title: Vitamin K-dependent carboxylation.
abstract: Vitamin K-dependent (VKD) protein carboxylation uses vitamin K epoxidation to convert Glus to carboxylated Glus (Glas), rendering VKD proteins active in physiologies that include hemostasis, apoptosis, bone mineralization, calcium homeostasis, growth control, and signal transduction. Clusters of Glus are modified by a processive carboxylase, generating a calcium-binding module that allows binding to either hydroxyapatite in the extracellular matrices or cell surfaces where anionic phospholipids become exposed, for example, during apoptosis or cell activation. Naturally occurring carboxylase mutations have been informative for function and are associated with bleeding complications and, surprisingly, a pseudoxanthoma elasticum (PXE)-like phenotype. A major advance in defining carboxylase function is the identification of the base that initiates carboxylation, which raises interesting possibilities for how vitamin K epoxidation is regulated by Glu substrate and carboxylase membrane topology. Vitamin K oxidoreductase (VKOR), the target of warfarin, generates the reduced vitamin K cofactor used by the carboxylase. Oxidation of active site thiols during vitamin K reduction inactivates VKOR, and activity is regenerated by an unknown reductase. The amounts of reduced vitamin K limit the capacity for carboxylation in cells, and overexpression of VKOR, but not carboxylase, improves carboxylation. However, the effect of VKOR overexpression is small, possibly because the reductase that regenerates VKOR activity is saturated. The review discusses these advances, as well as the potential impact of secretory components on carboxylation, which occurs during VKD protein secretion. Also discussed is the role of the carboxylase in mammals and lower organisms, including the bacterial pathogen Leptospira interrogans that has acquired a VKD carboxylase by horizontal transfer.
authors: Department of Molecular Cardiology, Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, Lerner Research Institute, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.
authors: Kathleen L
authors: KL
authors: Berkner
mesh_terms: D000818:Animals; D019735:Carbon-Carbon Ligases / Q000378:metabolism*; D002478:Cells, Cultured; D006801:Humans; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D010084:Oxidation-Reduction; D014812:Vitamin K / Q000737:chemistry / Q000494:pharmacology*; D010837:Vitamin K 1 / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D014812:Vitamin K; C016186:vitamin K1 oxide; D010837:Vitamin K 1; D016660:NAD(P)H Dehydrogenase (Quinone); D019735:Carbon-Carbon Ligases; C020660:glutamyl carboxylase