GAPDH

Official Full Name

glyceraldehyde-3-phosphate dehydrogenase

Organism

Homo sapiens

GeneID

2597

Background

This gene encodes a member of the glyceraldehyde-3-phosphate dehydrogenase protein family. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. The product of this gene catalyzes an important energy-yielding step in carbohydrate metabolism, the reversible oxidative phosphorylation of glyceraldehyde-3-phosphate in the presence of inorganic phosphate and nicotinamide adenine dinucleotide (NAD). The encoded protein has additionally been identified to have uracil DNA glycosylase activity in the nucleus. Also, this protein contains a peptide that has antimicrobial activity against E. coli, P. aeruginosa, and C. albicans. Studies of a similar protein in mouse have assigned a variety of additional functions including nitrosylation of nuclear proteins, the regulation of mRNA stability, and acting as a transferrin receptor on the cell surface of macrophage. Many pseudogenes similar to this locus are present in the human genome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2014]

Synonyms

G3PD; GAPD; HEL-S-162eP;

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Detailed Information

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) enzymes are a family of largely expressed oxidoreductases known for their important role in glycolysis. In glucose metabolism, it is catalyzing the phosphorylation of glyceraldehyde-3-phosphate (G3P) to 1,3-bisphosphoglycerate using nicotinamide adenine dinucleotide (NAD+) as a cofactor. It provides the biological starting point not only for the glycolytic synthesis of ATP but also for reducing equivalents accessible for oxidative phosphorylation. Generally, GAPDH is used as a housekeeping gene, or cytosolic control marker in protein and gene expression studies, as well as a reference loading control in routine biochemical analysis because of its sequence preservation and expression across species. However, recent experimental evidence show that beyond glycolytic functions, GAPDH is in reality a multifunctional protein that has been reported to bind nucleic acids, regulate gene expression/transcription, possess kinase/phosphotransferase activity, facilitate vesicular transport, and bind integral membrane ion pumps associated with cell Ca²⁺ release, as well as interact with a number of small key molecules, including ribozymes, p53, glutathione (GSH), and nitric oxide (NO). In addition, GAPDH also interacts and form complexes with neurodegenerative disease-related proteins, like huntingtin, β-amyloid and the β-amyloid precursor protein (AβPP).

Figure 1. Regulatory mechanisms of GAPDH by p53 and NO.

Binding of nucleic acids by GAPDH

Since the first report identifying GAPDH as a single-stranded DNA binding protein, a number of studies have described a range of nucleic acid binding partners. Various RNA species have been shown to interact with GAPDH both in vitro and in intact cells, with binding typically occurring at AU-rich elements (ARE) in the substrate RNA. Interestingly, the binding of GAPDH to ARE can have varied, and even opposite, consequences for mRNA stability and gene expression. Colony-stimulating factor 1 (CSF1) is a macrophage cytokine positively implicated in tumor progression. Recently, the binding of CSF1 mRNA by GAPDH has been demonstrated to stabilize the transcript and enhance CSF1 protein levels in ovarian cancer, whereas GAPDH depletion consistently results in a decrease in CSF1 mRNA and protein levels. In contrast with its role in stabilizing CSF1 mRNA, GAPDH binds to and facilitates the degradation of mRNA coding for the potent endothelial vasoconstrictor endothelin (ET)-1. The GAPDH-mediated degradation of ET-1 mRNA has been suggested to be caused by unwinding of the ET-1 mRNA and subsequent exposure to ribonucleases.

GAPDH as a pro-survival factor

Although GAPDH can trigger cell death by apoptosis, it can also work as a mediator of cell survival. GAPDH facilitates progression through mitosis by reversing SET-induced cyclin B-cdk1 inhibition through direct interactions with both proteins. Moreover, cancer cells typically rely heavily on glycolysis for ATP generation, even in the presence of oxygen (the Warburg effect), and frequently upregulate GAPDH to meet their energy requirements. Clearly, these cells expressing elevated GAPDH persist and, indeed, proliferate profusely, despite the demonstrated role for GAPDH as a potent inducer of apoptosis. Thus, GAPDH can both positively and negatively regulate cell proliferation and survival.

Because GAPDH is involved in an array of cellular processes, it may be expected to be subject to considerable regulation. Under normal cellular conditions, GAPDH exists predominantly as a homotetramer, a conformation required for its catalytic activity. Despite the common use of GAPDH as an experimental loading control, gene expression levels can change in response to a variety of stimuli, including oxidative stress and hypoxia, both of which cause an upregulation of GAPDH expression. A number of tumors develop a state of hypoxia owing to their high energy requirements and disorganized vasculature, which could therefore enhance GAPDH expression and facilitate an increase in the rate of glycolysis.

GAPDH and Alzheimer’s disease

In recent years, research conducted has revealed the involvement of the oxidoreductase, GAPDH, in Alzheimer’s disease (AD) pathology. Genetics and neuroproteomics have revealed high affinity interactions between GAPDH and neurodegenerative disease-associated proteins, including the β-amyloid (Aβ) precursor protein (AβPP), Aβ and neurofibrillary tangles. GAPDH is subject to several forms of oxidative modifications in brains of AD patients, which fundamentally disturb its chemical structure and biological function, including S-nitrosylation, S-glutathionylation, and its reaction with reactive oxygen species (ROS). Although the precise molecular mechanisms of many of the GAPDH interactions and processes are not yet clear, the structure, activity and subcellular localization of GAPDH remains crucial for understanding the countless roles it plays in normal and neuropathological cellular functions. Therefore, these findings open new approaches for diagnosis through using GAPDH as a biomarker and a promising therapeutic target to slow or cure neurodegeneration in brains of AD patients.

References:

Zhang J Y, et al. Critical protein GAPDH and its regulatory mechanisms in cancer cells. 2015.
Nicholls C, et al. GAPDH: A common enzyme with uncommon functions. Clinical & Experimental Pharmacology & Physiology, 2012, 39(8):0-0.
Kosova A A, et al. Role of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in DNA repair. Biochemistry, 2017, 82(6):643-654.
El K N, et al. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and Alzheimer's disease. Pathologie Biologie, 2014, 62(6):333-336.

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