Phytomenadione

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Phytomenadione
Vitamin K1.png
Clinical data
Trade names Mephyton, Hemophyt, others
Other namesVitamin K1, phytonadione, phylloquinone, (E)-phytonadione
AHFS/Drugs.com Monograph
Routes of
administration 		By mouth, subcutaneous, intramuscular, intravenous
ATC code
Legal status
Legal status
Identifiers
  • 2-methyl-3-[(E,7R,11R)-3,7,11,15-tetramethylhexadec-2-enyl]naphthalene-1,4-dione
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.001.422 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C31H46O2
Molar mass 450.707 g·mol−1
3D model (JSmol)
  • CC1=C(C(=O)c2ccccc2C1=O)C/C=C(\C)/CCC[C@H](C)CCC[C@H](C)CCCC(C)C
  • InChI=1S/C31H46O2/c1-22(2)12-9-13-23(3)14-10-15-24(4)16-11-17-25(5)20-21-27-26(6)30(32)28-18-7-8-19-29(28)31(27)33/h7-8,18-20,22-24H,9-17,21H2,1-6H3/b25-20+/t23-,24-/m1/s1 Yes check.svgY
  • Key:MBWXNTAXLNYFJB-NKFFZRIASA-N

Phytomenadione, also known as vitamin K1 or phylloquinone, is a vitamin found in food and used as a dietary supplement. [4] [5] It is on the World Health Organization's List of Essential Medicines. [6]

Contents

It is used to treat certain bleeding disorders, [5] including warfarin overdose, vitamin K deficiency, and obstructive jaundice. [5] Use is typically recommended by mouth, intramuscular injection or injection under the skin. [5] When given by injection benefits are seen within two hours. [5] It is also recommended for preventing and treating vitamin K deficiency bleeding (VKDB) in infants. [5] Many countries in the world choose intramuscular injections in newborn to keep them safe from VKDB. It is considered a safe treatment and saves many children from death and severe neurologic deficit every year. [7]

Side effects when given by injection may include pain at the site of injection. [5] Severe allergic reactions may occur when it is injected into a vein or muscle, but this has mainly happened when large doses of a certain type of supplement containing castor oil were given intravenously. [8] Use during pregnancy is considered safe, [9] use is also likely okay during breastfeeding. [10] It works by supplying a required component for making a number of blood clotting factors. [5] Food sources include green vegetables, vegetable oil, and some fruit. [11]

Phytomenadione was first isolated in 1939. [12] In 1943 Edward Doisy and Henrik Dam were given a Nobel Prize for its discovery. [12]

Terminology

Phytomenadione is often also called phylloquinone, vitamin K, [13] or phytonadione.

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

Medical uses

It is used to treat certain bleeding disorders, [5] including warfarin overdose (also overdose of similar compounds such as coumatetralyl), vitamin K deficiency, and obstructive jaundice. [5] It is used to prevent and treat vitamin K deficiency bleeding (VKDB) in infants. [5]

In Canada, phytomenadione (Hemophyt) is indicated for the treatment of anticoagulant poisoning in dogs. [1] [2]

Chemistry

Vitamin K is a fat-soluble vitamin that is stable in air and moisture but decomposes in sunlight. [14] K1 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. [15] [16]

Biological function

Animals

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. Vitamin K is required for bone protein formation.

In terms of distribution, phylloquinone typically occurs in higher levels in the liver, heart and pancreas, but in lower levels in the brain, kidneys, and lungs. [17]

Plants and cyanobacteria

Vitamin K1 is required for plant photosynthesis, where it participates in the Photosystem I electron transport chain. [18]

Biosynthesis

The biosynthesis of vitamin K1 via the transformation of chorismate occurs in nine steps. Biosynthesis of vitamin K1 (EN).svg
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: [19] [20] [21]

  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).

Related Research Articles

<span class="mw-page-title-main">Vitamin K</span> Fat-soluble vitamers

Vitamin K is a family of structurally similar, fat-soluble vitamers found in foods and marketed as dietary supplements. The human body requires vitamin K for post-synthesis modification of certain proteins that are required for blood coagulation or for controlling binding of calcium in bones and other tissues. The complete synthesis involves final modification of these so-called "Gla proteins" by the enzyme gamma-glutamyl carboxylase that uses vitamin K as a cofactor.

<span class="mw-page-title-main">Photosystem I</span> Second protein complex in photosynthetic light reactions

Photosystem I is one of two photosystems in the photosynthetic light reactions of algae, plants, and cyanobacteria. Photosystem I is an integral membrane protein complex that uses light energy to catalyze the transfer of electrons across the thylakoid membrane from plastocyanin to ferredoxin. Ultimately, the electrons that are transferred by Photosystem I are used to produce the moderate-energy hydrogen carrier NADPH. The photon energy absorbed by Photosystem I also produces a proton-motive force that is used to generate ATP. PSI is composed of more than 110 cofactors, significantly more than Photosystem II.

