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The Journal of Physical Chemistry. B May 2021Halobacteria, a type of archaea in high salt environments, have phytanyl ether phospholipid membranes containing up to 50% menaquinone. It is not understood why a high...
Halobacteria, a type of archaea in high salt environments, have phytanyl ether phospholipid membranes containing up to 50% menaquinone. It is not understood why a high concentration of menaquinone is required and how it influences membrane properties. In this study, menaquinone-8 headgroup and torsion parameters of isoprenoid tail are optimized in the CHARMM36 force field. Molecular dynamics simulations of archaeal bilayers containing 0 to 50% menaquinone characterize the distribution of menaquinone-8 and menaquinol-8, as well as their effects on mechanical properties and permeability. Menaquinone-8 segregates to the membrane midplane above concentrations of 10%, favoring an extended conformation in a fluid state. Menaquinone-8 increases the bilayer thickness but does not significantly alter the area compressibility modulus and lipid chain ordering. Counterintuitively, menaquinone-8 increases water permeability because it lowers the free energy barrier in the midplane. The thickness increase due to menaquinone-8 may help halobacteria ameliorate hyper-osmotic pressure by increasing the membrane bending constant. Simulations of the archaeal membranes with archaerhodopsin-3 show that the local membrane surface adjusts to accommodate the thick membranes. Overall, this study delineates the biophysical landscape of 50% menaquinone in the archaeal bilayer, demonstrates the mixing of menaquinone and menaquinol, and provides atomistic details about menaquinone configurations.
Topics: Archaea; Lipid Bilayers; Molecular Conformation; Molecular Dynamics Simulation; Vitamin K 2
PubMed: 33913729
DOI: 10.1021/acs.jpcb.1c01930 -
Blood Jun 2018Warfarin, an anticoagulant therapy used by millions worldwide, inhibits vitamin K epoxide reductase complex subunit 1 (VKORC1), thereby dampening the carboxylation and...
Warfarin, an anticoagulant therapy used by millions worldwide, inhibits vitamin K epoxide reductase complex subunit 1 (VKORC1), thereby dampening the carboxylation and the procoagulant potential of vitamin K–dependent coagulation factors. However, the detailed molecular mechanism by which warfarin inhibits VKORC1 remains the subject of debate. In this issue of , Rishavy et al puts this issue to rest by demonstrating that warfarin inhibits VKORC1 via a mechanism termed “the uncoupling of VKORC1.” The uncoupling of VKORC1 is significant because it highlights a potential cooperation of VKORC1 with a second warfarin-resistant vitamin K quinone reductase, thereby explaining how considerable carboxylation can proceed despite the presence of warfarin, and this may have direct implications for warfarin dosing in patients.
Topics: Fetal Death; Humans; Oxidoreductases; Vitamin K; Vitamin K Epoxide Reductases; Warfarin
PubMed: 29930151
DOI: 10.1182/blood-2018-05-843151 -
Archives of Disease in Childhood May 1987
Topics: Drug Administration Schedule; Humans; Infant, Newborn; Vitamin K; Vitamin K Deficiency Bleeding
PubMed: 3606174
DOI: 10.1136/adc.62.5.436 -
Microbial Cell Factories Apr 2021Vitamin K2 (menaquinone, MK) is an essential lipid-soluble vitamin with critical roles in blood coagulation and bone metabolism. Chemically, the term vitamin K2... (Review)
Review
Vitamin K2 (menaquinone, MK) is an essential lipid-soluble vitamin with critical roles in blood coagulation and bone metabolism. Chemically, the term vitamin K2 encompasses a group of small molecules that contain a common naphthoquinone head group and a polyisoprenyl side chain of variable length. Among them, menaquinone-7 (MK-7) is the most potent form. Here, the biosynthetic pathways of vitamin K2 and different types of MK produced by microorganisms are briefly introduced. Further, we provide a new aspect of MK-7 production, which shares a common naphthoquinone ring and polyisoprene biosynthesis pathway, by analyzing strategies for expanding the product spectrum. We review the findings of metabolic engineering strategies targeting the shikimate pathway, polyisoprene pathway, and menaquinone pathway, as well as membrane engineering, which provide comprehensive insights for enhancing the yield of MK-7. Finally, the current limitations and perspectives of microbial menaquinone production are also discussed. This article provides in-depth information on metabolic engineering strategies for vitamin K2 production by expanding the product spectrum.
