A team from the University of Valencia, the La Fe Hospital Health Research Institute and the INCLIVA Institute have participated in the identification of an enzyme (G6PD) as a possible therapeutic target in autoimmune diseases or in controlling exacerbated inflammatory responses such as the one caused by SARS-CoV-2 infection. The discovery has just been published in the Nature Chemical Biology journal.
The work is part of a project led by Joshua D. Rabinowitz, from Princeton University, and in which researchers from the La Fe Hospital Health Research Institute (IIS La Fe), the University of Valencia and the INCLIVA Health Research Institute from the Clinical Hospital of Valencia, among others, have participated.
The article reviews how our body is able to use the energy – understood in a broad sense – that is produced inside cells thanks to a process whose key enzyme is glucose-6-phosphate dehydrogenase (G6PD).
“NADPH is a key cofactor in cellular metabolism that acts as a bargaining chip in which to store the electrons yielded by certain nutrients to be subsequently used in key processes, such as the synthesis of cellular components that cannot be acquired from the outside by cells, the maintenance of antioxidant defense or the production of reactive oxygen species by some cells of the immune system, such as neutrophils. Although there are several nutrients from which NADPH can be obtained, it is accepted that in most situations the main source is glucose through the oxidative pathway of pentose phosphate whose key enzyme is glucose-6-phosphate dehydrogenase (G6PD)”, explains García Cañaveras.
Now, when G6PD is absent or its activity is reduced by an inhibitor, the human body looks for alternative ways to assimilate energy. But does this always happen? To answer this question, researchers used the most widely employed inhibitor for the G6PD enzyme and found that it was unable to decrease G6PD activity in cells. However, a compound developed by them and which they have baptized as G6PDi-1 did manage to do it.
The next step was to test this new inhibitor against a wide variety of cell types, including cancer and normal cells. The research team then discovered that enzyme inhibition only had consequences for T lymphocytes, specialized cells of the immune system that play a central role in defending against agents such as viruses and cancer / tumour cells, but whose uncontrolled activity can lead to autoimmune phenomena.
Although the developed compound is only effective in cultured cells and cannot be used in vivo yet, this study with Valencian participation points out that the inhibition of the G6PD enzyme could be a therapeutic alternative to explore in the future development of treatments against autoimmune diseases, or when controlling exacerbated immune responses such as those observed in CAR-T treatments or in the uncontrolled inflammatory response caused by SARS-CoV-2 infection.
The first authors of the article are Jon Ghergurovich and Juan Carlos García Cañaveras, a researcher at La Fe IIS and also a visiting researcher at Princeton University thanks to a Marie Sklodowska-Curie Global Fellowship grant funded by the European Union. On the part of the University of Valencia, the participation of the professor of Physiology Mª Carmen Gómez-Cabrera (UV-INCLIVA) has consisted of providing a model of overexpression of the G6PD enzyme, which has been used to modulate the intracellular levels of NADPH and the role of immune system cells in the study.
A small molecule G6PD inhibitor reveals immune dependence on pentose phosphate pathway. Jonathan M. Ghergurovich, Juan C. García-Cañaveras, Joshua Wang, Emily Schmidt, Zhaoyue Zhang, Tara TeSlaa, Harshel Patel, Li Chen, Emily C. Britt, Marta Piqueras-Nebot, Mari Carmen Gomez-Cabrera, Agustín Lahoz, Jing Fan, Ulf H. Beier, Hahn Kim & Joshua D. Rabinowitz.