Esha Sircar & Dr. Rajib Sengupta, Amity Institute of Biotechnology, Amity University Kolkata
Prof. Peter Reichard and Prof. Arne Holmgren are considered as two redox pioneers from Karolinska Institute (Sweden) for their enormous contribution to the research focused on thiol-dependent cellular redox homeostasis, related to cancer and many other diseases/disorders. In 1964, Prof. Peter Reichard and coworkers discovered the Thioredoxin system. Then, Prof. Arne Holmgren solely discovered Glutaredoxin in 1976. Till now, the search word “Thioredoxin” and “Glutaredoxin” in Pubmed results in 40,593 and 8,494 articles, respectively. This clearly shows the wide range of global research focusing on these two systems.
Thioredoxin (Trx), thioredoxin reductase (TrxR or TR), and NADPH form the complete Trx system. Whereas, the Glutaredoxin system includes Glutaredoxin (Grx), glutathione (GSH), glutathione reductase (GR), and NADPH. Both Trx and Grx are small ubiquitous proteins and have many different cellular isoforms to regulate different biochemical events. Spanning over the last 40 years, several research groups clearly showed the presence of two different classes of Grx (monothiol and dithiol) in microbes, plants, and animals.
In general, Grxs are catalyzing thiol-dependent disulfide reduction and S-deglutathionylation reactions. Dithiol Grxs have CXXC motif in the active site whereas the monothiol Grxs have a CXXS instead of two vicinal thiols for catalysis. In both the mechanisms, reduced glutathione (GSH) is playing a crucial role. Thus, the cellular concentrations of reduced and oxidised glutathione are critically linked to the activity of Grx systems. Interestingly, monothiol Grxs are playing a significant role in iron-sulfur (Fe-S) cluster delivery and iron sensing in mammals.
Excessive concentrations of reactive oxygen/nitrogen species inside the cells are causing oxidative/nitrosative stress. Cancer, diabetes, inflammation, and neurodegenerative diseases are found to be very much linked to the outcome of severe oxidative/nitrosative stress. Here, even dithiol mimetics of Trx and Grx can be used as drugs or prodrugs to combat the detrimental effects of the stress conditions.
Recently, our group has identified a novel S-denitrosylaze activity of Grxs. This is very crucial considering the role of Trx, protein disulfide isomerase, alcohol dehydrogenase III as cellular S-denitrosylazes. It will be interesting to map specific S-nitrosylated proteins (and S-nitrosothiols) substrates for each of the denitrosylaze system as Trx and Grx are the ubiquitous members among the denitrosylazes. The journey and legacy started by Prof. Reichard and Prof. Holmgren is still going on. In the future, further studies on the crosstalk and redundancy within the two redox systems will also help us to design and develop new drugs to tackle oxidative/nitrosative stress.
Also read: Molecules for Life- Thioredoxin System– Esha Sircar & Dr. Rajib Sengupta
Ref:
1. Glutaredoxin systems Christopher Horst Lillig, Carsten Berndt, Arne Holmgrens , Biochim Biophys Acta 2008 Nov;1780(11):1304-17, DOI: 10.1016/j.bbagen.2008.06.003
2. Thioredoxins, glutaredoxins, and peroxiredoxins—molecular mechanisms and health significance: from cofactors to antioxidants to redox signalling EM Hanschmann, JR Godoy, C Berndt, C Hudemann, CH Lillig Antioxidants & redox signaling 19 (13), 1539-1605
3. Characterization of mammalian glutaredoxin isoforms as S-denitrosylases. Xiaoyuan Ren , Rajib Sengupta, Jun Lu, Jon O. Lundberg and Arne Holmgren FEBS Letters 2019; 593 (14): 1799-1806.https://doi.org/10.1002/1873-3468.13454
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