Publications

• A non-canonical vitamin K cycle is a potent ferroptosis suppressor.

  Mishima E., Ito J., Wu Z., Nakamura T., Wahida A., Doll S., Tonnus W., Nepachalovich P., Eggenhofer E., Aldrovandi M., Henkelmann B., Yamada K.I., Wanninger J., Zilka O., Sato E., Feederle R., Hass D., Maida A., Mourao A.S.D., Linkermann A., Geissler E.K., Nakagawa K., Abe T., Fedorova M., Proneth B., Pratt D.A., Conrad M.

  Ferroptosis, a non-apoptotic form of cell death marked by iron-dependent lipid peroxidation¹, has a key role in organ injury, degenerative disease and vulnerability of therapy-resistant cancers². Although substantial progress has been made in understanding the molecular proce ... >> More

  Ferroptosis, a non-apoptotic form of cell death marked by iron-dependent lipid peroxidation¹, has a key role in organ injury, degenerative disease and vulnerability of therapy-resistant cancers². Although substantial progress has been made in understanding the molecular processes relevant to ferroptosis, additional cell-extrinsic and cell-intrinsic processes that determine cell sensitivity toward ferroptosis remain unknown. Here we show that the fully reduced forms of vitamin K-a group of naphthoquinones that includes menaquinone and phylloquinone³-confer a strong anti-ferroptotic function, in addition to the conventional function linked to blood clotting by acting as a cofactor for γ-glutamyl carboxylase. Ferroptosis suppressor protein 1 (FSP1), a NAD(P)H-ubiquinone reductase and the second mainstay of ferroptosis control after glutathione peroxidase-4^4,5, was found to efficiently reduce vitamin K to its hydroquinone, a potent radical-trapping antioxidant and inhibitor of (phospho)lipid peroxidation. The FSP1-mediated reduction of vitamin K was also responsible for the antidotal effect of vitamin K against warfarin poisoning. It follows that FSP1 is the enzyme mediating warfarin-resistant vitamin K reduction in the canonical vitamin K cycle⁶. The FSP1-dependent non-canonical vitamin K cycle can act to protect cells against detrimental lipid peroxidation and ferroptosis. << Less

  Nature 608:778-783(2022) [PubMed] [EuropePMC]

  This publication is cited by 2 other entries.

• Molecular basis of the catalytic differences among DT-diaphorase of human, rat, and mouse.

  Chen S., Knox R., Wu K., Deng P.S., Zhou D., Bianchet M.A., Amzel L.M.

  DT-diaphorase (EC 1.6.99.2), also referred to as NAD(P)H:(quinone-acceptor) oxidoreductase, is involved in the reductive activation process of several cytotoxic antitumor quinones and nitrobenzenes. It has been observed in our and other laboratories that the rat enzyme is significantly more effect ... >> More

  DT-diaphorase (EC 1.6.99.2), also referred to as NAD(P)H:(quinone-acceptor) oxidoreductase, is involved in the reductive activation process of several cytotoxic antitumor quinones and nitrobenzenes. It has been observed in our and other laboratories that the rat enzyme is significantly more effective in activating these drugs than the human and mouse enzymes. These results indicate that the available cytotoxic drugs are better substrates for the rat enzyme and are not the most ideal prodrugs for activation by DT-diaphorase in human tumors. In this study, using site-directed mutagenesis to replace residues in the rat enzyme with the human sequences and residues in the human enzyme with the rat sequences, we have found that residue 104 (Tyr in the rat enzyme and Gln in the human and mouse enzymes) is an important residue responsible for the catalytic differences between the rat and the human (and mouse) enzymes. With an exchange of a single amino acid, the rat mutant Y104Q behaved like the wild-type human enzyme, and the human mutant Q104Y behaved like the wild-type rat enzyme in their ability to reductively activate the cytotoxic drug CB 1954 (5-(aziridin-1-yl)-2,4-dinitrobenzamide). The study also confirms the conclusion of the x-ray structural analysis of rat enzyme that residue 130 (Thr in the rat enzyme and Ala in the human and mouse enzymes) is positioned near the binding region of the nicotinamide portion of NAD(P)H. This structural information is very important for designing suitable drugs and approaches for human cancer chemotherapy mediated by DT-diaphorase. << Less

  J. Biol. Chem. 272:1437-1439(1997) [PubMed] [EuropePMC]