VKOR paralog VKORC1L1 supports vitamin K–dependent protein carboxylation in vivo

Lacombe, Julie; Rishavy, Mark A.; Berkner, Kathleen L.; Ferron, Mathieu

doi:10.1172/jci.insight.96501

Cited by 33 publications

(53 citation statements)

References 23 publications

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“…Indeed, although VKORC1 knockout mice survive longer than GGCX -/- mice, they exhibited early postnatal lethality due to severe bleeding [ 68 ], which suggests VK recycling is critical in sustaining γ-carboxylation of blood clotting factors. A well evolutionary conserved structure and function of VKORs has been suggested [ 57 ], where the VKORC1 and VKORC1L1 paralogs probably arose from the duplication of a VKOR ancestor gene [ 29 , 30 , 31 , 46 , 56 , 57 , 60 , 61 ]. A ubiquitous gene expression of both vkorc1 and vkorc1l1 genes in vertebrates has been reported [ 29 , 30 , 31 , 56 , 60 , 61 ].…”

Section: Vitamin K Molecular Pathwaysmentioning

confidence: 99%

“…A well evolutionary conserved structure and function of VKORs has been suggested [ 57 ], where the VKORC1 and VKORC1L1 paralogs probably arose from the duplication of a VKOR ancestor gene [ 29 , 30 , 31 , 46 , 56 , 57 , 60 , 61 ]. A ubiquitous gene expression of both vkorc1 and vkorc1l1 genes in vertebrates has been reported [ 29 , 30 , 31 , 56 , 60 , 61 ]. In vertebrates, the highest vkorc1 expression is found in liver, consistent with being the main isoform that is responsible for recycling VK epoxide originated from hepatic γ-carboxylation of hemostasis-related VKDPs [ 60 , 61 ].…”

Section: Vitamin K Molecular Pathwaysmentioning

confidence: 99%

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Vitamin K in Vertebrates’ Reproduction: Further Puzzling Pieces of Evidence from Teleost Fish Species

2020

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Vitamin K (VK) is a fat-soluble vitamin that vertebrates have to acquire from the diet, since they are not able to de novo synthesize it. VK has been historically known to be required for the control of blood coagulation, and more recently, bone development and homeostasis. Our understanding of the VK metabolism and the VK-related molecular pathways has been also increased, and the two main VK-related pathways—the pregnane X receptor (PXR) transactivation and the co-factor role on the γ-glutamyl carboxylation of the VK dependent proteins—have been thoroughly investigated during the last decades. Although several studies evidenced how VK may have a broader VK biological function than previously thought, including the reproduction, little is known about the specific molecular pathways. In vertebrates, sex differentiation and gametogenesis are tightly regulated processes through a highly complex molecular, cellular and tissue crosstalk. Here, VK metabolism and related pathways, as well as how gametogenesis might be impacted by VK nutritional status, will be reviewed. Critical knowledge gaps and future perspectives on how the different VK-related pathways come into play on vertebrate’s reproduction will be identified and proposed. The present review will pave the research progress to warrant a successful reproductive status through VK nutritional interventions as well as towards the establishment of reliable biomarkers for determining proper nutritional VK status in vertebrates.

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Section: Vitamin K Molecular Pathwaysmentioning

confidence: 99%

Section: Vitamin K Molecular Pathwaysmentioning

confidence: 99%

Vitamin K in Vertebrates’ Reproduction: Further Puzzling Pieces of Evidence from Teleost Fish Species

2020

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“…It was suggested that, in HEK293 cells, VKORC1L1 could protect cells from oxidative stress in a vitamin K-dependent manner [ 39 ]. However, the inactivation of VKORC1L1 does not impact HEK293 cell survival in culture [ 41 , 42 ], and no obvious phenotype potentially associated with increased oxidative stress has been detected in Vkorc1l1 −/− mice, which are viable and develop normally in comparison to wild-type mice [ 36 , 45 ]. Overall, the genetic data are not in support of VKORC1L1 having a major role in protecting from oxidative stress, at least under physiological conditions.…”

