VKORC1L1, an enzyme rescuing the vitamin K 2,3-epoxide reductase activity in some extrahepatic tissues during anticoagulation therapy.
Vitamin K is involved in the γ-carboxylation of the vitamin K-dependent proteins, and vitamin K epoxide is a by-product of this reaction. Due to the limited intake of vitamin K, its regeneration is necessary and involves vitamin K 2,3-epoxide reductase (VKOR) activity. This activity is known to be supported by VKORC1 protein, but recently a second gene, VKORC1L1, appears to be able to support this activity when the encoded protein is expressed in HEK293T cells. Nevertheless, this protein was described as being responsible for driving the vitamin K-mediated antioxidation pathways. In this paper we precisely analyzed the catalytic properties of VKORC1L1 when expressed in Pichia pastoris and more particularly its susceptibility to vitamin K antagonists. Vitamin K antagonists are also inhibitors of VKORC1L1, but this enzyme appears to be 50-fold more resistant to vitamin K antagonists than VKORC1. The expression of Vkorc1l1 mRNA was observed in all tissues assayed, i.e. in C57BL/6 wild type and VKORC1-deficient mouse liver, lung, and testis and rat liver, lung, brain, kidney, testis, and osteoblastic cells. The characterization of VKOR activity in extrahepatic tissues demonstrated that a part of the VKOR activity, more or less important according to the tissue, may be supported by VKORC1L1 enzyme especially in testis, lung, and osteoblasts. Therefore, the involvement of VKORC1L1 in VKOR activity partly explains the low susceptibility of some extrahepatic tissues to vitamin K antagonists and the lack of effects of vitamin K antagonists on the functionality of the vitamin K-dependent protein produced by extrahepatic tissues such as matrix Gla protein or osteocalcin.
From the Unité Sous Contrat (USC) 1233 Institut National de Recherche Agronomique (INRA)-Vetagro Sup, Veterinary School of Lyon, 69280 Marcy l'Etoile, France and.
Abdessalem
A
Hammed
Benjamin
B
Matagrin
Gabriele
G
Spohn
Caroline
C
Prouillac
Etienne
E
Benoit
Virginie
V
Lattard
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D055162:Biocatalysis / Q000187:drug effects; D002460:Cell Line; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism; D009928:Organ Specificity / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014812:Vitamin K / Q000037:antagonists & inhibitors / Q000378:metabolism; D064417:Vitamin K Epoxide Reductases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014859:Warfarin / Q000494:pharmacology
D000925:Anticoagulants; D012333:RNA, Messenger; D014812:Vitamin K; D014859:Warfarin; D006899:Mixed Function Oxygenases; C531327:VKORC1L1 protein, human; D064417:Vitamin K Epoxide Reductases; D016660:NAD(P)H Dehydrogenase (Quinone); C507703:NQO1 protein, rat
Drug Resistance; Enzyme Inhibitors; Enzyme Kinetics; Hemostasis; VKORC1; VKORC1L1; Vitamin K; Vitamin K Antagonist; Vitamin K Epoxide Reductase