Vitamin K

Overview

• Vitamin K refers to a group of fat-soluble, quinone-derived compounds (primarily phylloquinone (K₁) and menaquinones (K₂)) that act as essential cofactors for γ-glutamyl carboxylase enzymes.
• Their principal biological role is to enable the post-translational γ-carboxylation of specific glutamate residues in proteins.
• This modification is essential for calcium binding and thus for normal blood clotting, bone mineralization, and vascular health.

Benefits

• Hemostasis: K-dependent carboxylation of clotting factors II, VII, IX, and X reduces bleeding risk.
• Bone health: Osteocalcin and matrix Gla-protein (MGP) require K for activation; higher intake correlates with higher bone mineral density and reduced fracture risk in older adults.
• Cardiovascular: Activated MGP inhibits arterial calcification; prospective cohorts show lower coronary artery calcium scores with higher K₂ intake.
• Metabolic: Vitamin K improves insulin sensitivity and glycemic control in type-2 diabetes via modulation of osteocalcin’s endocrine function.
• Cognitive: Emerging data suggest that higher dietary K is associated with slower cognitive decline, possibly through anti-inflammatory and vascular pathways.
• All benefits are dose-responsive and strongest when intake meets or exceeds recommended intakes.

How It Works

• Vitamin K functions as a catalytic cofactor for the enzyme γ-glutamyl carboxylase.
• This enzyme converts specific glutamate residues in target proteins to γ-carboxyglutamate (Gla).
• This reaction requires reduced vitamin K (vitamin K hydroquinone) and produces vitamin K epoxide.
• Vitamin K epoxide is recycled back to the active form by the vitamin K epoxide reductase (VKOR) complex—a target of the anticoagulant warfarin.
• Gla residues confer high affinity for calcium ions, enabling clotting factors, osteocalcin, and MGP to bind calcium and exert physiological effects.
• In bone, carboxylated osteocalcin facilitates hydroxyapatite binding; in vasculature, carboxylated MGP inhibits calcium deposition in the arterial wall.
• Vitamin K also modulates gene expression via activation of the nuclear receptor SXR (NR1I2), influencing inflammatory pathways and lipid metabolism.

Dosage

• The Institute of Medicine sets the Adequate Intake (AI) at 120 µg/day for adult men and 90 µg/day for adult women (phylloquinone equivalents).
• Supplementation typically ranges from 50 µg to 200 µg/day for general health.
• Higher doses (up to 1 mg/day) are used in research on bone and vascular outcomes.
• For patients on warfarin, any vitamin K supplement should be standardized (e.g., 100 µg phylloquinone) and taken at the same time each day to maintain a stable plasma level and avoid INR fluctuations.
• Menaquinone-7 (MK-7) is often dosed at 100–200 µg/day owing to its longer half-life (~3 days). Timing is flexible (with or without food), but consistency is key.
• In patients with malabsorption, higher doses (up to 5 mg/day) may be needed, but only under medical supervision.

Safety & Side Effects

• Vitamin K is generally well-tolerated; adverse effects are rare at typical supplemental doses.
• Reported side effects include mild gastrointestinal upset and, rarely, hypersensitivity reactions.
• The principal contraindication is concurrent use of vitamin K antagonists (e.g., warfarin, acenocoumarol).
• Abrupt changes in intake can destabilize anticoagulation, so any supplementation must be coordinated with a clinician.
• High-dose vitamin K (≥10 mg/day) may interfere with anticoagulation and could theoretically exacerbate hypercoagulable states in patients with thrombophilia, though evidence is limited.
• Pregnant and lactating women should meet, not exceed, the AI (90–120 µg/day) unless advised otherwise.
• Infants receive vitamin K1 (1 mg) prophylactically at birth to prevent hemorrhagic disease; supplemental vitamin K beyond this is unnecessary unless medically indicated.

Chemistry

• Vitamin K1 (phylloquinone) is 2-methyl-3-(3′-hydroxy-4′-methyl-2′-(3-oxobutyl)-phenyl)-1,4-naphthoquinone, with molecular formula C₃₁H₄₆O₂ and a molecular weight of 450.7 g/mol.
• Its structure comprises a 2-methyl-1,4-naphthoquinone core with a phytyl side-chain (a 20-carbon saturated, branched hydrocarbon) at the 3-position, conferring lipophilicity.
• Menaquinones (K₂) differ by the length and saturation of the isoprenoid side chain (e.g., MK-4 has four isoprene units; MK-7 has seven).
• The quinone ring undergoes redox cycling between quinone, hydroquinone, and epoxide forms during the carboxylation cycle.
• The high degree of unsaturation in the side chain influences tissue distribution and half-life; MK-7’s longer chain yields a plasma half-life of 2–3 days versus 1 hour for K₁.

Sources & Quality

• Natural dietary sources include leafy green vegetables (e.g., kale, spinach) for phylloquinone and fermented foods (e.g., natto, hard cheeses) for menaquinones, especially MK-7.
• Commercial supplements are derived from two main processes:
  • Extraction: phylloquinone is extracted from plant material using solvent-based methods (e.g., ethanol, supercritical CO₂) and purified by chromatography.
  • Fermentation: MK-7 is produced by bacterial fermentation (e.g., Bacillus subtilis or Bacillus natto) followed by purification.
• Synthetic routes exist but are less common due to cost and regulatory scrutiny.
• Quality considerations include verification of the specific K-form, absence of heavy metals, and compliance with pharmaco-peptide standards (e.g., USP, EFSA).
• Look for third-party testing (e.g., USP Verified, NSF) to ensure potency, purity, and correct labeling of the vitamin K isoform.