![]() Here we find that effects of the major predictor of warfarin dosage, SNP −1639 G>A, follow a general correlation that warfarin 50% inhibitory concentration decreases with cellular level of vitamin K epoxide reductase (VKORC1), suggesting stoichiometric inhibition. Improving the dosage management and antidotal efficacy requires mechanistic understanding. The paper Mishima Eikan et al, 2022: A non-canonical vitamin K cycle is a potent ferroptosis suppressor, was published in Nature on August 3, 2022.Dose control of warfarin is a major complication in anticoagulation therapy and overdose is reversed by the vitamin K antidote. ![]() Zijun Wu, was able to demonstrate that FSP1 can reduce Vitamin K to its hydroquinone form, and that this form of Vitamin K is a potent radical-trapping antioxidant – preventing membrane oxidation and corresponding ferroptotic cell death. Pratt’s laboratory, post-doctoral researcher Dr. Using methods previously developed in Prof. ** Professor Pratt’s group provided the research team with the chemical tools and expertise to show how Vitamin K and FSP1 work together to suppress membrane lipid oxidation. “Thus, new aspects of the role of vitamin K throughout the evolution of life are expected to be unveiled” Dr. In addition, since ferroptosis most likely constitutes one of the oldest types of cell death, the researchers hypothesize that vitamin K might be one of the most ancient types of naturally occurring antioxidants. They will serve as the stepping stone for the development of novel therapeutic strategies for diseases where ferroptosis has been implicated “, Dr. “Our results therefore link the two worlds of ferroptosis research and vitamin K biology. Unraveling the identity of this enzyme solved the last riddle of vitamin K metabolism in blood clotting and elucidated the molecular mechanism of why vitamin K constitutes the antidote for overdosing of warfarin. Since vitamin K is critically involved in blood clotting processes, the team further showed that FSP1 is responsible for the vitamin K-reduction pathway insensitive against warfarin, one of the most commonly prescribed anticoagulants.īreakthrough in understanding vitamin K metabolism In addition, they identified that FSP1 is the enzyme that efficiently reduces vitamin K to vitamin K hydroquinone, thereby driving a novel non-canonical vitamin K cycle. Pratt, co-author and University Research Chair in Free Radical Chemistry at the University of Ottawa**. “The reduced forms of Vitamin K and coenzyme Q10 are not very stable, so our finding that FSP1 can maintain them in their active (reduced) state is key to understanding how they are able to function to maintain cell viability.” explained Derek A. The research team now found that the fully reduced form of vitamin K (i.e., vitamin K hydroquinone) is, like the reduced form of coenzyme Q10, a strong lipophilic antioxidant and prevents ferroptosis by trapping oxygen radicals in lipid bilayers. At the time, the team showed that FSP1 reduced coenzyme Q10 to its hydroquinone, which suppressed ferroptosis. Marcus Conrad already identified an enzyme as a novel and strong inhibitor of ferroptosis: ferroptosis suppressor protein-1, short FSP1. Unraveling the long sought-after vitamin K reducing enzyme FSP1 Eikan Mishima, first author of the study explained. “Surprisingly, we identified that vitamin K, including phylloquinone (vitamin K1) and menaquinone-4 (vitamin K2), is able to efficiently rescue cells and tissues from undergoing ferroptosis” Dr. Marcus Conrad, both from the Institute of Metabolism and Cell Death at Helmholtz Munich, along with collaborators from Tohoku University (Japan), University of Ottawa (Canada) and Technical University of Dresden (Germany), systematically studied a number of naturally occurring vitamins, as well as their derivatives. To identify these new molecules, a team of researchers led by Dr. ![]() Since ferroptosis prevention is considered a highly promising approach for the therapy of many degenerative diseases, new mechanisms and compounds regulating ferroptosis are extensively being explored. Vitamin K is a potent ferroptosis suppressor Thus, the present findings put forward the concept that a vitamin K treatment might be a new powerful tool for treating these ferroptosis-related diseases. During the last years, ferroptosis has been implicated as a driver of Alzheimer’s disease and acute organ injuries among many other diseases. In addition, the team identified FSP1 as the warfarin-insensitive enzyme reducing vitamin K, the identity of which had been postulated but remained unknown for more than half a century. Ferroptosis is a natural form of cell death in which cellular iron plays an important role and which is characterized by the oxidative destruction of cellular membranes. The researchers discovered that the fully reduced form of vitamin K acts as an antioxidant efficiently inhibiting ferroptotic cell death.
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