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Thromb Haemost 2002; 87(06): 937-946
DOI: 10.1055/s-0037-1613115
Review Article
Schattauer GmbH

The Vitamin K-dependent Carboxylase

Steven R. Presnell
1   Department of Biology, CB #3280, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, USA
,
Darrel W. Stafford
1   Department of Biology, CB #3280, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, USA
› Author AffiliationsThis work was supported by National Institutes of Health grants HL48313 (D.W.S.)
Further Information

Publication History

Received 31 October 2001

Accepted after revision 14 December 2001

Publication Date:
08 December 2017 (online)

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  • References

  • 1 Stenflo J, Suttie JW. Vitamin K-dependent formation of gamma-carboxyglutamic acid. Annu Rev Biochem 1977; 46: 157-72.
    CrossrefPubMedSearch in Google Scholar
  • 2 Suttie JW. Mechanism of action of vitamin K: synthesis of gamma-carboxyglutamic acid. CRC Crit Rev Biochem 1980; 08: 191-223.
    PubMedSearch in Google Scholar
  • 3 Katayama K, Ericsson LH, Enfiel DL, Walsh KA, Neurath H, Davie EW, Titani K. Comparison of amino acid sequence of bovine coagulation factor IX (Christmas Factor) with that of other vitamin K-dependent plasma proteins. Proc Natl Acad Sci USA 1979; 76: 4990-4.
    CrossrefPubMedSearch in Google Scholar
  • 4 Nelsestuen GL. Role of gamma-carboxyglutamic acid. An unusual protein transition required for the calcium-dependent binding of prothrombin to phospholipid. J Biol Chem 1976; 251: 5648-56.
    PubMedSearch in Google Scholar
  • 5 Zwaal RF, Comfurius P, Bevers EM. Lipid-protein interactions in blood coagulation. Biochim Biophys Acta 1998; 1376: 433-53.
    CrossrefPubMedSearch in Google Scholar
  • 6 Roberts HR, Tabares AH. Overview of the coagulation reactions. In: Molecular Basis of Thrombosis and Hemostasis. High KA, Roberts HR. eds. New York: Marcel Dekker; 1995: 35-50.
    Search in Google Scholar
  • 7 Mann KG, Nesheim ME, Church WR, Haley P, Krishnaswamy S. Surface-dependent reactions of the vitamin K-dependent enzyme complexes. Blood 1990; 76: 1-16.
    PubMedSearch in Google Scholar
  • 8 Mann KG. Biochemistry and physiology of blood coagulation. Thromb Haemost 1999; 82: 165-74.
    Thieme ConnectPubMedSearch in Google Scholar
  • 9 Esmon CT, Suttie JW, Jackson CM. The functional significance of vitamin K action. Difference in phospholipid binding between normal and abnormal prothrombin. J Biol Chem 1975; 250: 4095-9.
    PubMedSearch in Google Scholar
  • 10 Malhotra OP, Nesheim ME, Mann KG. The kinetics of activation of normal and gamma-carboxyglutamic acid-deficient prothrombins. J Biol Chem 1985; 260: 279-87.
    PubMedSearch in Google Scholar
  • 11 Bovill EG, Mann KG. Warfarin and the biochemistry of the vitamin K-dependent proteins. Adv Exp Med Biol 1987; 214: 17-46.
    PubMedSearch in Google Scholar
  • 12 Esmon CT, Sadowski JA, Suttie JW. A new carboxylation reaction. The vitamin K-dependent incorporation of H14CO3 into prothrombin. J Biol Chem 1975; 250: 4744-8.
    PubMedSearch in Google Scholar
