Thioredoxin reductase as a pathophysiological factor and drug target

Area of Science:

• Biochemistry
• Enzymology
• Redox Biology

Background:

• Human cytosolic thioredoxin reductase (TrxR) is a crucial enzyme for maintaining cellular redox homeostasis.
• It catalyzes NADPH-dependent reductions, playing a role in oxidative stress defense and selenium metabolism.
• TrxR is implicated in various chronic diseases and cancer.

Purpose of the Study:

• To explore the multifaceted roles of human TrxR in cellular processes.
• To investigate the impact of selenium levels on TrxR activity.
• To examine TrxR as a therapeutic target for diseases and drug resistance.

Main Methods:

• Biochemical characterization of human TrxR.
• Enzyme kinetics and inhibition studies (e.g., with auranofin).
• Review of biochemical, virological, and clinical evidence linking TrxR to diseases.

Main Results:

• Human TrxR is a homodimeric enzyme with selenocysteine and FAD, involved in redox balance and selenium metabolism.
• Auranofin potently inhibits TrxR (Ki = 4 nM), targeting selenocysteine 496.
• TrxR activity is influenced by both selenium deficiency and oversupplementation.
• Evidence supports TrxR's role in chronic diseases (arthritis, AIDS, cancer) and tumor growth.
• TrxR inhibition by drugs like carmustine and cisplatin is linked to their anti-cancer effects.
• Drug resistance can be associated with high TrxR levels.
• Significant diversity exists in TrxR mechanisms across different organisms.

Conclusions:

• Human TrxR is central to redox homeostasis, selenium metabolism, and disease pathogenesis.
• TrxR is a validated therapeutic target, with inhibitors showing promise against cancer, bacterial, and parasitic infections.
• Understanding TrxR diversity is key to developing targeted therapies.