Difficulty Breathing

Thomas, M; Gebara, Bassam M.

doi:10.1177/000992280404300517

Cited by 6 publications

(3 citation statements)

References 12 publications

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“…Vitamin K is of main importance for many physiological processes as the exclusive cofactor of the γ-glutamyl carboxylase (GGCX) enzyme, which catalyzes a post-translational modification: γ-glutamyl carboxylation. This leads to the activation of vitamin K-dependent proteins (VKDPs) involved in bone metabolism [1,2], cancer progression and inflammatory response [3], oxidative stress [4], sphingolipid synthesis [5], and pancreas exocrine activity [6]. Vitamin K is also crucial for blood coagulation [7] (clotting factors are hepatic VKDPs), and for energy metabolism and arterial calcification prevention through the activation of osteocalcin [8] and matrix Gla protein [9], respectively, both being extrahepatic VKDPs.…”

Section: Introductionmentioning

confidence: 99%

Structural Insights into Phylloquinone (Vitamin K1), Menaquinone (MK4, MK7), and Menadione (Vitamin K3) Binding to VKORC1

et al. 2019

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Vitamin K family molecules—phylloquinone (K1), menaquinone (K2), and menadione (K3)—act as γ-glutamyl carboxylase (GGCX)-exclusive cofactors in their hydroquinone state, activating proteins of main importance for blood coagulation in the liver and for arterial calcification prevention and energy metabolism in extrahepatic tissues. Once GGCX is activated, vitamin K is found in the epoxide state, which is then recycled to quinone and hydroquinone states by vitamin K epoxide reductase (VKORC1). Nevertheless, little information is available concerning vitamin K1, K2, or K3 tissue distribution and preferential interactions towards VKORC1. Here we present a molecular modeling study of vitamin K1, menaquinones 4, 7 (MK4, MK7), and K3 structural interactions with VKORC1. VKORC1 was shown to tightly bind vitamins K1 and MK4 in the epoxide and quinone states, but not in the hydroquinone state; five VKORC1 residues were identified as crucial for vitamin K stabilization, and two other ones were essential for hydrogen bond formation. However, vitamin MK7 revealed shaky binding towards VKORC1, induced by hydrophobic tail interactions with the membrane. Vitamin K3 exhibited the lowest affinity with VKORC1 because of the absence of a hydrophobic tail, preventing structural stabilization by the enzyme. Enzymatic activity towards vitamins K1, MK4, MK7, and K3 was also evaluated by in vitro assays, validating our in silico predictions: VKORC1 presented equivalent activities towards vitamins K1 and MK4, but much lower activity with respect to vitamin MK7, and no activity towards vitamin K3. Our results revealed VKORC1’s ability to recycle both phylloquinone and some menaquinones, and also highlighted the importance of vitamin K’s hydrophobic tail size and membrane interactions.

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Section: Introductionmentioning

confidence: 99%

Structural Insights into Phylloquinone (Vitamin K1), Menaquinone (MK4, MK7), and Menadione (Vitamin K3) Binding to VKORC1

et al. 2019

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“…Vitamin K is, thus, crucial for blood coagulation through the activation of hepatic blood clotting factors II, VII, IX, and X. Vitamin K is also essential for energy metabolism and arterial calcification prevention through the activation of osteocalcin [4] and Matrix Gla Protein [5], respectively, which are both extrahepatic VKDPs. It was also described to be involved in bone metabolism [6,7], cancer progression, inflammatory response [8], oxidative stress [9], shingolipids synthesis [10], and pancreas exocrine activity [11].…”