Shikimic acid, more commonly known as its anionic form shikimate, is a cyclohexene, a cyclitol and a cyclohexanecarboxylic acid. It is an important biochemical metabolite in plants and microorganisms. Its name comes from the Japanese flower shikimi, from which it was first isolated in 1885 by Johan Fredrik Eykman. The elucidation of its structure was made nearly 50 years later.

<span class="mw-page-title-main">Chorismic acid</span> Chemical compound

Chorismic acid, more commonly known as its anionic form chorismate, is an important biochemical intermediate in plants and microorganisms. It is a precursor for:

<span class="mw-page-title-main">Menadione</span> Chemical compound

Menadione is a synthetic organic compound with the formula C6H4(CO)2C2H(CH3). It is an analog of 1,4-naphthoquinone with a methyl group in the 2-position. It is sometimes called vitamin K3. Use is allowed as a nutritional supplement in animal feed because of its vitamin K activity.

<span class="mw-page-title-main">Vitamin K deficiency bleeding</span> Medical condition

Vitamin K deficiency bleeding (VKDB) of the newborn, previously known as haemorrhagic disease of the newborn, is a rare form of bleeding disorder that affects newborns and young infants due to low stores of vitamin K at birth. It commonly presents with intracranial haemorrhage with the risk of brain damage or death.

<span class="mw-page-title-main">Aromatic amino acid</span> Amino acid having an aromatic ring

An aromatic amino acid is an amino acid that includes an aromatic ring.

<span class="mw-page-title-main">Menatetrenone</span> Form of vitamin K

Menatetrenone (INN), also known as menaquinone-4 (MK-4), is one of the nine forms of vitamin K2.

<span class="mw-page-title-main">NAD(P)H dehydrogenase (quinone)</span>

In enzymology, a NAD(P)H dehydrogenase (quinone) (EC 1.6.5.2) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Naphthoate synthase</span>

The enzyme 1,4-dihydroxy-2-naphthoyl-CoA synthase catalyzes the sixth step in the biosynthesis of phylloquinone and menaquinone, the two forms of vitamin K. In E. coli, 1,4-dihydroxy-2-naphthoyl-CoA synthase, formerly known as naphthoate synthase, is encoded by menB and uses O-succinylbenzoyl-CoA as a substrate and converts it to 1,4-dihydroxy-2-naphthoyl-CoA.

<span class="mw-page-title-main">O-succinylbenzoate—CoA ligase</span>

o-Succinylbenzoate—CoA ligase, encoded from the menE gene in Escherichia coli, catalyzes the fifth reaction in the synthesis of menaquinone. This pathway is called 1, 4-dihydroxy-2-naphthoate biosynthesis I. Vitamin K is a quinone that serves as an electron transporter during anaerobic respiration. This process of anaerobic respiration allows the bacteria to generate the energy required to survive.

<span class="mw-page-title-main">Chorismate synthase</span>

The enzyme chorismate synthase catalyzes the chemical reaction

2-Succinyl-6-hydroxy-2,4-cyclohexadiene-1-carboxylate synthase, also known as SHCHC synthase is encoded by the menH gene in Escherichia coli and functions in the synthesis of vitamin K. The specific step in the synthetic pathway that SHCHC synthase catalyzes is the conversion of 5-enolpyruvoyl-6-hydroxy-2-succinylcyclohex-3-ene-1-carboxylate to (1R,6R)-6-hydroxy-2-succinylcyclohexa-2,4-diene-1-carboxylate and pyruvate.

Vitamin K deficiency results from insufficient dietary vitamin K1 or vitamin K2 or both.

<span class="mw-page-title-main">Vitamin K reaction</span> Medical condition

Vitamin K reactions are adverse side effects that may occur after injection with vitamin K. The liver utilizes vitamin K to produce coagulation factors that help the body form blood clots which prevent excessive bleeding. Vitamin K injections are administered to newborns as a preventative measure to reduce the risk of hemorrhagic disease of the newborn (HDN).

<span class="mw-page-title-main">Shikimate pathway</span> Biosynthetic Pathway

The shikimate pathway is a seven-step metabolic pathway used by bacteria, archaea, fungi, algae, some protozoans, and plants for the biosynthesis of folates and aromatic amino acids. This pathway is not found in mammals.

Vitamin K<sub>2</sub> Group of vitamins and bacterial metabolites

Vitamin K2 or menaquinone (MK) is one of three types of vitamin K, the other two being vitamin K1 (phylloquinone) and K3 (menadione). K2 is both a tissue and bacterial product (derived from vitamin K1 in both cases) and is usually found in animal products or fermented foods.