Topics: Bacteria; Fermentation; Metabolic Engineering; Vitamin K 2
PubMed: 33849534
DOI: 10.1186/s12934-021-01574-7 -
Advances in Nutrition (Bethesda, Md.) Jun 2021A protective role for vitamin K in cardiovascular disease (CVD), a leading cause of morbidity and mortality, has been proposed because vitamin K-dependent proteins, such... (Review)
Review
A protective role for vitamin K in cardiovascular disease (CVD), a leading cause of morbidity and mortality, has been proposed because vitamin K-dependent proteins, such as matrix Gla (γ-carboxyglutamic acid) protein (MGP), are present in vascular tissue. MGP functions as a vascular calcification inhibitor-but only when it is carboxylated, which requires vitamin K. There is more than one naturally occurring form of vitamin K. Phylloquinone (vitamin K1) is found in plant-based foods, whereas menaquinones (vitamin K2) are a class of vitamin K compounds found in animal-based and fermented foods. Phylloquinone and menaquinones are capable of carboxylating MGP and other vitamin K-dependent proteins. In rodent models, high intakes of either phylloquinone or menaquinone reduced vascular calcification. Evidence of the relative importance of phylloquinone and menaquinone to CVD in humans is limited and controversial. In some observational studies, higher dietary menaquinone intake, but not phylloquinone intake, was associated with less coronary artery calcification (a subclinical manifestation of CVD) and a lower risk for clinical CVD events. These findings have led to claims that menaquinones have unique cardiovascular health benefits compared with phylloquinone. However, this claim is not supported by the results of the limited number of intervention trials conducted to date. The purpose of this review is to evaluate the strengths and limitations of the available evidence regarding the role of vitamin K in vascular calcification, CVD, and mortality.
Topics: Animals; Cardiovascular Diseases; Coronary Artery Disease; Humans; Vitamin K; Vitamin K 1; Vitamin K 2
PubMed: 33684212
DOI: 10.1093/advances/nmab004 -
The Plant Cell Oct 2015Phytol from chlorophyll degradation can be phosphorylated to phytyl-phosphate and phytyl-diphosphate, the substrate for tocopherol (vitamin E) synthesis. A candidate for...
Phytol from chlorophyll degradation can be phosphorylated to phytyl-phosphate and phytyl-diphosphate, the substrate for tocopherol (vitamin E) synthesis. A candidate for the phytyl-phosphate kinase from Arabidopsis thaliana (At1g78620) was identified via a phylogeny-based approach. This gene was designated VITAMIN E DEFICIENT6 (VTE6) because the leaves of the Arabidopsis vte6 mutants are tocopherol deficient. The vte6 mutant plants are incapable of photoautotrophic growth. Phytol and phytyl-phosphate accumulate, and the phytyl-diphosphate content is strongly decreased in vte6 leaves. Phytol feeding and enzyme assays with Arabidopsis and recombinant Escherichia coli cells demonstrated that VTE6 has phytyl-P kinase activity. Overexpression of VTE6 resulted in increased phytyl-diphosphate and tocopherol contents in seeds, indicating that VTE6 encodes phytyl-phosphate kinase. The severe growth retardation of vte6 mutants was partially rescued by introducing the phytol kinase mutation vte5. Double mutant plants (vte5 vte6) are tocopherol deficient and contain more chlorophyll, but reduced amounts of phytol and phytyl-phosphate compared with vte6 mutants, suggesting that phytol or phytyl-phosphate are detrimental to plant growth. Therefore, VTE6 represents the missing phytyl-phosphate kinase, linking phytol release from chlorophyll with tocopherol synthesis. Moreover, tocopherol synthesis in leaves depends on phytol derived from chlorophyll, not on de novo synthesis of phytyl-diphosphate from geranylgeranyl-diphosphate.
Topics: Arabidopsis; Arabidopsis Proteins; Biological Transport; Biosynthetic Pathways; Chlorophyll; Diphosphates; Mutation; Phosphorylation; Phosphotransferases; Phylogeny; Phytol; Plant Leaves; Seeds; Tocopherols
PubMed: 26452599
DOI: 10.1105/tpc.15.00395 -
Biomedicine & Pharmacotherapy =... Jan 2022Oxidative stress is considered the main cause of cellular damage in a number of neurodegenerative disorders. One suitable ways to prevent cell damage is the use of the...
Oxidative stress is considered the main cause of cellular damage in a number of neurodegenerative disorders. One suitable ways to prevent cell damage is the use of the exogenous antioxidant capacity of natural products, such as microalgae. In the present study, four microalgae extracts, isolated from the Persian Gulf, were screened to analyze their potential antioxidant activity and free radical scavenging using ABTS, DPPH, and FRAP methods. The methanolic extracts (D1M) of green microalgae derived from Chlorella sp. exhibited potent free radical scavenging activity. In order to characterize microalgae species, microscopic observations and analysis of the expression of 18S rRNA were performed. The antioxidant and neuroprotective effects of D1M on HO-induced toxicity in PC12 cells were investigated. The results demonstrated that D1M significantly decreased the release of nitric oxide (NO), formation of intracellular reactive oxygen species (ROS), and the level of malondialdehyde (MDA), whereas it enhanced the content of glutathione (GSH), and activity of heme oxygenase 1 (HO-1), NAD(P)H: quinone oxidoreductase 1 (NQO1), and catalase (CAT) in PC12 cells exposed to HO. The pretreatment of D1M improved cell viability as measured by the MTT assay and invert microscopy, reduced cell apoptosis as examined by flow cytometry analysis, increased mitochondrial membrane potential (MMP), and diminished caspase-3 activity. The GC/MS analysis revealed that D1M ingredients have powerful antioxidant and anti-inflammatory compounds, such as butylated hydroxytoluene (BHT), 2,4-di-tert-butyl-phenol (2,4-DTBP), and phytol. These results suggested that Chlorella sp. extracts have strong potential to be applied as neuroprotective agents, for the treatment of neurodegenerative disorders.
