Vitamin K metabolism and activation of dependent proteins

Vitamin K is recycled in the liver in order to maintain sufficient levels for activating vitamin K-dependent proteins (VKDP), including certain coagulation factors. In this process, vitamin K1 (taken up from the diet) is converted to vitamin K hydroquinone (KH2), either by the dithiol-dependent vitamin K-epoxide reductase (VKOR) or by NAD(P)H dehydrogenase quinone 1. KH2 is in turn oxidized to vitamin K epoxide (KO) by the enzyme gamma-glutamyl carboxylase (GGCX). During this conversion, GGCX activates the VKDPs by converting glutamate (Glu) to gamma-carboxyglutamate (Gla). Lastly, KO is converted back into vitamin K quinone by VKOR. Warfarin, a drug commonly used as a anticoagulant, inhibits VKOR, thus reducing the levels of VKH2 in the bloodstream. A too high dosage of warfarin can lead to heavy bleeding, a life-threatening condition. Threatment of this condition is a high dosis of Vitamine K, which is reduced to VHK2 by FSP1, a warfarin resistant reductase. The influence of FSP1 on this process, as well as its potential to eliminate lipid perozyl radicals, has been recently described in [https://doi.org/10.1038/s41586-022-05022-3 Nature(2022)] by Mishima et al.: A non-canonical vitamin K cycle is a potent ferroptosis suppressor.

维生素K在肝脏内循环利用，以维持激活维生素K依赖蛋白（VKDP）所需的充足水平，包括某些凝血因子。在此过程中，源自饮食的维生素K1通过二硫键依赖的维生素K-环氧酶还原酶（VKOR）或NAD(P)H脱氢酶黄素1转化为维生素K氢醌（KH2）。KH2随后由γ-谷氨酰羧化酶（GGCX）氧化为维生素K环氧（KO）。在此转换过程中，GGCX通过将谷氨酸（Glu）转化为γ-羧基谷氨酸（Gla）激活VKDP。最终，KO被VKOR还原为维生素K醌。华法林，一种常用于抗凝的药物，通过抑制VKOR，从而降低血液中VKH2的水平。华法林剂量过高可能导致严重出血，这是一种危及生命的状况。治疗此状况的方法是使用高剂量的维生素K，该维生素K被FSP1，一种对华法林具有耐药性的还原酶，还原为VHK2。最近，Mishima等人发表在[Nature(2022)]（https://doi.org/10.1038/s41586-022-05022-3）上的文章描述了FSP1对这一过程的影响，以及其消除脂质过氧自由基的潜在能力：一种非典型维生素K循环是一种有效的铁死亡抑制因子。