- 1
- USC 1233 RS2GP, INRA, VetAgro Sup, Univ Lyon, F-69280 Marcy l'Etoile, France. nolan.chatron@vetagro-sup.fr.
- 2
- USC 1233 RS2GP, INRA, VetAgro Sup, Univ Lyon, F-69280 Marcy l'Etoile, France. abdessalem.hammed@vetagro-sup.fr.
- 3
- USC 1233 RS2GP, INRA, VetAgro Sup, Univ Lyon, F-69280 Marcy l'Etoile, France. etienne.benoit@vetagro-sup.fr.
- 4
- USC 1233 RS2GP, INRA, VetAgro Sup, Univ Lyon, F-69280 Marcy l'Etoile, France. virginie.lattard@vetagro-sup.fr.
Nutrients. 2019 Jan 1;11(1). pii: E67. doi: 10.3390/nu11010067.
Structural Insights into Phylloquinone (Vitamin K1), Menaquinone (MK4, MK7), and Menadione (Vitamin K3) Binding to VKORC1.
Author information
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.
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