Différents états moléculaires du facteur II (prothrombine). Leur étude à l’aide de la staphylocoagulase et d’anticorps anti-facteur II

Josso, F; Lavergne, Jean‐Maurice; Gouault, M; Prou-Wartelle, O; Soulier, J.

doi:10.1055/s-0038-1651251

Cited by 49 publications

(11 citation statements)

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“…2 upon derivative formation), we have also examined peptides 4-10,5-11, 14-2 1 and 31-35 by mass spectrometry. We find that y-carboxyl glutamic acid is present not only as residues 7 and 8, in agreement with Stenflo's work [21], but also as residues 15, 17, 20, 21 and 33. We therefore have sound mass spectrometric evidence to show that all ten glutamic acids in the N-terminal region of prothrombin are substituted with a y-carboxyl group.…”

Section: Resultssupporting

confidence: 92%

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Primary structure of the vitamin K‐dependent part of prothrombin

1974

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Section: Resultssupporting

confidence: 92%

“…1) are both y-carboxyl glutamic acids [21]. This was based upon NMR data, and on the mass spectrum of the acetylated permethylated peptide.…”

Section: Resultsmentioning

confidence: 99%

Primary structure of the vitamin K‐dependent part of prothrombin

1974

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“…Second, the action of vitamin K in the deficient rat is only partially inhibited by cycloheximide and puromycin (12,191,250) whereas in the chick it is completely inhibited (184,192,282). Since the chick secretes an acarboxy form of plasma prothrombin, whereas the rat does not (36,173), the chick accumulates much less precursor in its liver than the rat and hence is more dependent than the rat upon ribosomal synthesis of precursor to sustain prothrombin secretion in response to vitamin K. It appears that the human and the cow resemble the chick in this regard more than the rat (36,116,245). Ganrot and Nilehn (88) first demonstrated the presence of a protein in the plasma of human subjects receiving dicumarol that reacted to antibodies against human prothrombin but did not demonstrate any biological activity in a stan dard clotting assay using factor X and thromboplastin.…”

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confidence: 99%

The Function and Metabolism of Vitamin K

Olson¹

1984

Annu. Rev. Nutr.

154

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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.

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“…The biosynthesis of prothrombin is vitamin K dependent, and deficiency of this vitamin or administration of the vitamin K antagonist, dicoumarol, gives rise to an abnormal prothrombin which does not function in blood coagulation (1)(2)(3)(4)(5)(6). The activation of prothrombin in vivo requires the binding of Ca2+ (7); abnormal prothrombin does not bind Ca2+ (2,8,9).…”

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Vitamin K Dependent Modifications of Glutamic Acid Residues in Prothrombin

Stenflo

Fernlund

Egan³

et al. 1974

Proc. Natl. Acad. Sci. U.S.A.

710

291

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A tetrapeptide, residues 6 to 9 in normal prothrombin, was isolated from the NH2-terminal, Ca2+-binding part of normal prothrombin. The electrophoretic mobility of the peptide was too high to be explained entirely by its amino-acid composition. According to 1H nuclear magnetic resonance spectroscopy and mass spectrometry, the peptide contained two residues of modified glutamic acid, -y-carboxyglutamic acid (3-amino-1,1,3-propanetricarboxylic acid), a hitherto unidentified amino acid. This amino acid gives normal prothrombin the Ca2 +_ binding ability that is necessary for its activation. Observations indicate that abnormal prothrombin, induced by the vitamin K antagonist, dicoumarol, lacks these modified glutamic acid residues and that this is the reason why abnormal prothrombin does not bind Ca2+ and is nonfunctioning in blood coagulation.Prothrombin is a plasma glycoprotein that is activated during the process of blood coagulation to the proteolytic enzyme thrombin. The biosynthesis of prothrombin is vitamin K dependent, and deficiency of this vitamin or administration of the vitamin K antagonist, dicoumarol, gives rise to an abnormal prothrombin which does not function in blood coagulation (1-6). The activation of prothrombin in vivo requires the binding of Ca2+ (7); abnormal prothrombin does not bind Ca2+ (2, 8, 9). During the activation of normal prothrombin an NH2-terminal fragment (molecular weight approximately 25,000) is split off; the difference between abnormal and normal prothrombin has been localized to this part of the molecule. Evidence has been produced that the difference is due to the lack of certain prosthetic groups in abnormal prothrombin (10-13).In an endeavour to define the difference between normal and abnormal prothrombin, the NH2-terminal fragments from both proteins were isolated and degraded further. A heptapeptide from normal prothrombin (residues 4 to 10) and a corresponding heptapeptide from abnormal prothrombin were isolated by BrCN degradation and trypsin digestion. The heptapeptide from normal prothrombin differed from the corresponding peptide in abnormal prothrombin in that it had a higher anodal electrophoretic mobility at pH 6.5 (13).By extensive proteolytic digestion, the heptapeptide from normal prothrombin was degraded to a tetrapeptide. This tetrapeptide, containing residues 6 to 9, still had an abnormally high anodal electrophoretic mobility at pH 6.5. This paper reports evidence that each of the two glutamic acid residues of this peptide are modified by replacement of one hydrogen on the -y carbon atom by a carboxyl group. This work will be described in greater detail elsewhere. MATERIALS AND METHODSIsolation of Tetrapeptide. The heptapeptide from normal prothrombin (residues 4 to 10) (ref. 13) was first thoroughly digested with aminopeptidase M (Sigma) and afterwards with carboxypeptidase B (Sigma). A tetrapeptide was isolated from the digest by gel chromatography on Sephadex G-25 superfine and obtained in pure form as judged by high voltage electrophoresis at...

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Différents états moléculaires du facteur II (prothrombine). Leur étude à l’aide de la staphylocoagulase et d’anticorps anti-facteur II

Cited by 49 publications

References 0 publications

Primary structure of the vitamin K‐dependent part of prothrombin

Primary structure of the vitamin K‐dependent part of prothrombin

The Function and Metabolism of Vitamin K

Vitamin K Dependent Modifications of Glutamic Acid Residues in Prothrombin

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