53.1

Metabolic Role and Effect of Deficiency

Vitamin K ( Fig. 53.1 ) refers to a group of fat-soluble molecules that are known for their essential role in facilitating blood coagulation by activating clotting factors (e.g., prothrombin and factors II, VII, IX, and X) in the liver. Antagonizing this effect of Vitamin K with the use drugs such as warfarin is the basis for clinical use of such medications in the prevention of thromboembolism in humans. At the metabolic level, Vitamin K serves as a cofactor for one microsomal enzyme, γ-carboxyglutamyl carboxylase (GGCX), which catalyzes the conversion of peptide-bound glutamate residues of specific proteins to γ-carboxyglutamate. Such conversion provides sites for calcium binding to the particular protein. Because the Vitamin K-dependent proteins (e.g., the blood-clotting factors, osteocalcin, and matrix γ-carboxyglutamic acid) serve in a variety of cellular reactions and are expressed in a variety of tissues, the vitamin assumes other functions beside blood coagulation including bone and cartilage metabolism, signal transduction, and cell proliferation. Vitamin K also appears to have physiological roles that are not related to its function as a cofactor for GGCX. From the above, it becomes clear that optimizing body homeostasis of Vitamin K brings about clear health benefits to humans (e.g., it decreases the risk of certain cardiovascular diseases and osteoporosis) . Vitamin K deficiency in normal human subjects is rare due to the ubiquitous distribution of the vitamin in the diet, its synthesis by normal gut microbiota, and the fact that only small quantities of the vitamin is required to serve as a cofactor in γ-glutamyl carboxylation reactions. The recent recognition of ability of many cell types to regenerate Vitamin K from its epoxide metabolite, via what is known as the Vitamin K cycle, also contributes to the low requirement of the vitamin as a cofactor (reviewed in Ref. ). Suboptimal/deficient levels of Vitamin K, however, do occur in patients with fat malabsorption disorders (e.g., pancreatic insufficiency, biliary tract disease, cystic fibrosis, bacterial overgrowth in the small intestine, chronic use of bile acid resins such as cholestyramine, short bowel syndrome), those receiving Vitamin K antagonists (e.g., warfarin), and those with inadequate body stores (like newborn infants, where IM administration of the vitamin is recommended to prevent hemorrhagic disease of the newborn). Suboptimal levels of Vitamin K have also been reported in individuals on broad-spectrum antibiotics for long periods (due to disturbance in gut microbiota). The adequate intake level for Vitamin K is set at 90 μg/day for women and 120 μg/day for men.

Chemical structure of Vitamin K compounds.

Like many other vitamins, the human body cannot synthesize Vitamin K endogenously, and therefore, must obtain the vitamin from exogenous sources via intestinal absorption. Thus, the intestine plays an important role in regulating and maintaining normal body level of the vitamin. The human intestine is exposed to two sources of Vitamin K: a dietary source and a microbiota source. Vitamin K exists in two major forms: Vitamin K ₁ (phylloquinone) and Vitamin K ₂ [represented by members of the menaquinones (MK) family]. All Vitamin K compounds share a common structure of 2-methyl-1,4-naphthoquinone ring (called menadione; Fig. 53.1 ) to which a hydrophobic polyisoprenoid side chain of varying length and degree of saturation is attached at position 3 of the ring. Vitamin K1 represents the majority (between 75% and 90%) of Vitamin K in Western diets, and is found in leafy green vegetables and in certain vegetable oils, such as soybean and olive oil. Vitamin K2 forms are found in liver and fermented products (e.g., cheese) ; they are also the forms generated by the gut microbiota. Members of the Vitamin K2 family are named according to the number of prenyl units present in the side chain, with MK-6, -7, -8, -10, and -11 forms representing the major forms produced by the gut microbiota. Bioavailability of the gut microbiota-generated Vitamin K2 forms has been documented and their contribution to human nutrition is established.