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Special Issue "Vitamin K and Vitamin K-Dependent Proteins in Relation to Human Health"

A special issue of Nutrients (ISSN 2072-6643).

Deadline for manuscript submissions: closed (15 May 2015)

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Guest Editor
Dr. Martin J. Shearer

The Centre for Haemostasis and Thrombosis, St. Thomas’ Hospital, Westminster Bridge Road, London SE1 7EH, UK
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Interests: metabolism, nutrition and cell biology of vitamin K; clinical pathology with focus on haemostasis and therapeutic aspects of vitamin K and vitamin K antagonists; methods for the assessment of vitamin K status
Guest Editor
Dr. Leon J. Schurgers

Department of Biochemistry - Vascular Aspects, Faculty of Medicine, Health & Life Science, P.O. Box 616, UNS50/Box8, 6200 MD Maastricht, The Netherlands
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Interests: vitamin K-dependent (Gla) proteins; haemostasis and vascular calcification; biology and biochemistry of ectopic calcification; phenotypic switching of vascular smooth muscle cells

Special Issue Information

Dear Colleagues,

Vitamin K comprises a group of highly lipophilic molecules that posses a common 2-methyl-1, 4-naphthoquinone nucleus and a variable polyisoprenoid side chain at the 3-position that can vary in both length and degree of saturation.  In nature these forms are found as a single plant form (phylloquinone or vitamin K1) and a series of bacterial forms (menaquinones or vitamin K2).  Vitamin K acts as a cofactor for a microsomal enzyme, γ-carboxyglutamyl carboxylase (GGCX) that serves to transform specific peptide-bound glutamate residues found in certain specialized proteins to γ-carboxyglutamate (Gla).  This posttranslational protein modification is the only firmly established biochemical function of vitamin K.  The resultant vitamin K-dependent (VKD) proteins, or Gla proteins, are diverse in both structure and function and are found in many cell and tissue types.  The best known example of the health role of vitamin K-mediated protein γ-carboxylation is in the synthesis of several VKD blood coagulation proteins, which are essential for the maintenance of extracellular haemostasis.  An overt deficiency of vitamin K results in bleeding and although rare in most populations, vitamin K deficiency bleeding (VKDB) in early infancy has potentially devastating and fatal consequences because bleeding commonly occurs within the brain.  For this reason it is recommended that all newborn infants should receive vitamin K prophylaxis.  On the other hand, the deliberate lowering of circulating VKD-coagulation factors by the therapeutic administration of vitamin K antagonists (VKA) such as warfarin is used to treat and prevent thrombotic disorders.  The functions of most non-coagulation Gla proteins remain uncertain, but are suspected to play roles in processes as diverse as bone and cardiovascular mineralization, vascular integrity, energy metabolism, immune response, brain metabolism, and in cellular growth, survival, and signalling.  For the most part, extrapolations of the cellular properties of extrahepatic Gla proteins to tangible health benefits are unclear or fuzzy as are the health consequences of their undercarboxylation.  However, there is evidence that higher nutritional intakes of vitamin K are required to enable maximal γ-carboxylation of certain extrahepatic Gla proteins such as osteocalcin and matrix Gla protein (MGP).  Osteocalcin and MGP currently represent the best studied extrahepatic Gla proteins with respect to their putative roles in bone and cardiovascular health respectively.  In addition, osteocalcin may play a role in regulating energy metabolism.  Much current interest focuses on the role of MGP as an inhibitor of vascular mineralization particularly in renal disease and in patients taking VKA.  Interestingly, although VKA have been in clinical use for decades, recent evidence suggests that they may cause unintended health consequences by disrupting the function of MGP resulting in calcification and loss of functional integrity of the vessel wall.  Apart from the role of vitamin K in γ-carboxylation there is evidence that some forms, particularly menaquinone-4 (MK-4), have a direct influence on cellular functions.

