salicylates and Vitamin-K-Deficiency

Since the discovery of gamma-carboxyglutamic acid a decade ago, great progress has been made in advancing our knowledge of the function and metabolism of vitamin K. The distribution of this new amino acid in proteins of diverse origin and the presence of the vitamin K-dependent carboxylase in diverse tissues have emphasized the widespread significance in biology of a new triad: vitamin K, Gla, and calcium. New knowledge has been obtained on the importance of the utilization and reutilization of vitamin K, whose body pools are extremely low for a fat-soluble vitamin, for the posttranslational carboxylation of peptide-bound glutamate residues in the vitamin K-dependent proteins. The regulation of the activation of the vitamin K-vitamin K-epoxide cycle by drugs and nutrients appears to be the key to controlling the synthesis of vitamin K-dependent proteins, eight of which are involved in blood coagulation. The purification of the vitamin K-dependent gamma-glutamyl carboxylase has turned out to be a more formidable task than anyone had imagined. Many of the questions about its complicated mechanism, utilizing as it does four substrates (KH2, O2, CO2, and a Glu-containing peptide), cannot be answered until the enzyme is homogeneous. Basically, the vitamin K-dependent carboxylase system consists of a specialized microsomal electron transport system coupled to a carbon dioxide fixation. The reaction does not require ATP but apparently utilizes the energy of vitamin KH2 oxidation to perform the chemical work required in Gla synthesis. Why a quinone is employed in this system when other mechanisms exist for CO2 fixation is still mysterious unless the whole process goes by one electron transport. Whether the final CO2 addition to the gamma-methylene group of glutamic acid is a radical reaction is unsettled. Since this enzyme is an intrinsic membrane-bound protein, the scientific attack on its structure and function is at one of the present frontiers of molecular biology. A view of the synthesis of vitamin K-dependent proteins in the RER is shown in Figure 9. Finally, the nutritional requirements for vitamin K in humans are unknown. An unknown fraction of vitamin K in humans is derived from menaquinone biosynthesis in the intestinal flora. Contributions from diet and biosynthesis have not yet been quantitated. Sensitive HPLC methods for measuring plasma phylloquinone are now available, and related methods for measuring long-chain menaquinones can be developed.

Topics: 4-Hydroxycoumarins; Amino Acid Sequence; Animals; Carbon-Carbon Ligases; DNA; DNA, Recombinant; Electron Transport; Genetic Variation; Humans; Immunologic Techniques; Intestinal Absorption; Kinetics; Ligases; Microsomes, Liver; Mixed Function Oxygenases; Nutritional Requirements; Peptides; Protein Binding; Protein Precursors; Protein Sorting Signals; Prothrombin; Quinone Reductases; RNA, Messenger; Salicylates; Tissue Distribution; Vitamin A; Vitamin E; Vitamin K; Vitamin K 1; Vitamin K Deficiency; Vitamin K Epoxide Reductases

Topics: Administration, Oral; Animals; Anticoagulants; Blood Coagulation; Blood Coagulation Factors; Blood Proteins; Clofibrate; Coumarins; Dicumarol; Disulfiram; Ethyl Biscoumacetate; Female; Heparin; Intestinal Absorption; Liver; Phenylbutazone; Protein Binding; Prothrombin; Prothrombin Time; Rabbits; Rats; Salicylates; Sulfonamides; Vitamin K; Vitamin K Deficiency; Warfarin

Topics: Animals; Anticoagulants; Barbiturates; Blood Coagulation; Blood Coagulation Factors; Cholestyramine Resin; Clofibrate; Disulfiram; Diuretics; Dogs; Drug Interactions; Heparin; Humans; In Vitro Techniques; Intestinal Absorption; Kinetics; Liver Diseases; Phenylbutazone; Protein Binding; Prothrombin Time; Rats; Receptors, Drug; Salicylates; Serum Albumin; Time Factors; Vitamin K; Vitamin K Deficiency

Topics: Blood Coagulation Disorders; Blood Coagulation Factors; Blood Coagulation Tests; Humans; Propylthiouracil; Prothrombin; Salicylates; Vitamin K; Vitamin K Deficiency