Topics: Animals; Antioxidants; Apoptosis; Butylated Hydroxytoluene; Cell Survival; Chlorella; Free Radical Scavengers; Hydrogen Peroxide; Membrane Potential, Mitochondrial; Neurodegenerative Diseases; Neuroprotective Agents; Oxidative Stress; PC12 Cells; Phenols; Phytol; Rats; Reactive Oxygen Species
PubMed: 34775236
DOI: 10.1016/j.biopha.2021.112415 -
BMC Cancer Sep 2023Abelson (ABL) tyrosine kinase inhibitors (TKIs) are effective against chronic myeloid leukemia (CML); however, many patients develop resistance during ABL TKI therapy....
BACKGROUND
Abelson (ABL) tyrosine kinase inhibitors (TKIs) are effective against chronic myeloid leukemia (CML); however, many patients develop resistance during ABL TKI therapy. Vitamin K2 (VK2) is a crucial fat-soluble vitamin used to activate hepatic coagulation factors and treat osteoporosis. Although VK2 has demonstrated impressive anticancer activity in various cancer cell lines, it is not known whether VK2 enhances the effects of asciminib, which specifically targets the ABL myristoyl pocket (STAMP) inhibitor.
METHOD
In this work, we investigated whether VK2 contributed to the development of CML cell lines. We also investigated the efficacy of asciminib and VK2 by using K562, ponatinib-resistant K562 (K562 PR), Ba/F3 BCR-ABL, and T315I point mutant Ba/F3 (Ba/F3 T315I) cells.
RESULTS
Based on data from the Gene Expression Omnibus (GEO) database, gamma-glutamyl carboxylase (GGCX) and vitamin K epoxide reductase complex subunit 1 (VKORC1) were elevated in imatinib-resistant patients (GSE130404). UBIA Prenyltransferase Domain Containing 1 (UBIAD1) was decreased, and K562 PR cells were resistant to ponatinib. In contrast, asciminib inhibited CML cells and ponatinib resistance in a dose-dependent manner. CML cells were suppressed by VK2. Caspase 3/7 activity was also elevated, as was cellular cytotoxicity. Asciminib plus VK2 therapy induced a significantly higher level of cytotoxicity than use of each drug alone. Asciminib and VK2 therapy altered the mitochondrial membrane potential.
CONCLUSIONS
Asciminib and VK2 are suggested as a novel treatment for ABL-TKI-resistant cells since they increase treatment efficacy. Additionally, this treatment option has intriguing clinical relevance for patients who are resistant to ABL TKIs.
Topics: Humans; Vitamin K 2; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Protein Kinase Inhibitors; Tyrosine; Vitamin K Epoxide Reductases
PubMed: 37670241
DOI: 10.1186/s12885-023-11304-4 -
Frontiers in Cellular and Infection... 2022Malaria is one of the most widespread parasitic diseases, especially in Africa, Southeast Asia and South America. One of the greatest problems for control of the disease...
Malaria is one of the most widespread parasitic diseases, especially in Africa, Southeast Asia and South America. One of the greatest problems for control of the disease is the emergence of drug resistance, which leads to a need for the development of new antimalarial compounds. The biosynthesis of isoprenoids has been investigated as part of a strategy to identify new targets to obtain new antimalarial drugs. Several isoprenoid quinones, including menaquinone-4 (MK-4/vitamin K2), α- and γ-tocopherol and ubiquinone (UQ) homologs UQ-8 and UQ-9, were previously detected in cultures of in asexual stages. Herein, we described for the first time the presence of phylloquinone (PK/vitamin K1) in and discuss the possible origins of this prenylquinone. While our results in metabolic labeling experiments suggest a biosynthesis of PK prenylation phytyl pyrophosphate (phytyl-PP) with phytol being phosphorylated, on the other hand, exogenous PK attenuated atovaquone effects on parasitic growth and respiration, showing that this metabolite can be transported from extracellular environment and that the mitochondrial electron transport system (ETS) of is capable to interact with PK. Although the natural role and origin of PK remains elusive, this work highlights the PK importance in plasmodial metabolism and future studies will be important to elucidate in seeking new targets for antimalarial drugs.
Topics: Antimalarials; Humans; Malaria; Malaria, Falciparum; Plasmodium falciparum; Vitamin K 1
PubMed: 35531326
DOI: 10.3389/fcimb.2022.869085 -
Lancet (London, England) Mar 2020
Topics: Anticoagulants; Atrial Fibrillation; Fibrinolytic Agents; Humans; Percutaneous Coronary Intervention; Pyridines; Thiazoles; Vitamin K
PubMed: 32171405
DOI: 10.1016/S0140-6736(20)30031-3