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Introducing the ‘K’ Family

Vitamin K probably receives the least amount of attention among all the fat-soluble vitamins, except when issues with blood clotting, or more recently, bone health, arise. However, vitamin K constitutes an entire family of compounds with important and diverse biological activities.

Meet the Family

All compounds belonging to the vitamin K family are identified by their 2-methyl-1,4-naphthoquinone ring, also known as the ‘quinone’ ring, but they differ in length and saturation of the carbon tail. These compounds naturally occur as two vitamers: phylloquinone (vitamin K1) and menaquinone (vitamin K2). Phylloquinones are set apart as a 2-methyl-1,4-naphthoquinone, with a 3-phytyl substituent, whereas menaquinones contain isoprene with various chain lengths. Therefore, the subtypes are identified as menaquinone-n (MK-n), where n represents the number of isoprenoid side chain residues. For example, MK-4 has four isoprene residues in its side chain and is the most biologically active menaquinone. There are nine menaquinone subtypes.

There is one lesser-known member of the vitamin K family – vitamin K3, also known as menadione. This form is usually supplied as synthetic vitamin K; however, it is also naturally produced as a precursor to MK-4 in the bacterial conversion of phylloquinone to MK-4.

Phylloquinone (vitamin K1)

Phylloquinone is the most abundant form of vitamin K and is produced by green plants. Therefore, it is supplied in the diet through dark green leafy vegetables such as kale, spinach, Swiss chard, collards, mustard greens, parsley, and cilantro. Dark green non-leafy vegetables including broccoli, cabbage, and Brussels sprouts also contribute to our total vitamin K intake. The current dietary reference values for vitamin K are based on phylloquinone because of its role in coagulation.

Menaquinone (vitamin K2)

Most menaquinone is produced by anaerobic bacteria in the lower gastrointestinal tract such as Bacteroides and E. coli, which convert vitamin K1 to K2. Small amounts can be directly obtained by consuming animal products such as liver, fermented cheese, and eggs, as well as fermented soybean products. It is the main tissue storage form of vitamin K in mammals, but not usually supplied directly.

Roles of Vitamin K

The most common biological roles of vitamin K are as an enzyme cofactor for γ-carboxylation of coagulation proteins (factors II, VII, IX, and X), osteocalcin and matrix Gla, found in bone and cartilage. However, the roles of vitamin K extend beyond blood clotting and bone metabolism.

Brain Health

Vitamin K may also play a role in the metabolism of sphingolipids, which are found in copious amounts in brain cell membranes and myelin-rich regions of the neurological system, making this vitamin an integral part of brain health. Sphingolipids participate in cell proliferation, differentiation, senescence, and cell-cell interactions. Dysfunctions in sphingolipid metabolism have been linked to age-related cognitive decline and neurodegenerative diseases such as Alzheimer’s disease. Vitamin K is also a cofactor to the γ-glutamyl carboxylase enzyme, which acts upon the TAM (Tyro3, Axl, and Mer) family of receptors that are highly concentrated in the brain and neurological tissues. These receptors are involved in various cellular processes including cell growth, survival, and apoptosis. Finally, MK-4 has been shown to possess antioxidant and anti-inflammatory properties, both of which are critical components for brain health.

Peripheral Arterial Disease

Both phylloquinone and menaquinones have been studied as agents that guard against peripheral arterial disease by reducing vascular calcification. In a prospective cohort study with 36,629 participants, a high intake of menaquinones was associated with a reduced risk of peripheral arterial disease, especially in those with hypertension.

Type 2 Diabetes

In a prospective cohort study in 38,094 Dutch men and women, aged 20–70 years, dietary intake of phylloquinone and menaquinones was associated with a reduced risk of type 2 diabetes. As mentioned earlier, vitamin K carboxylates the protein osteocalcin. This protein is not only involved in bone mineralization, but also insulin sensitivity by regulating the expression of insulin genes and β-cell proliferation markers. High concentrations of carboxylated osteocalcin improve insulin sensitivity.

Prostate Cancer

Vitamin K has also been studied for its anticarcinogenic activities, and especially against prostate cancer. A high intake of menaquinones has been linked to a reduced risk of prostate cancer. The proposed mechanism was rooted in the concentration of vitamin K-dependent carboxylated osteocalcin. Low levels of carboxylated osteocalcin were significantly associated with advanced stage prostate cancer.

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