GAPDH - Glyceraldehyde-3-phosphate dehydrogenase | Elisa - Clia - Antibody - Protein

Background

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a crucial enzyme in glycolysis, the metabolic pathway that breaks down glucose to produce energy. GAPDH catalyzes the sixth step of glycolysis, where it converts glyceraldehyde-3-phosphate to 1,3-bisphosphoglycerate, using NAD+ as a cofactor and producing NADH in the process. Beyond its well-established role in metabolism, GAPDH has been found to participate in various non-glycolytic processes, including transcriptional regulation, DNA repair, membrane fusion, and apoptosis. This multifunctionality makes GAPDH a protein of significant interest in both basic and clinical research.

Protein Structure

GAPDH is a tetrameric enzyme, with each subunit comprising several key structural domains:

• NAD+-Binding Domain: Located at the N-terminus, this domain binds NAD+, a cofactor essential for the enzyme's dehydrogenase activity.
• Catalytic Domain: The active site of GAPDH, where the substrate glyceraldehyde-3-phosphate is converted to 1,3-bisphosphoglycerate.
• C-terminal Domain: Involved in the dimerization and tetramerization of the enzyme, ensuring its proper structural and functional conformation.

Each subunit of GAPDH is approximately 37 kDa, and the functional enzyme is a tetramer with a total molecular weight of around 150 kDa.

Classification and Subtypes

GAPDH belongs to the dehydrogenase family of enzymes and is highly conserved across different species. While the primary form of GAPDH is ubiquitous and involved in glycolysis, there are tissue-specific isoforms and splice variants that may have specialized functions.

Function and Biological Significance

GAPDH is a multifunctional enzyme with roles extending beyond glycolysis:

• Glycolysis: The primary function of GAPDH is in glycolysis, where it catalyzes the reversible oxidative phosphorylation of glyceraldehyde-3-phosphate to 1,3-bisphosphoglycerate, a key step in energy production.
• Nuclear Functions: GAPDH is involved in DNA repair and regulation of transcription. It can bind to single-stranded DNA and participate in the maintenance of genomic integrity.
• Apoptosis: GAPDH can translocate to the nucleus during oxidative stress and apoptosis, where it participates in the regulation of apoptotic pathways.
• Membrane Fusion: GAPDH has been implicated in the process of vesicle transport and membrane fusion, particularly in neurons.
• Protein-Nucleic Acid Interactions: GAPDH can interact with RNA and influence mRNA stability and translation.

Clinical Issues

GAPDH is associated with several diseases and clinical conditions:

• Cancer: Altered GAPDH expression and activity have been observed in various cancers. Its role in glycolysis, which is often upregulated in tumor cells (the Warburg effect), makes it a potential target for cancer therapy.
• Neurodegenerative Diseases: GAPDH is implicated in neurodegenerative diseases such as Alzheimer's and Parkinson's. Its role in apoptosis and oxidative stress responses links it to neuronal cell death and disease progression.
• Diabetes: GAPDH activity can be affected by hyperglycemia and oxidative stress, contributing to the complications associated with diabetes.
• Cardiovascular Diseases: Oxidative modifications of GAPDH can impair its function, contributing to vascular dysfunction and atherosclerosis.

Summary

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a key enzyme in glycolysis that also participates in various non-metabolic processes such as transcription regulation, DNA repair, apoptosis, and membrane fusion. Structurally, GAPDH is a tetramer composed of NAD+-binding, catalytic, and C-terminal domains. Beyond its role in energy metabolism, GAPDH's involvement in cellular processes makes it a protein of significant interest in diverse biological contexts. Dysregulation of GAPDH is associated with several diseases, including cancer, neurodegenerative disorders, diabetes, and cardiovascular diseases. Understanding the multifaceted roles of GAPDH is essential for developing therapeutic strategies targeting these conditions.