This Special Issue of Nutrients focuses on advances that extend our knowledge of the biochemical functions and health roles played by both the micronutrient vitamin K and its target Gla proteins.  The scope of potential topics is wide and may include studies in population and patient groups, animal models and at the cellular level.  Examples include the presentation, diagnosis, incidence, causes, and prevention of deficiency syndromes of which the most obvious is bleeding in infancy but also extend to other putative roles of vitamin K such as in bone and cardiovascular health.  In trying to define extrahepatic functions of vitamin K it is important to obtain evidence of pathophysiological signatures that may derive from chronic suboptimal vitamin K intakes or as a consequence of vitamin K antagonists.  An important related question is whether the pathophysiology can be ameliorated or prevented by judicious vitamin K supplementation.  Equally important to our understanding of the human physiology of vitamin K are studies that define the relative functional importance of individual vitamers and how differences in their availability and metabolism affect their biological activity.  Recent highlights in metabolism include the delineation of the importance of vitamin K epoxide reductase (VKOR) to maintaining vitamin K status and the intriguing hypothesis that its paralog VKOR-like 1 enzyme (VKORL1) may serve an antioxidant function.  Another highlight illustrating the importance of metabolism to vitamin K function is the discovery that the enzyme UbiA prenyltransferase-containing domain 1 (UBIAD1) participates in the cellular conversion of phylloquinone to MK-4 with menadione as a metabolic intermediate.  We invite authors to submit reviews or original research on any of the above topics.

Dr. Martin J. Shearer
Dr. Leon J. Schurgers
Guest Editors

Manuscript Submission Information

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Keywords

  • phylloquinone
  • menaquinones
  • γ-carboxyglutamyl carboxylase (GGCX)
  • vitamin K-dependent (Gla) proteins
  • vitamin K nutrition
  • assessment of vitamin K status
  • vitamin K deficiency bleeding (VKDB) of early infancy
  • metabolism and cell biology of vitamin K
  • role of vitamin K in human health and disease
  • vitamin K, Gla proteins and bone health
  • vitamin K, Gla-proteins and cardiovascular calcification
  • vitamin K and management of oral vitamin K antagonists
  • vitamin K epoxide reductase and vitamin K epoxide reductase-like 1
  • UbiA prenyltransferase-containing domain 1

Published Papers (11 papers)

