Disease relevance of VITAMIN K1

• The other 631 ADEs were detected from automated signals, the most common of which were diphenhydramine hydrochloride and naloxone hydrochloride use, high serum drug levels, leukopenia, and the use of phytonadione and antidiarrheals [1].
• Recruitment of a foreign quinone into the A(1) site of photosystem I. I. Genetic and physiological characterization of phylloquinone biosynthetic pathway mutants in Synechocystis sp. pcc 6803 [2].
• The affected gene, called PHYLLO, consists of a fusion of four previously individual eubacterial genes, menF, menD, menC, and menH, required for the biosynthesis of phylloquinone in photosynthetic cyanobacteria and the respiratory menaquinone in eubacteria [3].
• Intravenous (IV) phytonadione, while effective, is associated with a small risk of serious anaphylactic reactions [4].
• BACKGROUND: After a first episode of venous thromboembolism, patients are treated with vitamin K (phytonadione) antagonists [5].

High impact information on VITAMIN K1

• Plasma vitamin K1 (phylloquinone) was assayed in normal adults and pregnant women at term and their babies by a method based on high-performance liquid chromatography [6].
• Deficiency in Phylloquinone (Vitamin K1) Methylation Affects Prenyl Quinone Distribution, Photosystem I Abundance, and Anthocyanin Accumulation in the Arabidopsis AtmenG Mutant [7].
• An Arabidopsis mutant, AtmenG, carrying a T-DNA insertion in the gene At1g23360 is devoid of phylloquinone, but contains an increased amount of 2-phytyl-1,4-naphthoquinone [7].
• Phylloquinone is a compound present in all photosynthetic plants serving as cofactor for Photosystem I-mediated electron transport [3].
• Phylloquinone and 2-phytyl-1,4-naphthoquinone in thylakoid membranes of wild type and AtmenG, respectively, predominantly localize to photosystem I, whereas excess amounts of prenyl quinones are stored in plastoglobules [7].

Chemical compound and disease context of VITAMIN K1

• Interruption of the phylloquinone (PhQ) biosynthetic pathway by interposon mutagenesis of the menA and menB genes in Synechocystis sp. PCC 6803 results in plastoquinone-9 (PQ-9) occupying the A(1) site and functioning in electron transfer from A(0) to the FeS clusters in photosystem (PS) I (Johnson, T [8].
• Phylloquinone (vitamin K(1)) is synthesized in cyanobacteria and in chloroplasts of plants, where it serves as electron carrier of photosystem I. The last step of phylloquinone synthesis in cyanobacteria is the methylation of 2-phytyl-1,4-naphthoquinone by the menG gene product [7].
• A patient with celiac disease was seen with a severe bleeding diathesis associated with deficiencies of factor V. The deficiencies of vitamin K-dependent clotting factors were rapidly reversed with parenteral administration of phytonadione [9].
• A mild vitamin K deficiency was induced in 12 healthy adult men and women by dietary restriction of phylloquinone (40 microg/d, days 1-11) and by administration of warfarin (1.0 mg/d, days 5-11) [10].
• Hemorrhagic death, hemorrhage and a decrease in prothrombin index caused by 1.20% BHT were prevented by simultaneously adding phylloquinone (0.68 mumole/kg/day) [11].

Biological context of VITAMIN K1

• Whether these biphasic kinetics reflect unidirectional electron transfer, involving only the PsaA-side phylloquinone or bi-directional electron transfer, involving both the PsaA- and PsaB-side phylloquinones, has been the source of some controversy [12].
• In an effort to identify amino acid residues near the phylloquinone binding sites, all tryptophans and histidines that are conserved between PsaA and PsaB in the region of the 10th and 11th transmembrane alpha-helices were mutated in Chlamydomonas reinhardtii [13].
• METHODS: Twenty-two patients with asymptomatic prolongation of prothrombin time were prospectively randomized and treated with 1 mg of phytonadione IV or 1 mg SC [4].
• OBJECTIVE: The objective of this study was to compare, in younger and older adults, the relative bioavailability of phylloquinone from a vegetable with that of a fortified oil [14].
• RESULTS: There was an increase and subsequent decrease in measures of bone formation (P = 0.002) and resorption (P = 0.08) after dietary phylloquinone restriction and repletion, respectively [15].

