A variant of prothrombin induced in cattle by prolonged administration of Warfarin

Prowse, C. V.; Mattock, P.; Esnouf, M. P.; Russell, Amy M.

doi:10.1016/0005-2795(76)90058-1

Cited by 28 publications

(12 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition to the four classical vitamin K-dependent coagulation proen zymes, factors II, VII, IX, and X, shown in Table 1, four additional ,,-carboxy containing coagulation factors have been isolated over the past four years . These are protein C (239), protein S (50), protein M (226), and protein Z (207) . All have an amino acid sequence homologous to that of prothrombin for re sidues 1-40 (106) , and all require calcium ions for activity.…”

Section: Introductionmentioning

confidence: 99%

The Function and Metabolism of Vitamin K

Olson¹

1984

Annu. Rev. Nutr.

155

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 99%

The Function and Metabolism of Vitamin K

Olson¹

1984

Annu. Rev. Nutr.

155

View full text Add to dashboard Cite

show abstract

“…Concomitantly, in other investigations, levels of physiologically active vitamin K-dependent factors were found to be markedly decreased or totally absent from human [32][33][34] and bovine plasma [35][36][37][38]46]. In several of these [34,37,47] and other studies, an inhibitory effect on thrombin gen eration in human and bovine plasma was initially reported. However, the inhibitory substance was never isolated, fully characterized or measured by antibodies.…”

Section: Section 1 Historical Perspectivesmentioning

confidence: 84%

“…Follow ing anticoagulant drug administration, immunoreactive levels of prothrombin were found to be higher than those obtained by clotting assays [32][33][34][35]45]. Concomitantly, in other investigations, levels of physiologically active vitamin K-dependent factors were found to be markedly decreased or totally absent from human [32][33][34] and bovine plasma [35][36][37][38]46]. In several of these [34,37,47] and other studies, an inhibitory effect on thrombin gen eration in human and bovine plasma was initially reported.…”

Section: Section 1 Historical Perspectivesmentioning

confidence: 98%

“…The anticoagulant effects of warfarin derivatives reside in their antag onism to the functions of vitamin K [31]. They pre vent the post ribosomal carboxylation of glutamic acids, a step essential in the synthesis of five physio logically active clotting factors, prothrombin, Fac tors VII, IX, X and protein C. These are vitamin In dependent proenzymes, and the administration of anticoagulants in human [32][33][34], bovine [35][36][37][38][39], murine [40], canine [41], and avian [42] species re sults in the synthesis of structurally defective pro teins. In a functional one-stage clotting assay [43] or one of its modifications that use physiologic activators, the abnormal proteins cannot be mea sured.…”

Section: Section 1 Historical Perspectivesmentioning

confidence: 99%

“…Defective vitamin K-dependent factors were identi fied in plasma when it was recognized that these structurally defective proteins possess the ability to interact with antibodies raised against normal fac tors [32][33][34]39,40]. The antibody approach was used successfully to elucidate the role of anticoagulants on the mode of synthesis of inactive proteins [36,40], to prove the physical and chemical changes introduced [37,39], and to identify the immuno chemical properties of the functionally defective proteins circulating in plasma [33,37,39,44]. Follow ing anticoagulant drug administration, immunoreactive levels of prothrombin were found to be higher than those obtained by clotting assays [32][33][34][35]45].…”

Section: Section 1 Historical Perspectivesmentioning

confidence: 99%

See 2 more Smart Citations