Oxidation-resistant GAPDH mutation impacts cell growth, tumor development and fatty acid metabolism in mammals

Researchers investigated how altering the oxidation process in the GAPDH enzyme influences mammalian cell behavior, tumor progression and fat processing. The study by Deepti Talwar, Colin G. Miller and several others was published on April 6.

According to the study, the glycolytic enzyme GAPDH has a distinctive property: its active site cysteine undergoes oxidation when there's a rise in intracellular hydrogen peroxide (H2O2) levels. While some metabolic enzymes like pyruvate kinase are sensitive to oxidation, GAPDH's H2O2 reactivity at its thiol site stands out for being higher than most protein thiols. This oxidation process can result in the enzyme's reversible inhibition, the study stated. Interestingly, while it was once believed that GAPDH oxidation might inadvertently damage the protein, research over the past 15 years suggests it's beneficial for cells exposed to oxidants. It redirects glucose flow, bolstering cells' tolerance to H2O2. Yet, according to the study, the exact role of GAPDH oxidation in mammals, especially concerning oxPPP activation, remains a topic of debate and intrigue.

The study states that when GAPDH encounters hydrogen peroxide, it quickly becomes inactive. Our study reveals that both human and mouse cells that have a version of GAPDH without this oxidation mechanism maintain their enzyme function. However, these cells don't boost their oxidative defense as effectively. This limitation becomes evident in how cells grow without attachment and how tumor spheroids develop; elevated internal peroxide levels constrain them.

According to the study, tumors face a growth restriction when exposed to peroxide. This is even more pronounced if their GAPDH can't undergo oxidation. Adding more oxidative stress, like through chemotherapy or radiation, further compounds this effect. Notably, in mice that don't have this oxidizable GAPDH feature, there's a noticeable shift in how fats are processed in organs like the kidneys and heart. This may be the body's way of adjusting to the absence of this oxidation pathway. Collectively, the research underscores how critical the oxidation process in GAPDH is for both normal and disease-related functions in mammals.

Nature: Deepti Talwar, et al., The GAPDH redox switch safeguards reductive capacity and enables survival of stressed tumour cells, Nature Metabolism (2023). https://doi.org/10.1038/s42255-023-00781-3