Section: Introductionmentioning

confidence: 99%

Establishment of the Variation of Vitamin K Status According to Vkorc1 Point Mutations Using Rat Models

et al. 2019

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Vitamin K is crucial for many physiological processes such as coagulation, energy metabolism, and arterial calcification prevention due to its involvement in the activation of several vitamin K-dependent proteins. During this activation, vitamin K is converted into vitamin K epoxide, which must be re-reduced by the VKORC1 enzyme. Various VKORC1 mutations have been described in humans. While these mutations have been widely associated with anticoagulant resistance, their association with a modification of vitamin K status due to a modification of the enzyme efficiency has never been considered. Using animal models with different Vkorc1 mutations receiving a standard diet or a menadione-deficient diet, we investigated this association by measuring different markers of the vitamin K status. Each mutation dramatically affected vitamin K recycling efficiency. This decrease in recycling was associated with a significant alteration of the vitamin K status, even when animals were fed a menadione-enriched diet suggesting a loss of vitamin K from the cycle due to the presence of the Vkorc1 mutation. This change in vitamin K status resulted in clinical modifications in mutated rats only when animals receive a limited vitamin K intake totally consistent with the capacity of each strain to recycle vitamin K.

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“…GGCX is responsible for a posttranscriptional modification, γ-glutamyl carboxylation, leading to the activation of vitamin K-dependent proteins (VKPDs). VKPDs are involved in many physiological processes, such as bone metabolism, 1,2 oxidative stress, 3 pancreas exocrine activity, 4 cancer progression and inflammatory response, 5 sphingolipid synthesis, 6 energy metabolism, 7 arterial calcification prevention, 8 and blood coagulation. 9 The vitamin K hydroquinone state is used for GGCX enzyme activation, after which vitamin K is reduced to its epoxide state, exhibiting no biological activity.…”

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confidence: 99%

Structural Investigation of the Vitamin K Epoxide Reductase (VKORC1) Binding Site with Vitamin K

et al. 2020

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The vitamin K epoxide reductase (VKORC1) enzyme is of primary importance in many physiological processes, i.e., blood coagulation, energy metabolism, and arterial calcification prevention, due to its role in the vitamin K cycle. Indeed, VKORC1 catalyzes reduction of vitamin K epoxide to quinone and then to hydroquinone. However, the three-dimensional VKORC1 structure remains experimentally undetermined, because of the endoplasmic reticulum membrane location of this enzyme. Here we present a molecular modeling investigation of the VKORC1 enzymatic site structure and function, supported by in vitro enzymatic assays. Four VKORC1 mutants were designed in silico (F55G, F55Y, N80G, and F83G) based on a previous study that identified residues F55, N80, and F83 as being crucial for vitamin K epoxide binding. F55G, N80G, and F83G nonconservative mutants were all predicted to be inactive by molecular modeling analyses. However, the F55Y conservative mutant was expected to be active compared to wild-type VKORC1. In vitro enzymatic assays performed on recombinant proteins assessed our molecular modeling hypotheses and led us to describe the role of accurate VKORC1 active site residues with respect to VKORC1. Residues F55, N80, and F83 appeared to act in a concerted manner to keep vitamin K epoxide close to the C135 catalytic residue. Residues F55 and N80 prevent naphthoquinone head rotation away from the active site, assisted by residue F83 that prevents vitamin K from sliding outside the enzymatic pocket, through hydrophobic tail stabilization. Our results thus highlighted the specific functions of VKORC1 catalytic pocket residues and evidenced the ability of our structural model to predict biological effects of VKORC1 mutations.

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Difficulty Breathing

Abstract: The following Brief Report was written by a resident. A discussion by a member of the resident's faculty follows. We invite any resident to submit such articles, together with commentary by a faculty member.

Cited by 6 publications

References 12 publications

Structural Insights into Phylloquinone (Vitamin K1), Menaquinone (MK4, MK7), and Menadione (Vitamin K3) Binding to VKORC1

Structural Insights into Phylloquinone (Vitamin K1), Menaquinone (MK4, MK7), and Menadione (Vitamin K3) Binding to VKORC1

Establishment of the Variation of Vitamin K Status According to Vkorc1 Point Mutations Using Rat Models

Structural Investigation of the Vitamin K Epoxide Reductase (VKORC1) Binding Site with Vitamin K

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