Abstract
Vitamin K is an essential nutrient involved in the regulation of blood clotting and tissue mineralization. Vitamin K oxidoreductase (VKORC1) converts vitamin K epoxide into reduced vitamin K, which acts as the co-factor for the γ-carboxylation of several proteins, including coagulation factors produced by the liver. VKORC1 is also the pharmacological target of warfarin, a widely used anticoagulant. Vertebrates possess a VKORC1 paralog, VKORC1-like 1 (VKORC1L1), but until very recently, the importance of VKORC1L1 for protein γ-carboxylation and hemostasis in vivo was not clear. Here, we first review the current knowledge on the structure, function and expression pattern of VKORC1L1, including recent data establishing that, in the absence of VKORC1, VKORC1L1 can support vitamin K-dependent carboxylation in the liver during the pre- and perinatal periods in vivo. We then provide original data showing that the partial redundancy between VKORC1 and VKORC1L1 also exists in bone around birth. Recent studies indicate that, in vitro and in cell culture models, VKORC1L1 is less sensitive to warfarin than VKORC1. Genetic evidence is presented here, which supports the notion that VKORC1L1 is not the warfarin-resistant vitamin K quinone reductase present in the liver. In summary, although the exact physiological function of VKORC1L1 remains elusive, the latest findings clearly established that this enzyme is a vitamin K oxidoreductase, which can support γ-carboxylation in vivo.
Highlights
Vitamin K, Gamma-Carboxylation and Vitamin K OxidoreductaseVitamin K is an essential nutrient that is needed to support normal coagulation and to prevent abnormal calcification of arteries and cartilages [1,2]
If VKORC1L1 can support vitamin K reduction and γ-carboxylation in the liver during the prenatal and perinatal period, why does it fail to compensate for the absence of VKORC1 after one week following birth? One plausible answer to this question was that VKORC1 and VKORC1L1 are differentially expressed during development
VKORC1L1, when expressed at a sufficient level, can sustain vitamin K-dependent carboxylation in the adult liver and prevent bleeding and lethality [45]. These results provide a biological explanation for 30-year-old clinical observations, showing that vitamin K-dependent coagulation factor activities and level in plasma are, on average, 75% lower in normal human fetuses compared to adults [51,52]
Summary
Vitamin K is an essential nutrient that is needed to support normal coagulation and to prevent abnormal calcification of arteries and cartilages [1,2]. These phylogenic studies suggest that the ancestral VKOR enzyme appeared during evolution before GGCX, potentially fulfilling a function not linked to protein carboxylation Supporting this idea, bacterial VKOR homologues have been shown to be involved in disulfide bond formation in the periplasm [20,21]. Bacterial VKOR homologues have been shown to be able to reduce vitamin K to vitamin K hydroquinone in vitro, they do not seem to reduce vitamin K 2,3-epoxide in the same assay. This is in line with the observation that vitamin K 2,3-epoxide is not present in bacteria [23]. The putative ubiquinone reductase activity of these enzymes remains speculative, since it has not been tested experimentally
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