Abstract
Vitamin K family molecules—phylloquinone (K1), menaquinone (K2), and menadione (K3)—act as γ-glutamyl carboxylase (GGCX)-exclusive cofactors in their hydroquinone state, activating proteins of main importance for blood coagulation in the liver and for arterial calcification prevention and energy metabolism in extrahepatic tissues. Once GGCX is activated, vitamin K is found in the epoxide state, which is then recycled to quinone and hydroquinone states by vitamin K epoxide reductase (VKORC1). Nevertheless, little information is available concerning vitamin K1, K2, or K3 tissue distribution and preferential interactions towards VKORC1. Here we present a molecular modeling study of vitamin K1, menaquinones 4, 7 (MK4, MK7), and K3 structural interactions with VKORC1. VKORC1 was shown to tightly bind vitamins K1 and MK4 in the epoxide and quinone states, but not in the hydroquinone state; five VKORC1 residues were identified as crucial for vitamin K stabilization, and two other ones were essential for hydrogen bond formation. However, vitamin MK7 revealed shaky binding towards VKORC1, induced by hydrophobic tail interactions with the membrane. Vitamin K3 exhibited the lowest affinity with VKORC1 because of the absence of a hydrophobic tail, preventing structural stabilization by the enzyme. Enzymatic activity towards vitamins K1, MK4, MK7, and K3 was also evaluated by in vitro assays, validating our in silico predictions: VKORC1 presented equivalent activities towards vitamins K1 and MK4, but much lower activity with respect to vitamin MK7, and no activity towards vitamin K3. Our results revealed VKORC1’s ability to recycle both phylloquinone and some menaquinones, and also highlighted the importance of vitamin K’s hydrophobic tail size and membrane interactions.
Highlights
Vitamin K is of main importance for many physiological processes as the exclusive cofactor of the γ-glutamyl carboxylase (GGCX) enzyme, which catalyzes a post-translational modification: γ-glutamyl carboxylation
C132 and C135 residues form the catalytic site of VKORC1, whereas
Simulations were performed in replica on each vitamin K–VKORC1 complex, and the two trajectories were concatenated and analyzed as one 200-ns molecular dynamics (MD) simulation
Summary
Vitamin K is of main importance for many physiological processes as the exclusive cofactor of the γ-glutamyl carboxylase (GGCX) enzyme, which catalyzes a post-translational modification: γ-glutamyl carboxylation. This leads to the activation of vitamin K-dependent proteins (VKDPs) involved in bone metabolism [1,2], cancer progression and inflammatory response [3], oxidative stress [4], sphingolipid synthesis [5], and pancreas exocrine activity [6]. The 163-amino acid protein named vitamin K epoxide reductase (VKORC1) has been shown to support vitamin KE to vitamin KQ reduction, and vitamin KQ to vitamin KH reduction [14,15]—no activity was evidenced towards vitamin KH. C132 and C135 residues form the catalytic site of VKORC1 (the CxxC motif being the active site of most oxidoreductases family proteins), whereas
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
