Carboxylative efficacy of trans and cisMK7 and comparison with other vitamin K isomers

Abstract

Carboxylative enzymes are involved in many pathways and their regulation plays a crucial role in many of these pathways. In particular, γ‐glutamylcarboxylase (GGCX) converts glutamate residues (Glu) into γ‐carboxyglutamate (Gla) of the vitamin K‐dependent proteins (VKDPs) activating them. VKDPs include at least 17 proteins involved in processes such as blood coagulation, blood vessels calcification, and bone mineralization. VKDPs are activated by the reduced form of vitamin K, naturally occurring as vitamin K1 (phylloquinone) and K2 (menaquinones, MKs). Among these, MK7 is the most efficient in terms of bioavailability and biological effect. Similarly to other trans isomers, it is produced by natural fermentation or chemically in both trans and cis. However, the efficacy of the biological effect of the different isomers and the impact on humans are unknown. Our study assessed carboxylative efficacy of trans and cis MK7 and compared it with other vitamin K isomers, evaluating both the expression of residues of carboxylated Gla‐protein by western blot analysis and using a cell‐free system to determine the GGCX activity by HPLC. Trans MK7H2 showed a higher ability to carboxylate the 70 KDa GLA‐protein, previously inhibited in vitro by warfarin treatment. However, cis MK7 also induced a carboxylation activity albeit of a small extent. The data were confirmed chromatographically, in which a slight carboxylative activity of cis MK7H2 was demonstrated, comparable with both K1H2 and oxidized trans MK7 but less than trans MK7H2. For the first time, a difference of biological activity between cis and trans configuration of menaquinone‐7 has been reported.

Potential Drug–Nutrient Interactions of 45 Vitamins, Minerals, Trace Elements, and Associated Dietary Compounds with Acetylsalicylic Acid and Warfarin—A Review of the Literature

“…Only when there is hepatic vitamin K sufficiency is vitamin K transported to extrahepatic tissues [315]. Lack of menaquinone-7-trans (the vitamin K2, MK-7-trans form) results in the inactivation of extrahepatic vitamin K-dependent proteins such as matrix GLA protein [316,317] and osteocalcin [318]. The role of the ABCB1 protein in K vitamin transintestinal efflux has been explored in animal models [319].…”

“…This result cannot be transposed to all forms of Ginkgo Biloba, as literature reports have documented serious interactions [331]. Specific supplementation of menaquinone-7-trans (K2, MK7-trans) could specifically target Matrix GLA protein function [316,317], but it is impractical on a clinical level, as low doses of MK-7 supplementation significantly influenced INR values (with a mean value of INR dropping by 40%) [332] (Table 2) (Figure 3).…”

Integrated microfluidic devices for point-of-care detection of bio-analytes and disease

“…Vitamin K deficiency symptoms include spontaneous cutaneous purpura, epistaxis, gastrointestinal, genitourinary, or other bleeding. 159–161…”

“…Vitamin K deficiency symptoms include spontaneous cutaneous purpura, epistaxis, gastrointestinal, genitourinary, or other bleeding. [159][160][161] Vitamin K is the most lipophilic and least abundant vitamin. Measurement is a challenging task in human samples.…”

The Effect of Iron Oxide Nanoparticles on the Menaquinone-7 Isomer Composition and Synthesis of the Biologically Significant All-Trans Isomer

“…MK-7 exists as geometric isomers, and solely all- trans MK-7 is bioactive. The cis forms of the vitamin have comparatively little or no biological significance, and it has been ascertained that cis MK-7 has considerably compromised carboxylative capacity and biological function compared to the all- trans isomer [ 6 , 8 , 32 , 33 ]. The bioactivity of MK-7 is related to the configuration of double bonds in its isoprenoid chain, which influences the shape of the molecule and its ability to interact with subcellular structures [ 32 , 34 ].…”