Section: Expression Pattern Of Vkorc1 and mentioning

confidence: 99%

“…The survival of Vkorc1 −/− mice on a pure C57Bl/6J background was reanalyzed and it was found that the VKORC1 deficiency was compatible with postnatal survival for more than one week after birth, but that all Vkorc1 −/− animals died before 20 days after birth, with a median survival of 9.5 days. In addition, prothrombin and GGCX are γ-carboxylated in e18.5 Vkorc1 −/− embryos and newborns, but not in one-week-old Vkorc1 −/− pups [ 45 ]. These observations suggested the existence of a second enzyme, which could support vitamin K-dependent γ-carboxylation in the liver during embryogenesis and perinatally.…”

Section: Evidence That Vkorc1l1 Supports Gamma-carboxylation In VImentioning

confidence: 99%

VKORC1L1, An Enzyme Mediating the Effect of Vitamin K in Liver and Extrahepatic Tissues

Lacombe

Ferron

2018

Nutrients

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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.

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“…Lethal hemorrhaging is also observed in VKORC1‐null mice . A VKORC1 paralog, VKORC1‐like 1, also reduces KO and supports VKD protein carboxylation in vivo, but its physiologic role is not well understood. Defining how these individual carboxylation components support VKD protein carboxylation is essential, given the broad biological impact of this family of proteins.…”

Section: Introductionmentioning

confidence: 99%

Exon 2 skipping eliminates γ‐glutamyl carboxylase activity, indicating a partial splicing defect in a patient with vitamin K clotting factor deficiency

Rishavy

Hallgren

Zhang

et al. 2019

Journal of Thrombosis and Haemostasis

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Background: Mutations in the γ-glutamyl carboxylase (GGCX), which is required for vitamin K-dependent (VKD) protein activation, can result in vitamin K clotting factor deficiency (VKCFD1). A recent report described a VKCFD1 patient with a homozygous carboxylase mutation that altered splicing and deleted exon 2 (Δ2GGCX). Only Δ2GGCX RNA was observed in the patient.Objectives: Loss of exon 2 results in the deletion of carboxylase sequences thought to be important for membrane topology and consequent function. Carboxylase activity is required for life, and we therefore tested whether the Δ2GGCX mutant is active.Methods: HEK 293 cells were edited by the use of CRISPR-Cas9 to eliminate endogenous carboxylase. Recombinant wild-type GGCX and recombinant Δ2GGCX were then expressed and tested for carboxylation of the VKD protein factor IX. A second approach was used to monitor carboxylation biochemically, using recombinant carboxylases expressed in insect cells that lack endogenous carboxylase. Results and conclusions: Δ2GGCX activity was undetectable in both assays, which is strikingly different from the low levels of carboxylase activity observed with other VKCFD1 mutants. The similarity in clotting function between patients with Δ2GGCX and these mutations must therefore arise from a novel mechanism. Low levels of properly spliced carboxylase RNA that produce full-length protein would not have been observed in the previous study. The results suggest that the splicing defect is incomplete. Δ2GGCX RNA has been detected in normal human liver, and has been designated carboxylase isoform 2; however, Δ2GGCX protein was not observed in normal human liver. The lack of activity and protein expression suggest that isoform 2 is not physiologically relevant to normal VKD protein carboxylation. K E Y W O R D Sγ-glutamyl carboxylase, blood coagulation disorders, CRISPR-Cas, inherited, vitamin K, VKCFD1

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VKOR paralog VKORC1L1 supports vitamin K–dependent protein carboxylation in vivo

Cited by 33 publications

References 23 publications

Vitamin K in Vertebrates’ Reproduction: Further Puzzling Pieces of Evidence from Teleost Fish Species

Vitamin K in Vertebrates’ Reproduction: Further Puzzling Pieces of Evidence from Teleost Fish Species

VKORC1L1, An Enzyme Mediating the Effect of Vitamin K in Liver and Extrahepatic Tissues

Exon 2 skipping eliminates γ‐glutamyl carboxylase activity, indicating a partial splicing defect in a patient with vitamin K clotting factor deficiency

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