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Research

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Open AccessArticle
Phylloquinone and Menaquinone-4 Tissue Distribution at Different Life Stages in Male and Female Sprague–Dawley Rats Fed Different VK Levels Since Weaning or Subjected to a 40% Calorie Restriction since Adulthood
Nutrients 2016, 8(3), 141; https://doi.org/10.3390/nu8030141
Received: 22 December 2015 / Revised: 13 February 2016 / Accepted: 19 February 2016 / Published: 4 March 2016
Cited by 5 | PDF Full-text (1679 KB) | HTML Full-text | XML Full-text
Abstract
Whether through the vitamin K-dependent proteins or the individual K vitamers, vitamin K (VK) is associated with a number of age-related conditions (e.g., osteoporosis, atherosclerosis, insulin resistance, cognitive decline). In light of this, we investigated the influence of lifetime dietary VK exposure on [...] Read more.
Whether through the vitamin K-dependent proteins or the individual K vitamers, vitamin K (VK) is associated with a number of age-related conditions (e.g., osteoporosis, atherosclerosis, insulin resistance, cognitive decline). In light of this, we investigated the influence of lifetime dietary VK exposure on the tissue distribution of phylloquinone (K1) and menaquinone-4 (MK-4) vitamers in 3-, 12- and 22-month-old male and female rats fed different K1 diets since weaning or subjected to a 40% calorie restricted diet (CR) since adulthood. Dietary K1 intakes around the minimal amount required for normal blood coagulation had no significant influence on body weights of both male and female rats at different life stages. Tissue contents of the K vitamers differed according to organs, were generally higher in females than in males, and increased with K1 intake. The MK-4/total VK ratios tended to be increased in old age possibly reflecting an increased physiological demand for MK-4 during aging. Our study also confirmed the greater susceptibility of male rats to low VK containing diet, notably at a younger age. Despite lifelong higher K1 intakes per unit body weight, tissue K1 and MK-4 contents at 20 months were generally lower in CR rats compared to their ad libitum (AL) counterparts. Whether the lower tissue MK-4 content is the result of lower synthesis from K1 or greater tissue utilization remains to be determined. However, the more youthful coagulation profile observed in old CR rats (vs. AL rats) tends to support the notion that CR is associated with greater utilization of the K vitamers to sustain physiological functions. Full article
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Open AccessArticle
Menaquinone-7 Supplementation to Reduce Vascular Calcification in Patients with Coronary Artery Disease: Rationale and Study Protocol (VitaK-CAC Trial)
Nutrients 2015, 7(11), 8905-8915; https://doi.org/10.3390/nu7115443
Received: 5 August 2015 / Revised: 8 October 2015 / Accepted: 10 October 2015 / Published: 28 October 2015
Cited by 19 | PDF Full-text (363 KB) | HTML Full-text | XML Full-text
Abstract
Coronary artery calcification (CAC) develops early in the pathogenesis of atherosclerosis and is a strong and independent predictor of cardiovascular disease (CVD). Arterial calcification is caused by an imbalance in calcification regulatory mechanisms. An important inhibitor of calcification is vitamin K-dependent matrix Gla [...] Read more.
Coronary artery calcification (CAC) develops early in the pathogenesis of atherosclerosis and is a strong and independent predictor of cardiovascular disease (CVD). Arterial calcification is caused by an imbalance in calcification regulatory mechanisms. An important inhibitor of calcification is vitamin K-dependent matrix Gla protein (MGP). Both preclinical and clinical studies have shown that inhibition of the vitamin K-cycle by vitamin K antagonists (VKA) results in elevated uncarboxylated MGP (ucMGP) and subsequently in extensive arterial calcification. This led us to hypothesize that vitamin K supplementation may slow down the progression of calcification. To test this, we designed the VitaK-CAC trial which