Molecular Pathways and Roles for Vitamin K2-7 as a Health-Beneficial Nutraceutical: Challenges and Opportunities

Abstract

Vitamin K2-7, also known as menaquinone-7 (MK-7) is a form of vitamin K that has health-beneficial effects in osteoporosis, cardiovascular disease, inflammation, cancer, Alzheimer's disease, diabetes and peripheral neuropathy. Compared to vitamin K1 (phylloquinone), K2-7 is absorbed more readily and is more bioavailable. Clinical studies have unequivocally demonstrated the utility of vitamin K2-7 supplementation in ameliorating peripheral neuropathy, reducing bone fracture risk and improving cardiovascular health. We examine how undercarboxylated osteocalcin (ucOC) and matrix Gla protein (ucMGP) are converted to carboxylated forms (cOC and cMGP respectively) by K2-7 acting as a cofactor, thus facilitating the deposition of calcium in bones and preventing vascular calcification. K2-7 is beneficial in managing bone loss because it upregulates osteoprotegerin which is a decoy receptor for RANK ligand (RANKL) thus inhibiting bone resorption. We also review the evidence for the health-beneficial outcomes of K2-7 in diabetes, peripheral neuropathy and Alzheimer's disease. In addition, we discuss the K2-7-mediated suppression of growth in cancer cells via cell-cycle arrest, autophagy and apoptosis. The mechanistic basis for the disease-modulating effects of K2-7 is mediated through various signal transduction pathways such as PI3K/AKT, MAP Kinase, JAK/STAT, NF-κB, etc. Interestingly, K2-7 is also responsible for suppression of proinflammatory mediators such as IL-1α, IL-1β and TNF-α. We elucidate various genes modulated by K2-7 as well as the clinical pharmacometrics of vitamin K2-7 including K2-7-mediated pharmacokinetics/pharmacodynamics (PK/PD). Further, we discuss the current status of clinical trials on K2-7 that shed light on dosing strategies for maximum health benefits. Taken together, this is a synthetic review that delineates the health-beneficial effects of K2-7 in a clinical setting, highlights the molecular basis for these effects, elucidates the clinical pharmacokinetics of K2-7, and underscores the need for K2-7 supplementation in the global diet.

Keywords: cancer; clinical trial; diabetes; menaquinone; neuropathy; nutraceutical; osteocalcin; vitamin K2-7.

FIGURE 1

Chemical structures of (A) Phylloquinone (vitamin K1); and (B) Menadione (vitamin K3).

FIGURE 2

(A) General chemical structure of vitamin K2 family; (B) Chemical structure of menaquinone-4 (MK-4); and (C) Chemical structure of menaquinone-7 (MK-7).

FIGURE 3

Schematic representation of vitamin K2-7 synthesis. In glycerol dissimilation pathway, overexpression of enzymes glycerol kinase (GlpK) and glycerol-3-phosphate dehydrogenase (GlpD) leads to conversion of glycerol (Gly) to dihydroxyacetone phosphate (DHAP). Conversion of DHAP to methylglyoxal (MG) and glyceraldehyde-1-phosphate (G1P) is prevented by deleting mgsA and araM. DHAP is interconverted to glyceraldehyde-3-phosphate (G3P) which is converted to pyruvate (Pyr). Pyr enters the methylerythritol pathway (MEP) in which the end product is heptaprenyl pyrophosphate (HepPP). Synthesis of HepPP is enhanced by overexpression of enzyme heptaprenyl diphosphate synthase (HepS). HepPP enters MK-7 pathway to form MK-7 (vitamin K2-7). AroG^D146N and PyrG^E156K are overexpressed in shikimate (SA) pathway and pyrimidine metabolism pathway respectively to lead the components of both the pathways towards MK-7 pathway and form MK-7 as the end product (Adapted from (Yang et al., 2020)).

FIGURE 4

Role of vitamin K2-7 in osteoporosis and vascular calcification. Vitamin K2-7 facilitates carboxylation of glutamate (Glu) residue present on matrix Gla protein (MGP) leading to formation of carboxylated MGP (cMGP) and aids in phosphorylation of MGP leading to its activation; activated MGP inhibits bone morphogenetic protein 2 (BMP2) resulting in prevention of vascular calcification. K2-7 also is a cofactor in conversion of undercarboxylated osteocalcin (ucOC) to carboxylated osteocalcin (cOC); cOC has an affinity for calcium ions and facilitates the transport of calcium to bone for bone formation. Receptor activator for nuclear factor kappa ligand (RANKL) binds to RANK receptor and activates osteoclasts which results in bone resorption; vitamin K2-7 augments the expression of osteoprotegerin (OPG) which is a decoy receptor for RANKL and abrogates RANK-RANKL binding thus inhibiting bone resorption.

FIGURE 5

Role of vitamin K2-7 in Alzheimer’s disease. Vitamin K2-7 facilitates carboxylation of glutamate (Glu) residue present on growth arrest-specific protein 6 (Gas6) to γ-carboxyglutamate (Gla) leading to its activation, activated Gas6 binds to AXL receptor tyrosine kinase (AXL RTK) and initiates phosphoinositide 3-kinase/protein kinase B/BCL-2-associated death promoter protein (PI3K/AKT/BAD) signaling, BAD has an inhibitory effect on Caspase 3, this abrogates apoptosis and provides protection by K2-7 against β-amyloid (Aβ)-induced cytotoxicity. In cytosol, reactive oxygen species (ROS) activates Janus kinase-Signal transducer and activator of transcription protein (JAK-STAT) pathway resulting in transcription of BCL-2-associated X protein (BAX), BAX causes release of cytochrome c from mitochondria, cytochrome c leads to activation of Caspase 3 that results in apoptosis; vitamin K2-7 abrogates apoptosis by inhibiting Caspase 3.