  • 13 Suttie JW. Vitamin K-dependent carboxylase. Annu Rev Biochem 1985; 54: 459-77.
    CrossrefPubMedSearch in Google Scholar
  • 14 Vermeer C. The vitamin K-dependent carboxylation reaction. Mol Cell Biochem 1984; 61: 17-35.
    PubMedSearch in Google Scholar
  • 15 Price PA. Role of vitamin K-dependent proteins in bone metabolism. Annu Rev Nutr 1988; 08: 565-83.
    CrossrefPubMedSearch in Google Scholar
  • 16 Manfioletti G, Brancolini C, Avanzi G, Schneider C. The protein encoded by a growth arrest-specific gene (Gas6) is a new member of the vitamin K-dependent proteins related to protein S, a negative coregulator in the blood coagulation cascade. Mol Cell Biol 1993; 13: 4976-85.
    CrossrefPubMedSearch in Google Scholar
  • 17 Stitt TN, Conn G, Gore M, Lai C, Bruno J, Radziejewski C, Mattsson K, Fisher J, Gies DR, Jones PF. The anticoagulation factor protein S and its relative, Gas6, are ligands for the Tyro 3/Axl family of receptor tyrosine kinases. Cell 1995; 80: 661-70.
    CrossrefPubMedSearch in Google Scholar
  • 18 Kulman JD, Harris JE, Haldeman BA, Davie EW. Primary structure and tissue distribution of two novel proline-rich gamma-carboxyglutamic acid proteins. Proc Natl Acad Sci USA 1997; 94: 9058-62.
    CrossrefPubMedSearch in Google Scholar
  • 19 Kulman JD, Harris JE, Xie L, Davie EW. Identification of two novel transmembrane gamma-carboxyglutamic acid proteins expressed broadly in fetal and adult tissues. Proc Natl Acad Sci USA 2001; 98: 1370-5.
    CrossrefPubMedSearch in Google Scholar
  • 20 Carlisle TL, Suttie JW. Vitamin K-dependent carboxylase: subcellular location of the carboxylase and enzymes involved in vitamin K metabolism in rat liver. Biochemistry 1980; 19: 1161-7.
    CrossrefPubMedSearch in Google Scholar
  • 21 Stanton C, Taylor R, Wallin R. Processing of prothrombin in the secretory pathway. Biochem J 1991; 277: 59-65.
    CrossrefPubMedSearch in Google Scholar
  • 22 Bristol JA, Ratcliffe JV, Roth DA, Jacobs MA, Furie BC, Furie B. Biosynthesis of prothrombin: intracellular localization of the vitamin K-dependent carboxylase and the sites of gamma-carboxylation. Blood 1996; 88: 2585-93.
    PubMedSearch in Google Scholar
  • 23 Vermeer C. Gamma-carboxyglutamate-containing proteins and the vitamin K-dependent carboxylase. Biochem J 1990; 266: 625-36.
    CrossrefPubMedSearch in Google Scholar
  • 24 Wu SM, Morris DP, Stafford DW. Identification and purification to near homogeneity of the vitamin K-dependent carboxylase. Proc Natl Acad Sci USA 1991; 88: 2236-40.
    CrossrefPubMedSearch in Google Scholar
  • 25 Wu SM, Cheung WF, Frazier D, Stafford DW. Cloning and expression of the cDNA for human gamma-glutamyl carboxylase. Science 1991; 254: 1634-6.
    CrossrefPubMedSearch in Google Scholar
  • 26 Tie J-K, Wu SM, Jin D-Y, Nicchitta CV, Stafford DW. A topological study of the human gamma-glutamyl carboxylase. Blood 2000; 96: 973-8.
    PubMedSearch in Google Scholar
  • 27 Brody T, Suttie JW. Evidence for the glycoprotein nature of vitamin K-dependent carboxylase from rat liver. Biochim Biophys Acta 1987; 923: 1-7.
    CrossrefPubMedSearch in Google Scholar