analyses effects of menaquinone-7 (MK-7) supplementation on progression of CAC. The trial is a double-blind, randomized, placebo-controlled trial including patients with coronary artery disease (CAD). Patients with a baseline Agatston CAC-score between 50 and 400 will be randomized to an intervention-group (360 microgram MK-7) or a placebo group. Treatment duration will be 24 months. The primary endpoint is the difference in CAC-score progression between both groups. Secondary endpoints include changes in arterial structure and function, and associations with biomarkers. We hypothesize that treatment with MK-7 will slow down or arrest the progression of CAC and that this trial may lead to a treatment option for vascular calcification and subsequent CVD. Full article
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Open AccessArticle
Prevalence and Predictors of Functional Vitamin K Insufficiency in Mothers and Newborns in Uganda
Nutrients 2015, 7(10), 8545-8552; https://doi.org/10.3390/nu7105408
Received: 10 July 2015 / Accepted: 28 September 2015 / Published: 16 October 2015
Cited by 4 | PDF Full-text (201 KB) | HTML Full-text | XML Full-text
Abstract
Vitamin K deficiency bleeding (VKDB) in infancy is a serious but preventable cause of mortality or permanent disability. Lack of epidemiologic data for VKDB in sub-Saharan Africa hinders development and implementation of effective prevention strategies. We used convenience sampling to consecutively enroll mothers [...] Read more.
Vitamin K deficiency bleeding (VKDB) in infancy is a serious but preventable cause of mortality or permanent disability. Lack of epidemiologic data for VKDB in sub-Saharan Africa hinders development and implementation of effective prevention strategies. We used convenience sampling to consecutively enroll mothers delivering in a southwestern Uganda Hospital. We collected socio-demographic and dietary information, and paired samples of maternal venous and neonatal cord blood for the immunoassay of undercarboxylated prothrombin (PIVKA-II), a sensitive marker of functional vitamin K (VK) insufficiency. We used univariable and multivariable logistic regression models to identify predictors of VK insufficiency. We detected PIVKA-II of ≥0.2 AU (Arbitrary Units per mL)/mL (indicative of VK insufficiency) in 33.3% (47/141) of mothers and 66% (93/141) of newborns. Importantly, 22% of babies had PIVKA-II concentrations ≥5.0 AU/mL, likely to be associated with abnormal coagulation indices. We found no significant predictors of newborn VK insufficiency, including infant weight (AOR (adjusted odds ratio) 1.85, 95% CI (confidence interval) 0.15–22.49), gender (AOR 0.54, 95% CI 0.26–1.11), term birth (AOR 0.72, 95% CI 0.20–2.62), maternal VK-rich diet (AOR 1.13, 95% CI 0.55–2.35) or maternal VK insufficiency (AOR 0.99, 95% CI 0.47–2.10). VK insufficiency is common among mothers and newborn babies in southwestern Uganda, which in one fifth of babies nears overt deficiency. Lack of identifiable predictors of newborn VK insufficiency support strategies for universal VK prophylaxis to newborns to prevent VKDB. Full article
Open AccessArticle
Total and Differential Phylloquinone (Vitamin K1) Intakes of Preterm Infants from All Sources during the Neonatal Period
Nutrients 2015, 7(10), 8308-8320; https://doi.org/10.3390/nu7105393
Received: 26 July 2015 / Revised: 2 September 2015 / Accepted: 16 September 2015 / Published: 25 September 2015
Cited by 3 | PDF Full-text (231 KB) | HTML Full-text | XML Full-text
Abstract
All newborns require phylloquinone after birth to prevent vitamin K deficiency bleeding. Babies born prematurely may be at particular risk of deficiency without adequate supplementation during infancy. The main sources of phylloquinone in preterm babies during the neonatal period are the prophylactic dose [...] Read more.
