Menaquinones (K2 Family of Vitamins): The Fermentation Factors, Arterial Guardians, Extra-Hepatic K2

Menaquinones is the family of bacterial-synthesized vitamins, with long-chain forms like MK-4 and MK-7 serving as sustained-release guardians of cardiovascular and skeletal health by activating proteins that properly direct calcium into bones and away from arteries.

1. Overview:

Menaquinones, known as Vitamin K2, are a family of compounds with polyisoprenyl side chains of varying lengths (MK-4 to MK-13). They are produced by bacteria and are particularly effective at activating extra-hepatic vitamin K-dependent proteins (like osteocalcin in bone and Matrix Gla Protein (MGP) in arteries) due to their longer half-life and tissue distribution compared to K1.

2. Origin & Common Forms:

Synthesized by bacteria. Supplemental forms include MK-4 (synthetic, short-acting) and MK-7 (natural from natto, long-acting).

3. Common Supplemental Forms: Standard & Enhanced

· Menaquinone-4 (MK-4): A synthetic, short-chain form. It has a short half-life (~1-2 hours) and requires high, frequent dosing. Used therapeutically in Japan for osteoporosis.

· Menaquinone-7 (MK-7): The premier supplemental form, derived from fermented natto soybeans. It has a long half-life (~72 hours), allowing for once-daily dosing at low mcg amounts and sustained activation of Gla proteins.

4. Natural Origin:

· Sources:

· MK-4: Found in animal products (organ meats, egg yolks, dairy from grass-fed animals). It can also be synthesized in small amounts by the body from K1.

· MK-5 through MK-13: Found in fermented foods: natto (MK-7 is abundant), hard cheeses, sauerkraut, and curdled dairy. Produced by the fermenting bacteria.

· Precursors: Bacteria synthesize menaquinones using precursors from their own metabolism. Humans cannot synthesize the menadione ring.

5. Synthetic / Man-made:

· Process: MK-4 is produced via chemical synthesis. MK-7 for supplements is produced via large-scale fermentation of Bacillus subtilis natto (the natto bacterium), followed by extraction and purification.

6. Commercial Production:

· Precursors: Soybeans or other growth media for bacterial fermentation (MK-7).

· Process: For MK-7, natto fermentation is scaled in bioreactors. The fermented product is extracted with solvents, and MK-7 is purified via chromatography. The final product is a highly concentrated extract.

· Purity & Efficacy: High-quality MK-7 supplements are standardized to >99% purity (all-trans isomer, the bioactive form). Efficacy is proven by its ability to maximally carboxylate osteocalcin and MGP at doses of 90-200 mcg/day.

7. Key Considerations:

The MK-7 Advantage. Due to its long half-life and high bioavailability, low-dose MK-7 (e.g., 100-200 mcg) provides stable, 24-hour activation of vitamin K-dependent proteins outside the liver, making it the form of choice for supporting cardiovascular and bone health without interfering with warfarin therapy at nutritional doses.

8. Structural Similarity:

Shares the same naphthoquinone "head" as K1, but with a side chain made of repeating isoprene units (the "mena" chain). The length of this chain determines its half-life and tissue distribution.

9. Biofriendliness:

· Utilization: Absorbed with dietary fat. Long-chain menaquinones (like MK-7) are incorporated into chylomicrons and have a prolonged circulation time, allowing delivery to extra-hepatic tissues.

· Metabolism & Excretion: Recycled via the vitamin K epoxide reductase (VKOR) complex. Excess is excreted.

· Toxicity: Extremely low. No adverse effects have been found even at high doses in studies.

10. Known Benefits (Clinically Supported):

· Cardiovascular Health: Long-term supplementation with MK-7 improves arterial elasticity and reduces arterial stiffness (via MGP activation).

· Bone Health: Improves osteocalcin carboxylation, leading to improved bone strength and reduced fracture risk in postmenopausal women.

· Dental Health: Supports osteocalcin activity in dentin.

11. Purported Mechanisms:

· Activation of Extra-Hepatic Gla Proteins: The primary mechanism. Fully carboxylates:

· Matrix Gla Protein (MGP): A potent inhibitor of vascular calcification.

· Osteocalcin: The key non-collagen protein in bone that binds calcium to the hydroxyapatite matrix.

· Synergy with Vitamin D: D upregulates the production of osteocalcin and MGP, while K2 activates them.

12. Other Possible Benefits Under Research:

· Potential role in insulin sensitivity and glucose metabolism (via osteocalcin).

· Supporting kidney health and reducing vascular calcification in CKD.

· Anti-inflammatory and anti-cancer properties.

13. Side Effects:

· Minor & Transient: Rare. Isolated reports of palpitations at initiation, which typically subside.

· To Be Cautious About: Warfarin Users: While low-dose MK-7 (≤100 mcg) may not significantly affect INR, caution and medical supervision are still required. High-dose MK-4 can interfere.

14. Dosing & How to Take:

· MK-7 Dose: 90-200 mcg per day is the clinically studied range for cardiovascular and bone benefits.

· MK-4 Dose: Much higher, typically 1.5-45 mg (1500-45000 mcg) per day in divided doses, as used in Japanese studies.

· How to Take: With the largest meal of the day containing fat.

15. Tips to Optimize Benefits:

· Synergistic Combinations: Vitamin D3: The essential partner. D3 upregulates Gla protein synthesis, K2 activates them. Magnesium: Supports bone matrix and vascular function.

· Form Choice: MK-7 from natto is the superior form for sustained, systemic benefits at a low dose.

16. Not to Exceed / Warning / Interactions:

· Drug Interactions: Vitamin K Antagonists (Warfarin): Discuss with a doctor. Low-dose MK-7 may be compatible with stable INR monitoring. Orlistat & Bile Acid Sequestrants: May reduce absorption.

· Medical Conditions: Those with severe kidney disease on dialysis should use under medical guidance due to altered mineral metabolism.

17. LD50 & Safety:

· Acute Toxicity (LD50): Not established; considered non-toxic.

· Human Safety: Excellent safety profile in long-term human trials.

18. Consumer Guidance:

· Label Literacy: Seek out "Vitamin K2 (as Menaquinone-7)" or "MK-7." Check the source: "from natto fermentation" is ideal.

· Quality Assurance: Crucial for MK-7. Choose brands that specify "all-trans" isomer content (the active form) and use third-party testing, as some products contain inactive cis-isomers.

· Manage Expectations: It is a long-term protector, not an acute treatment. Effects on arterial stiffness and bone markers occur over months to years of consistent use.