Glyceraldehyde 3-phosphate dehydrogenase

Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is a key enzyme in glycolysis and is involved in gluconeogenesis, playing a pivotal role in energy metabolism by catalyzing the sixth step of glycolysis. This enzyme converts glyceraldehyde 3-phosphate into 1,3-bisphosphoglycerate, using NAD+ as a cofactor and producing NADH in the process. GAPDH is highly conserved across species and is present in nearly all organisms, from prokaryotes to eukaryotes, highlighting its essential role in cellular metabolism.

Function

GAPDH has traditionally been recognized for its role in energy production within the cell. However, recent studies have uncovered that GAPDH has multiple functions beyond glycolysis, including involvement in nuclear transcription, phosphorylation, and apoptosis. It also plays a role in the regulation of gene expression and has been implicated in various diseases, such as cancer and neurodegenerative diseases, due to its non-glycolytic functions.

Structure

The enzyme is typically a tetramer composed of four identical subunits. Each subunit binds to a glyceraldehyde 3-phosphate molecule and a NAD+ molecule, facilitating the redox reaction that converts the substrate into 1,3-bisphosphoglycerate. The active site of GAPDH, where the catalytic process occurs, is highly conserved, which is indicative of the enzyme's critical role in metabolism.

Clinical Significance

Due to its ubiquitous expression and vital role in cellular metabolism, GAPDH is often used as a loading control in Western blot and qPCR experiments to ensure equal sample loading and to normalize the expression of target genes. However, its involvement in various cellular processes beyond glycolysis has led to a reevaluation of its use as a housekeeping gene in certain contexts.

Alterations in GAPDH activity and expression have been associated with several diseases. In cancer, overexpression of GAPDH has been observed and is thought to contribute to the high glycolytic rate seen in many tumors, known as the Warburg effect. In neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, GAPDH has been implicated in disease progression through its roles in apoptosis and gene regulation.

Research

GAPDH continues to be a subject of intense research, not only for its central role in metabolism but also for its involvement in various cellular processes and diseases. Understanding the full range of GAPDH's functions and regulation may provide new insights into disease mechanisms and potential therapeutic targets.

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  PDB 1cer EBI

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  PDB 2czc EBI

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  D-glyceraldehyde-3-phosphate

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  D-glycerate 1,3-bisphosphate