All newborns require phylloquinone after birth to prevent vitamin K deficiency bleeding. Babies born prematurely may be at particular risk of deficiency without adequate supplementation during infancy. The main sources of phylloquinone in preterm babies during the neonatal period are the prophylactic dose of phylloquinone given at birth, and that derived from parenteral and/or enteral feeding. This observational study formed part of a prospective, multicentre, randomised, controlled trial that examined the vitamin K status of preterm infants after random allocation to one of three phylloquinone prophylactic regimens at birth (0.5 or 0.2 mg intramuscularly or 0.2 mg intravenously). In this nutritional sub-study we quantified the proportional and total phylloquinone intakes of preterm infants within the neonatal period from all sources. Almost all infants had average daily phylloquinone intakes that were in excess of the currently recommended amounts. In infants who did not receive parenteral nutrition, the bolus dose of phylloquinone given at birth was the major source of phylloquinone intake, whereas in infants who received parenteral nutrition, the intake from the parenteral preparation exceeded that from the bolus dose by a ratio of approximately 3:1. Our study supports the concern of others that preterm infants who receive current parenteral nutrition formulations may be receiving excessive vitamin K. Full article
Open AccessArticle
High-Dose Menaquinone-7 Supplementation Reduces Cardiovascular Calcification in a Murine Model of Extraosseous Calcification
Nutrients 2015, 7(8), 6991-7011; https://doi.org/10.3390/nu7085318
Received: 15 May 2015 / Revised: 30 July 2015 / Accepted: 6 August 2015 / Published: 18 August 2015
Cited by 15 | PDF Full-text (909 KB) | HTML Full-text | XML Full-text
Abstract
Cardiovascular calcification is prevalent in the aging population and in patients with chronic kidney disease (CKD) and diabetes mellitus, giving rise to substantial morbidity and mortality. Vitamin K-dependent matrix Gla-protein (MGP) is an important inhibitor of calcification. The aim of this study was [...] Read more.
Cardiovascular calcification is prevalent in the aging population and in patients with chronic kidney disease (CKD) and diabetes mellitus, giving rise to substantial morbidity and mortality. Vitamin K-dependent matrix Gla-protein (MGP) is an important inhibitor of calcification. The aim of this study was to evaluate the impact of high-dose menaquinone-7 (MK-7) supplementation (100 µg/g diet) on the development of extraosseous calcification in a murine model. Calcification was induced by 5/6 nephrectomy combined with high phosphate diet in rats. Sham operated animals served as controls. Animals received high or low MK-7 diets for 12 weeks. We assessed vital parameters, serum chemistry, creatinine clearance, and cardiac function. CKD provoked increased aortic (1.3 fold; p < 0.05) and myocardial (2.4 fold; p < 0.05) calcification in line with increased alkaline phosphatase levels (2.2 fold; p < 0.01). MK-7 supplementation inhibited cardiovascular calcification and decreased aortic alkaline phosphatase tissue concentrations. Furthermore, MK-7 supplementation increased aortic MGP messenger ribonucleic acid (mRNA) expression (10-fold; p < 0.05). CKD-induced arterial hypertension with secondary myocardial hypertrophy and increased elastic fiber breaking points in the arterial tunica media did not change with MK-7 supplementation. Our results show that high-dose MK-7 supplementation inhibits the development of cardiovascular calcification. The protective effect of MK-7 may be related to the inhibition of secondary mineralization of damaged vascular structures. Full article
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Open AccessArticle
Dietary Vitamin K Intake Is Associated with Cognition and Behaviour among Geriatric Patients: The CLIP Study
Nutrients 2015, 7(8), 6739-6750; https://doi.org/10.3390/nu7085306
Received: 15 June 2015 / Revised: 16 July 2015 / Accepted: 24 July 2015 / Published: 12 August 2015
Cited by 8 | PDF Full-text (236 KB) | HTML Full-text | XML Full-text
Abstract
Our objective was to determine whether dietary vitamin K intake was associated with cognition and behavior among older adults. 192 consecutive participants ≥65 years, recruited in the cross-sectional CLIP (Cognition and LIPophilic vitamins) study, were separated into two groups according to the tertiles [...] Read more.
