Human Vitamin K 2,3-Epoxide Reductase Complex Subunit 1-like 1 (VKORC1L1) Mediates Vitamin K-dependent Intracellular Antioxidant Function

• Published in: The Journal of biological chemistry Vol. 286; no. 17; pp. 15085 - 15094
• Main Authors: Westhofen, Philipp, Watzka, Matthias, Marinova, Milka, Hass, Moritz, Kirfel, Gregor, Müller, Jens, Bevans, Carville G., Müller, Clemens R., Oldenburg, Johannes
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 29.04.2011; American Society for Biochemistry and Molecular Biology
• Subjects: Antioxidant; Antioxidants - metabolism; Cell Biology; Cell Line; Cell Survival; Endoplasmic Reticulum (ER); Endoplasmic Reticulum - metabolism; Enzyme Kinetics; Humans; Hydrogen Peroxide; Intracellular Space - metabolism; Kinetics; Membrane Proteins; Mixed Function Oxygenases - biosynthesis; Mixed Function Oxygenases - genetics; Mixed Function Oxygenases - metabolism; Oxidation-Reduction; Oxidative Stress; Protein Subunits; Reactive Oxygen Species (ROS); Vitamin K; Vitamin K 1; Vitamin K Epoxide Reductases; VKOR; VKORC1; VKORC1L1; VKR; Membrane Proteins; VKOR; VKORC1; VKORC1L1; Reactive Oxygen Species (ROS); Enzyme Kinetics; Antioxidant; VKR; Endoplasmic Reticulum (ER); Vitamin K
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M110.210971

Human vitamin K 2,3-epoxide reductase complex subunit 1-like 1 (VKORC1L1), expressed in HEK 293T cells and localized exclusively to membranes of the endoplasmic reticulum, was found to support both vitamin K 2,3-epoxide reductase (VKOR) and vitamin K reductase enzymatic activities. Michaelis-Menten kinetic parameters for dithiothreitol-driven VKOR activity were: Km (μm) = 4.15 (vitamin K1 epoxide) and 11.24 (vitamin K2 epoxide); Vmax (nmol·mg−1·hr−1) = 2.57 (vitamin K1 epoxide) and 13.46 (vitamin K2 epoxide). Oxidative stress induced by H2O2 applied to cultured cells up-regulated VKORC1L1 expression and VKOR activity. Cell viability under conditions of no induced oxidative stress was increased by the presence of vitamins K1 and K2 but not ubinquinone-10 and was specifically dependent on VKORC1L1 expression. Intracellular reactive oxygen species levels in cells treated with 2,3-dimethoxy-1,4-naphthoquinone were mitigated in a VKORC1L1 expression-dependent manner. Intracellular oxidative damage to membrane intrinsic proteins was inversely dependent on VKORC1L1 expression and the presence of vitamin K1. Taken together, our results suggest that VKORC1L1 is responsible for driving vitamin K-mediated intracellular antioxidation pathways critical to cell survival.