SIRT3: A Promising Drug Target and Biomarker for the Treatment of Neurodegenerative Disorders

Target Name: SIRT3

NCBI ID: G23410

SIRT3

SIRT3: A Promising Drug Target and Biomarker for the Treatment of Neurodegenerative Disorders

Introduction

SIRT3, a member of the SIRT family of NAD+-dependent dehydrogenases, has been found to be involved in regulating multiple biochemical processes in cells. The role and dysregulation of SIRT3 in neurodegenerative diseases have attracted extensive research interest. This article will elaborate on the potential role of SIRT3 in drug development and disease treatment, and explore the potential and challenges of SIRT3 as a biomarker in clinical application.

The role and structure of SIRT3

SIRT3 is a coding gene that belongs to the NAD+-dependent dehydrogenase family. Members of this family play important roles in many biological processes, such as cellular metabolism, oxidative stress, and apoptosis. SIRT3 maintains normal metabolic functions in vivo mainly by regulating intracellular NAD+ levels.

Structure and function of SIRT3

The gene encoding SIRT3 is located on human chromosome 1p36.1. The protein encoded by the SIRT3 gene consists of 394 amino acids and its molecular weight is 41 kDa. The active site of SIRT3 is located at its C-terminus, which includes a conserved acidic cysteine 鈥嬧?媟esidue that is strongly hydrophilic and susceptible to oxidative stress.

The biological function of SIRT3 is mainly reflected in its NAD+-dependent dehydrogenase activity. The active site of SIRT3 has high NAD+ affinity, can reduce NAD+ to NADH, and plays a key role in the oxidative stress process. The active site of SIRT3 contains multiple conserved amino acid residues, which are critical to the activity of SIRT3.

Application of SIRT3 in disease treatment

The role and dysregulation of SIRT3 in neurodegenerative diseases have attracted extensive research interest. Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and Huntington's disease, are closely related to dysregulation of SIRT3 activity.

1. The relationship between neurodegenerative diseases and dysregulation of SIRT3 activity

Many neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, are closely related to dysregulation of SIRT3 activity. Studies have found that the activity of SIRT3 is significantly reduced in these diseases, leading to an imbalance in intracellular NAD+ levels, thereby exacerbating the disease process. In addition, SIRT3 gene expression levels are also affected by these diseases, resulting in reduced amounts of SIRT3 in nerve cells.

2. Drug candidates for SIRT3

To treat neurodegenerative diseases, researchers have identified multiple SIRT3 modulators as drug candidates. These drugs usually regulate intracellular NAD+ levels by interfering with the activity of SIRT3, thereby improving the metabolic state of nerve cells.

(1) NAD+ supplements

NAD+ is a necessary prosthetic group for SIRT3 activity, so supplementing NAD+ may have a positive impact on SIRT3 activity. A variety of NAD+ supplements have been discovered, such as NAD+ analogs, nicotinamide, and fumaric acid. These substances can increase intracellular NAD+ levels, thereby increasing SIRT3 activity.

(2) Activator of SIRT3

The activity of SIRT3 is regulated by a variety of modifications, including phosphorylation, substrate level regulation, etc. Therefore, increasing SIRT3 activity by regulating SIRT3 substrate levels is a potential drug design idea. A variety of SIRT3 activators have been discovered, such as DAP-1, Pyroptidine and Kresol.

(3) Antagonists of SIRT3

The activity of SIRT3 is regulated by various factors, including SIRT

Protein Name: Sirtuin 3

Functions: NAD-dependent protein deacetylase (PubMed:12186850, PubMed:12374852, PubMed:16788062, PubMed:18680753, PubMed:18794531, PubMed:23283301, PubMed:24121500, PubMed:24252090, PubMed:19535340). Activates or deactivates mitochondrial target proteins by deacetylating key lysine residues (PubMed:12186850, PubMed:12374852, PubMed:16788062, PubMed:18680753, PubMed:18794531, PubMed:23283301, PubMed:24121500, PubMed:24252090). Known targets include ACSS1, IDH, GDH, SOD2, PDHA1, LCAD, SDHA and the ATP synthase subunit ATP5PO (PubMed:16788062, PubMed:18680753, PubMed:24121500, PubMed:24252090, PubMed:19535340). Contributes to the regulation of the cellular energy metabolism (PubMed:24252090). Important for regulating tissue-specific ATP levels (PubMed:18794531). In response to metabolic stress, deacetylates transcription factor FOXO3 and recruits FOXO3 and mitochondrial RNA polymerase POLRMT to mtDNA to promote mtDNA transcription (PubMed:23283301). Acts as a regulator of ceramide metabolism by mediating deacetylation of ceramide synthases CERS1, CERS2 and CERS6, thereby increasing their activity and promoting mitochondrial ceramide accumulation (By similarity)

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