Our objective was to determine whether dietary vitamin K intake was associated with cognition and behavior among older adults. 192 consecutive participants ≥65 years, recruited in the cross-sectional CLIP (Cognition and LIPophilic vitamins) study, were separated into two groups according to the tertiles of dietary phylloquinone intake (i.e., lowest third below 207 µg/day versus the other two thirds combined). Daily dietary phylloquinone intake was estimated from 50-item interviewer-administered food frequency questionnaire. Cognition was assessed with Mini-Mental State Examination (MMSE); behaviour with Frontotemporal Behavioral Rating Scale (FBRS). Age, gender, social problems, education, body mass index (BMI), comorbidities, history of stroke, use vitamin K antagonists, inadequate fatty fish intake, serum thyroid-stimulating hormone (TSH), vitamin B12, albumin, and estimated glomerular filtration rate were used as confounders. Compared to participants in the lowest third of dietary phylloquinone intake (n = 64), those with higher intake had higher (i.e., better) mean MMSE score (22.0 ± 5.7 versus 19.9 ± 6.2, p = 0.024) and lower (i.e., better) FBRS score (1.5 ± 1.2 versus 1.9 ± 1.3, p = 0.042). In multivariate linear regressions, log dietary phylloquinone intake was positively associated with MMSE score (adjusted β = 1.66, p = 0.013) and inversely associated with FBRS score (adjusted β = −0.33, p = 0.037). Specifically, log dietary phylloquinone intake correlated negatively with FBRS subscore of physical neglect (r = −0.24, p = 0.001). Higher dietary phylloquinone intake was associated with better cognition and behavior among older adults. Full article
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Open AccessArticle
Phylogeny of the Vitamin K 2,3-Epoxide Reductase (VKOR) Family and Evolutionary Relationship to the Disulfide Bond Formation Protein B (DsbB) Family
Nutrients 2015, 7(8), 6224-6249; https://doi.org/10.3390/nu7085281
Received: 18 May 2015 / Revised: 25 June 2015 / Accepted: 9 July 2015 / Published: 29 July 2015
Cited by 4 | PDF Full-text (1555 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
In humans and other vertebrate animals, vitamin K 2,3-epoxide reductase (VKOR) family enzymes are the gatekeepers between nutritionally acquired K vitamins and the vitamin K cycle responsible for posttranslational modifications that confer biological activity upon vitamin K-dependent proteins with crucial roles in hemostasis, [...] Read more.
In humans and other vertebrate animals, vitamin K 2,3-epoxide reductase (VKOR) family enzymes are the gatekeepers between nutritionally acquired K vitamins and the vitamin K cycle responsible for posttranslational modifications that confer biological activity upon vitamin K-dependent proteins with crucial roles in hemostasis, bone development and homeostasis, hormonal carbohydrate regulation and fertility. We report a phylogenetic analysis of the VKOR family that identifies five major clades. Combined phylogenetic and site-specific conservation analyses point to clade-specific similarities and differences in structure and function. We discovered a single-site determinant uniquely identifying VKOR homologs belonging to human pathogenic, obligate intracellular prokaryotes and protists. Building on previous work by Sevier et al. (Protein Science 14:1630), we analyzed structural data from both VKOR and prokaryotic disulfide bond formation protein B (DsbB) families and hypothesize an ancient evolutionary relationship between the two families where one family arose from the other through a gene duplication/deletion event. This has resulted in circular permutation of primary sequence threading through the four-helical bundle protein folds of both families. This is the first report of circular permutation relating distant a-helical membrane protein sequences and folds. In conclusion, we suggest a chronology for the evolution of the five extant VKOR clades. Full article
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Review