1-4-dihydroxy-2-napthoate (DHNA) polyprenyltransferase (EC 2.5.1.74)is an enzyme that catalyzes the chemical reaction: all-trans-nonaprenyl diphosphate + 1-4-dihydroxy-2-napthoate + H+ demethylmenaquinol-9 + diphosphate + carbon dioxide

The enzyme 1,4-dihydroxy-2-naphthoyl-CoA hydrolase (EC 3.1.2.28; systematic name 1,4-dihydroxy-2-naphthoyl-CoA hydrolase) catalyses the following reaction:

<span class="mw-page-title-main">O-succinylbenzoate synthase</span>

o-Succinylbenzoate synthase (OSBS) (EC 4.2.1.113) is an enzyme encoded by the menC gene in E.coli, and catalyzes the dehydration of 2-succinyl-6-hydroxy-2,4-cyclohexadiene-1-carboxylate (SHCHC) to form 4-(2'-carboxyphenyl)-4-oxobutyrate, also called o-succinylbenzoate or OSB, hence the name of the enzyme. This reaction is the fourth step in the menaquinone biosynthetic pathway, which is used by bacteria to synthesize menaquinone, also known as vitamin K2.

References

  1. 1 2 "Notice: Multiple additions to the Prescription Drug List (PDL) [2023-08-30]". Health Canada . 26 October 2023. Retrieved 3 January 2024.
  2. 1 2 https://pdf.hres.ca/dpd_pm/00071484.PDF [ bare URL PDF ]
  3. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 Oct 2023.
  4. ↑ Watson RR (2014). Diet and Exercise in Cystic Fibrosis. Academic Press. p. 187. ISBN   9780128005880. Archived from the original on 2016-12-30.
  5. 1 2 3 4 5 6 7 8 9 10 11 "Phytonadione". The American Society of Health-System Pharmacists. Archived from the original on 29 December 2016. Retrieved 8 December 2016.
  6. ↑ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl: 10665/325771 . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  7. ↑ Furman L (27 July 2018). "American Academy of Pediatrics on vitamin k in the newborn period".
  8. ↑ Riegert-Johnson DL, Volcheck GW (October 2002). "The incidence of anaphylaxis following intravenous phytonadione (vitamin K1): a 5-year retrospective review". Annals of Allergy, Asthma & Immunology. 89 (4): 400–406. doi:10.1016/S1081-1206(10)62042-X. PMID   12392385.
  9. ↑ Bailey B (February 2003). "Are there teratogenic risks associated with antidotes used in the acute management of poisoned pregnant women?". Birth Defects Research. Part A, Clinical and Molecular Teratology. 67 (2): 133–140. doi:10.1002/bdra.10007. PMID   12769509.
  10. ↑ "Phytonadione Use During Pregnancy". Drugs.com. Archived from the original on 29 December 2016. Retrieved 29 December 2016.
  11. ↑ "Vitamin K". Office of Dietary Supplements. U.S. National Institutes of Health. 11 February 2016. Archived from the original on 31 December 2016. Retrieved 30 December 2016.
  12. 1 2 Sneader W (2005). Drug Discovery: A History. John Wiley & Sons. p. 243. ISBN   9780471899792. Archived from the original on 2016-12-30.
  13. ↑ 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): 1105–1117. doi:10.1093/jn/112.6.1105. PMID   7086539.
  14. ↑ Institute of Medicine (US) Panel on Micronutrients. "Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc". Washington (DC): National Academies Press (US). Retrieved 25 November 2021– via NCBI.
  15. ↑ 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 . S2CID   84602152.
  16. ↑ Palace GP, Franke JE, Warden JT (May 1987). "Is phylloquinone an obligate electron carrier in photosystem I?". FEBS Letters. 215 (1): 58–62. Bibcode:1987FEBSL.215...58P. doi: 10.1016/0014-5793(87)80113-8 . PMID   3552735. S2CID   42983611.
  17. ↑ Bus K, Szterk A (December 2021). "Relationship between Structure and Biological Activity of Various Vitamin K Forms". Foods. 10 (12): 3136. doi: 10.3390/foods10123136 . PMC   8701896 . PMID   34945687.
  18. ↑ Basset GJ, Latimer S, Fatihi A, Soubeyrand E, Block A (2017). "Phylloquinone (Vitamin K1): Occurrence, Biosynthesis and Functions". Mini Reviews in Medicinal Chemistry. 17 (12): 1028–1038. doi:10.2174/1389557516666160623082714. PMID   27337968.
  19. ↑ Reumann S (2013). "Biosynthesis of vitamin K1 (phylloquinone) by plant peroxisomes and its integration into signaling molecule synthesis pathways". Peroxisomes and their Key Role in Cellular Signaling and Metabolism. Subcellular Biochemistry. Vol. 69. Springer Netherlands. pp. 213–29. doi:10.1007/978-94-007-6889-5_12. ISBN   9789400768888. PMID   23821151.
  20. ↑ 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): 5599–5603. Bibcode:2009PNAS..106.5599W. doi: 10.1073/pnas.0900738106 . PMC   2660889 . PMID   19321747.
  21. ↑ Van Oostende C, Widhalm JR, Furt F, Ducluzeau AL, Basset GJ (2011). "Vitamin K1 (Phylloquinone)". Advances in Botanical Research. 59: 229–261. doi:10.1016/B978-0-12-385853-5.00001-5. ISBN   9780123858535.
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