  • 28 Berkner KL, Harbeck M, Lingenfelter S, Bailey C, Sanders-Hinck CM, Suttie JW. Purification and identification of bovine liver gamma-carboxylase. Proc Natl Acad Sci USA 1992; 89: 6242-6.
    CrossrefPubMedSearch in Google Scholar
  • 29 Wu SM, Mutucumarana VP, Geromanos S, Stafford DW. The propeptide binding site of the bovine gamma-glutamyl carboxylase. J Biol Chem 1997; 272: 11718-22.
    CrossrefPubMedSearch in Google Scholar
  • 30 Wu SM, Stafford DW, Frazier LD, Fu YY, High KA, Chu K, Sanchez-Vega B, Solera J. Genomic sequence and transcription start site for the human gamma-glutamyl carboxylase. Blood 1997; 89: 4058-62.
    PubMedSearch in Google Scholar
  • 31 Kuo WL, Stafford DW, Cruces J, Gray J, Solera J. Chromosomal localization of the gamma-glutamyl carboxylase gene at 2p12. Genomics 1995; 25: 746-8.
    CrossrefPubMedSearch in Google Scholar
  • 32 Romero EE, Deo R, Velazquez-Estades LJ, Roth DA. Cloning, structural organization, and transcriptional activity of the rat vitamin K-dependent gamma-glutamyl carboxylase gene. Biochem Biophys Res Commun 1998; 248: 783-8.
    CrossrefPubMedSearch in Google Scholar
  • 33 Romero EE, Velazquez-Estades LJ, Deo R, Schapiro B, Roth DA. Cloning of rat vitamin K-dependent gamma-glutamyl carboxylase and developmentally regulated gene expression in post-implantation embryos. Exp Cell Res 1998; 243: 334-6.
    CrossrefPubMedSearch in Google Scholar
  • 34 Zhu A, Raymond R, Zheng X, Westrick R, Furie BC, Furie B, Kaufman RJ, Ginsburg D. Abnormalities of development and hemostasis in gamma-carboxylase deficient mice. Blood 1998; 92: 152a Abstract 611..
    PubMedSearch in Google Scholar
  • 35 Wallin R, Suttie JW. Vitamin K-dependent carboxylase: evidence for cofractionation of carboxylase and epoxidase activities, and for carboxylation of a high-molecular-weight microsomal protein. Arch Biochem Biophys 1982; 214: 155-63.
    CrossrefPubMedSearch in Google Scholar
  • 36 Morris DP, Soute BA, Vermeer C, Stafford DW. Characterization of the purified vitamin K-dependent gamma-glutamyl carboxylase. J Biol Chem 1993; 268: 8735-42.
    PubMedSearch in Google Scholar
  • 37 Sadowski JA, Esmon CT, Suttie JW. Vitamin K-dependent carboxylase. Requirements of the rat liver microsomal enzyme system. J Biol Chem 1976; 251: 2770-6.
    PubMedSearch in Google Scholar
  • 38 Wood GM, Suttie JW. Vitamin K-dependent carboxylase. Stoichiometry of vitamin K epoxide formation, gamma-carboxyglutamyl formation, and gamma-glutamyl-3H cleavage. J Biol Chem 1988; 263: 3234-9.
    PubMedSearch in Google Scholar
  • 39 Larson AE, Friedman PA, Suttie JW. Vitamin K-dependent carboxylase. Stoichiometry of carboxylation and vitamin K 2,3-epoxide formation. J Biol Chem 1981; 256: 11032-5.
    PubMedSearch in Google Scholar
  • 40 Dowd P, Hershline R, Ham SW, Naganathan S. Vitamin K and energy transduction: a base strength amplification mechanism. Science 1995; 269: 1684-91.
    CrossrefPubMedSearch in Google Scholar
  • 41 Dowd P, Ham SW, Geib SJ. Mechanism of action of Vitamin K. J Am Chem Soc 1991; 113: 7734-43.
    CrossrefPubMedSearch in Google Scholar
  • 42 Ham SW, Dowd P. On the mechanism of Vitamin K. A new nonenzymic model. J Am Chem Soc 1990; 112: 1660-1.