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Open AccessReview
Concepts and Controversies in Evaluating Vitamin K Status in Population-Based Studies
Nutrients 2016, 8(1), 8; https://doi.org/10.3390/nu8010008
Received: 25 September 2015 / Revised: 4 December 2015 / Accepted: 9 December 2015 / Published: 2 January 2016
Cited by 29 | PDF Full-text (2994 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
A better understanding of vitamin K’s role in health and disease requires the assessment of vitamin K nutritional status in population and clinical studies. This is primarily accomplished using dietary questionnaires and/or biomarkers. Because food composition databases in the US are most complete [...] Read more.
A better understanding of vitamin K’s role in health and disease requires the assessment of vitamin K nutritional status in population and clinical studies. This is primarily accomplished using dietary questionnaires and/or biomarkers. Because food composition databases in the US are most complete for phylloquinone (vitamin K1, the primary form in Western diets), emphasis has been on phylloquinone intakes and associations with chronic diseases. There is growing interest in menaquinone (vitamin K2) intakes for which the food composition databases need to be expanded. Phylloquinone is commonly measured in circulation, has robust quality control schemes and changes in response to phylloquinone intake. Conversely, menaquinones are generally not detected in circulation unless large quantities are consumed. The undercarboxylated fractions of three vitamin K-dependent proteins are measurable in circulation, change in response to vitamin K supplementation and are modestly correlated. Since different vitamin K dependent proteins are implicated in different diseases the appropriate vitamin K-dependent protein biomarker depends on the outcome under study. In contrast to other nutrients, there is no single biomarker that is considered a gold-standard measure of vitamin K status. Most studies have limited volume of specimens. Strategic decisions, guided by the research question, need to be made when deciding on choice of biomarkers. Full article
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Open AccessReview
New Insights into the Pros and Cons of the Clinical Use of Vitamin K Antagonists (VKAs) Versus Direct Oral Anticoagulants (DOACs)
Nutrients 2015, 7(11), 9538-9557; https://doi.org/10.3390/nu7115479
Received: 15 May 2015 / Revised: 28 October 2015 / Accepted: 5 November 2015 / Published: 17 November 2015
Cited by 12 | PDF Full-text (1560 KB) | HTML Full-text | XML Full-text
Abstract
Vitamin K-antagonists (VKA) are the most widely used anticoagulant drugs to treat patients at risk of arterial and venous thrombosis for the past 50 years. Due to unfavorable pharmacokinetics VKA have a small therapeutic window, require frequent monitoring, and are susceptible to drug [...] Read more.
Vitamin K-antagonists (VKA) are the most widely used anticoagulant drugs to treat patients at risk of arterial and venous thrombosis for the past 50 years. Due to unfavorable pharmacokinetics VKA have a small therapeutic window, require frequent monitoring, and are susceptible to drug and nutritional interactions. Additionally, the effect of VKA is not limited to coagulation, but affects all vitamin K-dependent proteins. As a consequence, VKA have detrimental side effects by enhancing medial and intimal calcification. These limitations stimulated the development of alternative anticoagulant drugs, resulting in direct oral anticoagulant (DOAC) drugs, which specifically target coagulation factor Xa and thrombin. DOACs also display non-hemostatic vascular effects via protease-activated receptors (PARs). As atherosclerosis is characterized by a hypercoagulable state indicating the involvement of activated coagulation factors in the genesis of atherosclerosis, anticoagulation could have beneficial effects on atherosclerosis. Additionally, accumulating evidence demonstrates vascular benefit from high vitamin K intake. This review gives an update on oral anticoagulant treatment on the vasculature with a special focus on calcification and vitamin K interaction. Full article
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Open AccessReview
Structural Modeling Insights into Human VKORC1 Phenotypes
Nutrients 2015, 7(8), 6837-6851; https://doi.org/10.3390/nu7085313
Received: 20 May 2015 / Revised: 3 August 2015 / Accepted: 6 August 2015 / Published: 14 August 2015
Cited by 7 | PDF Full-text (287 KB) | HTML Full-text | XML Full-text
Abstract
Vitamin K 2,3-epoxide reductase complex subunit 1 (VKORC1) catalyses the reduction of vitamin K and its 2,3-epoxide essential to sustain γ-carboxylation of vitamin K-dependent proteins. Two different phenotypes are associated with mutations in human VKORC1. The majority of mutations cause resistance to 4-hydroxycoumarin- [...] Read more.
Vitamin K 2,3-epoxide reductase complex subunit 1 (VKORC1) catalyses the reduction of vitamin K and its 2,3-epoxide essential to sustain γ-carboxylation of vitamin K-dependent proteins. Two different phenotypes are associated with mutations in human VKORC1. The majority of mutations cause resistance to 4-hydroxycoumarin- and indandione-based vitamin K antagonists (VKA) used in the prevention and therapy of thromboembolism. Patients with these mutations require greater doses of VKA for stable anticoagulation than patients without mutations. The second phenotype, a very rare autosomal-recessive bleeding disorder caused by combined deficiency of vitamin K dependent clotting factors type 2 (VKCFD2) arises from a homozygous Arg98Trp mutation. The bleeding phenotype can be corrected by vitamin K administration. Here, we summarize published experimental data and in silico modeling results in order to rationalize the mechanisms of VKA resistance and VKCFD2. Full article
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Open AccessReview
VKORC1 and VKORC1L1: Why do Vertebrates Have Two Vitamin K 2,3-Epoxide Reductases?
Nutrients 2015, 7(8), 6250-6280; https://doi.org/10.3390/nu7085280
Received: 18 May 2015 / Revised: 8 July 2015 / Accepted: 15 July 2015 / Published: 30 July 2015
Cited by 7 | PDF Full-text (726 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Among all cellular life on earth, with the exception of yeasts, fungi, and some prokaryotes, VKOR family homologs are ubiquitously encoded in nuclear genomes, suggesting ancient and important biological roles for these enzymes. Despite single gene and whole genome duplications on the largest [...] Read more.
Among all cellular life on earth, with the exception of yeasts, fungi, and some prokaryotes, VKOR family homologs are ubiquitously encoded in nuclear genomes, suggesting ancient and important biological roles for these enzymes. Despite single gene and whole genome duplications on the largest evolutionary timescales, and the fact that most gene duplications eventually result in loss of one copy, it is surprising that all jawed vertebrates (gnathostomes) have retained two paralogous VKOR genes. Both VKOR paralogs function as entry points for nutritionally acquired and recycled K vitamers in the vitamin K cycle. Here we present phylogenetic evidence that the human paralogs likely arose earlier than gnathostomes, possibly in the ancestor of crown chordates. We ask why gnathostomes have maintained these paralogs throughout evolution and present a current summary of what we know. In particular, we look to published studies about tissue- and developmental stage-specific expression, enzymatic function, phylogeny, biological roles and associated pathways that together suggest subfunctionalization as a major influence in evolutionary fixation of both paralogs. Additionally, we investigate on what evolutionary timescale the paralogs arose and under what circumstances in order to gain insight into the biological raison d’être for both VKOR paralogs in gnathostomes. Full article
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