregulation and aging.