Phytomenadione

Phytomenadione, also known as vitamin K1 or phylloquinone, is a vitamin found in food and used as a dietary supplement.[1][2] As a supplement it is used to treat certain bleeding disorders.[2] This includes in warfarin overdose, vitamin K deficiency, and obstructive jaundice.[2] It is also recommended to prevent and treat hemorrhagic disease of the newborn.[2] Use is typically recommended by mouth or injection under the skin.[2] Use by injection into a vein or muscle is recommended only when other routes are not possible.[2] When given by injection benefits are seen within two hours.[2]

Phytomenadione
Clinical data
Trade namesMephyton, others
Other namesVitamin K1, phytonadione, phylloquinone, (E)-phytonadione
AHFS/Drugs.comMonograph
Pregnancy
category
  • US: C (Risk not ruled out)
    Routes of
    administration    		by mouth, subQ, IM, IV
    ATC code
    Legal status
    Legal status
    Identifiers
    CAS Number
    PubChem CID
    DrugBank
    ChemSpider
    UNII
    ChEBI
    ChEMBL
    CompTox Dashboard (EPA)
    ECHA InfoCard100.001.422
    Chemical and physical data
    FormulaC31H46O2
    Molar mass450.70 g/mol g·mol−1
    3D model (JSmol)

    Common side effects when given by injection include pain at the site of injection and altered taste.[2] Severe allergic reactions may occur when it is injected into a vein or muscle.[2] It is unclear if use during pregnancy is safe; however, use is likely okay during breastfeeding.[3] It works by supplying a required component for making a number of blood clotting factors.[2] Found sources include green vegetables, vegetable oil, and some fruit.[4]

    Phytomenadione was first isolated in 1939.[5] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[6] The wholesale cost in the developing world is about 0.11 to 1.27 USD for a 10 mg vial.[7] In the United States a course of treatment costs less than 25 USD.[8] In 1943 Edward Doisy and Henrik Dam were given a Nobel Prize for its discovery.[5]

    Terminology

    Phytomenadione is often also called phylloquinone, vitamin K,[9] or phytonadione. Sometimes a distinction is made between phylloquinone, which is considered to be a natural substance, and phytonadione, which is considered to be a synthetic substance.[10]

    A stereoisomer of phylloquinone is called vitamin k1 (note the difference in capitalization).

    Chemistry

    Vitamin K is a fat-soluble vitamin that is stable in air and moisture but decomposes in sunlight. It is a polycyclic aromatic ketone, based on 2-methyl-1,4-naphthoquinone, with a 3-phytyl substituent. It is found naturally in a wide variety of green plants, particularly in leaves, since it functions as an electron acceptor during photosynthesis, forming part of the electron transport chain of photosystem I.[11][12]

    The best-known function of vitamin K in animals is as a cofactor in the formation of coagulation factors II (prothrombin), VII, IX, and X by the liver. It is also required for the formation of anticoagulant factors protein C and S. It is commonly used to treat warfarin toxicity, and as an antidote for coumatetralyl.

    Vitamin K is required for bone protein formation.

    Biosynthesis
    The biosynthesis of vitamin K1 via the transformation of chorismate occurs in nine steps.

    Vitamin K1 is synthesized from chorismate, a compound produced from shikimate via the shikimate pathway. The conversion of chorismate to vitamin K­1 comprises a series of nine steps:[13][14]

    1. Chorismate is isomerized to isochorismate by isochorismate synthase, or MenF (menaquinone enzyme).
    2. Addition of 2-oxoglutarate to isochorismate by PHYLLO, a multifunctional protein comprising three different enzymatic activities (MenD, H, and C).
    3. Elimination of pyruvate by PHYLLO.
    4. Aromatization to yield o-succinyl benzoate by PHYLLO.
    5. O-succinylbenzoate activation to corresponding CoA ester by MenE.
    6. Naphthoate ring formation by naphthoate synthase (MenB/NS).
    7. Thiolytic release of CoA by a thioesterase (MenH).
    8. Attachment of phytol chain to the naphthoate ring (MenA/ABC4).
    9. Methylation of the precursor at position 3 (MenG).   

    See also

    References
    1. Watson RR (2014). Diet and Exercise in Cystic Fibrosis. Academic Press. p. 187. ISBN 9780128005880. Archived from the original on 2016-12-30.
    2. "Phytonadione". The American Society of Health-System Pharmacists. Archived from the original on 29 December 2016. Retrieved 8 December 2016.
    3. "Phytonadione Use During Pregnancy". Drugs.com. Archived from the original on 29 December 2016. Retrieved 29 December 2016.
    4. "Office of Dietary Supplements – Vitamin K". ods.od.nih.gov. 11 February 2016. Archived from the original on 31 December 2016. Retrieved 30 December 2016.
    5. Sneader W (2005). Drug Discovery: A History. John Wiley & Sons. p. 243. ISBN 9780471899792. Archived from the original on 2016-12-30.
    6. "WHO Model List of Essential Medicines (19th List)" (PDF). World Health Organization. April 2015. Archived (PDF) from the original on 13 December 2016. Retrieved 8 December 2016.
    7. "Vitamin K1". International Drug Price Indicator Guide. Archived from the original on 10 May 2017. Retrieved 8 December 2016.
    8. Hamilton R (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 229. ISBN 9781284057560.
    9. Haroon Y, Shearer MJ, Rahim S, Gunn WG, McEnery G, Barkhan P (June 1982). "The content of phylloquinone (vitamin K1) in human milk, cows' milk and infant formula foods determined by high-performance liquid chromatography". The Journal of Nutrition. 112 (6): 1105–17. doi:10.1093/jn/112.6.1105. PMID 7086539.
    10. "Vitamin K". Retrieved 2009-03-18.
    11. Itoh S, Iwaki M (1989). "Vitamin K1 (Phylloquinone) Restores the Turnover of FeS centers of Ether-extracted Spinach PSI Particles". FEBS Letters. 243 (1): 47–52. doi:10.1016/0014-5793(89)81215-3.
    12. Palace GP, Franke JE, Warden JT (May 1987). "Is phylloquinone an obligate electron carrier in photosystem I?". FEBS Letters. 215 (1): 58–62. doi:10.1016/0014-5793(87)80113-8. PMID 3552735.
    13. Reumann S (2013). "Biosynthesis of vitamin K1 (phylloquinone) by plant peroxisomes and its integration into signaling molecule synthesis pathways". Sub-Cellular Biochemistry. Subcellular Biochemistry. Springer Netherlands. 69: 213–29. doi:10.1007/978-94-007-6889-5_12. ISBN 9789400768888. PMID 23821151.
    14. Widhalm JR, van Oostende C, Furt F, Basset GJ (April 2009). "A dedicated thioesterase of the Hotdog-fold family is required for the biosynthesis of the naphthoquinone ring of vitamin K1". Proceedings of the National Academy of Sciences of the United States of America. 106 (14): 5599–603. doi:10.1073/pnas.0900738106. PMC 2660889. PMID 19321747.
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