Anatomical context of VITAMIN K1

• For the knee, only the PR for osteophytes and the adjusted mean number of knee joints with osteophytes decreased significantly with increasing plasma phylloquinone levels (PR decreased from 1.0 to 0.6, P=0.01) [16].
• The uptake of lipoprotein-borne phylloquinone (vitamin K1) by osteoblasts and osteoblast-like cells: role of heparan sulfate proteoglycans and apolipoprotein E [17].
• Variations of phylloquinone concentration in human milk at various stages of lactation and in cow's milk at various seasons [18].
• Ten nanomoles of phylloquinone injected into the femoral vein on day 3 of feeding 1.2% BHT increased the prothrombin concentration from 28% of normal to 100% of normal within 18 to 24 hours [11].
• MK-9 epoxide, and to a lesser extent MK-9, was preferentially localized in the mitochondria, while higher concentrations of phylloquinone were found in the microsomes [19].

Associations of VITAMIN K1 with other chemical compounds

• Recruitment of a foreign quinone into the A1 site of photosystem I. Altered kinetics of electron transfer in phylloquinone biosynthetic pathway mutants studied by time-resolved optical, EPR, and electrometric techniques [20].
• We estimate the redox potential of plastoquinone-9 in the A(1) site to be more oxidizing than phylloquinone so that electron transfer from Q(-) to F(X) is thermodynamically unfavorable in the menA and menB mutants [20].
• Targeted inactivation of the menA and menB genes, which code for phytyl transferase and 1,4-dihydroxy-2-naphthoate synthase, respectively, prevented the synthesis of phylloquinone, thereby confirming the participation of these two gene products in the biosynthetic pathway [2].
• CONCLUSIONS: For patients who are excessively anticoagulated with warfarin, small doses of SC phytonadione may not correct the INR as rapidly or as effectively as when administered IV [4].
• These results show that undercarboxylated osteocalcin, plasma phylloquinone, and urinary gamma-carboxyglutamic acid excretion appear to be sensitive measures of vitamin K nutritional status because all of these variables were responsive to changes in dietary intake [21].

Gene context of VITAMIN K1

• The menD(-) and menE(-) strains were generated, and both were found to lack phylloquinone [22].
• The menD and menE homologs code for 2-succinyl-6-hydroxyl-2,4-cyclohexadiene-1-carboxylate synthase and O-succinylbenzoic acid-CoA synthase in the phylloquinone biosynthetic pathway of Synechocystis sp. PCC 6803 [22].
• The mutated nuclear gene encoded 1,4-dihydroxy-2-naphtoic acid phytyltransferase, an enzyme of phylloquinone biosynthesis, and high-performance liquid chromatography analysis revealed that the abc4 mutant contained no phylloquinone, and only about 3% plastoquinone [23].
• The directionality of electron transfer in Photosystem I (PS I) is investigated using site-directed mutations in the phylloquinone (QK) and FX binding regions of Synnechocystis sp. PCC 6803 [24].
• Therefore, the loss of phylloquinone methylation affects photosystem I stability or turnover, and the limitation in functional photosystem I complexes results in overreduction of photosystem II under high light [7].

Analytical, diagnostic and therapeutic context of VITAMIN K1

• As demonstrated by radioimmunoassay, selective barium salt adsorption, and two coagulation assays which discriminate between precursor- and mature-prothrombin, these cells retained their ability to synthesize precursor prothrombin (preprothrombin) in the absence of exogenous phylloquinone (vitamin K) [25].
• Sensitive HPLC methods for measuring plasma phylloquinone are now available, and related methods for measuring long-chain menaquinones can be developed [26].
• CONCLUSION: For patients with supratherapeutic international normalized ratio values, our survey suggests that a substantial number of anticoagulation clinics underutilize oral phytonadione [27].
• Oral administration of phytonadione has been shown to be an effective alternative to the intravenous route, but these methods have never been compared directly [28].
• Treatment of excessive anticoagulation with phytonadione (vitamin K): a meta-analysis [29].

References