    CrossrefPubMedSearch in Google Scholar
  • 43 Kuliopulos A, Hubbard BR, Lam Z, Koski IJ, Furie B, Furie BC, Walsh CT. Dioxygen transfer during vitamin K-dependent carboxylase catalysis. Biochemistry 1992; 31: 7722-8.
    CrossrefPubMedSearch in Google Scholar
  • 44 Sadowski JA, Schnoes HK, Suttie JW. Vitamin K epoxidase: properties and relationship to prothrombin synthesis. Biochemistry 1977; 16: 3856-63.
    CrossrefPubMedSearch in Google Scholar
  • 45 Flowers RA, Naganathan S, Dowd P, Arnett EM, Ham SW. Thermochemical investigation of the oxygenation of Vitamin K. J Am Chem Soc 1993; 115: 9409-16.
    CrossrefPubMedSearch in Google Scholar
  • 46 Berkner KL, Pudota BN. Vitamin K-dependent carboxylation of the carboxylase. Proc Natl Acad Sci USA 1998; 95: 466-71.
    CrossrefPubMedSearch in Google Scholar
  • 47 Stanley TB, Jin DY, Lin PJ, Stafford DW. The propeptides of the vitamin K-dependent proteins possess different affinities for the vitamin K-dependent carboxylase. J Biol Chem 1999; 274: 16940-4.
    CrossrefPubMedSearch in Google Scholar
  • 48 Sugiura I, Furie B, Walsh CT, Furie BC. Propeptide and glutamatecontaining substrates bound to the vitamin K-dependent carboxylase convert its vitamin K epoxidase function from an inactive to an active state. Proc Natl Acad Sci USA 1997; 94: 9069-74.
    CrossrefPubMedSearch in Google Scholar
  • 49 Larson AE, Witlon DS, Suttie JW. Factors affecting the Vitamin K-dependent microsomal carboxylation system. Fed Proc FASEB 1979; 38: 786 Abstract 3410..
    PubMedSearch in Google Scholar
  • 50 De Metz M, Soute BA, Hemker HC, Vermeer C. The inhibition of vitamin K-dependent carboxylase by cyanide. FEBS Lett 1982; 137: 253-6.
    CrossrefPubMedSearch in Google Scholar
  • 51 Presnell SR, Stafford DW. Unpublished observations. 2000
    PubMedSearch in Google Scholar
  • 52 Mack DO, Suen ET, Girardot JM, Miller JARD, Johnson BC. Soluble enzyme system for vitamin K-dependent carboxylation. J Biol Chem 1976; 251: 3269-76.
    PubMedSearch in Google Scholar
  • 53 Suttie JW, Lehrman SR, Geweke LO, Hageman JM, Rich DH. Vitamin K-dependent carboxylase: requirements for carboxylation of soluble peptide and substrate specificity. Biochem Biophys Res Commun 1979; 86: 500-7.
    CrossrefPubMedSearch in Google Scholar
  • 54 Canfield LM. Vitamin K-dependent oxygenase/carboxylase; differential inactivation by sulfhydryl reagents. Biochem Biophys Res Commun 1987; 148: 184-91.
    CrossrefPubMedSearch in Google Scholar
  • 55 Pudota BN, Miyagi M, Hallgren KW, West KA, Crabb JW, Misono KS, Berkner KL. Identification of the vitamin K-dependent carboxylase active site: Cys-99 and Cys-450 are required for both epoxidation and carboxylation. Proc Natl Acad Sci USA 2000; 97: 13033-8.
    CrossrefPubMedSearch in Google Scholar
  • 56 Bouchard BA, Furie B, Furie BC. Glutamyl substrate-induced exposure of a free cysteine residue in the vitamin K-dependent gamma-glutamyl carboxylase is critical for vitamin K epoxidation. Biochemistry 1999; 38: 9517-23.
    CrossrefPubMedSearch in Google Scholar
  • 57 Hildebrandt EF, Suttie JW. Mechanism of coumarin action: sensitivity of vitamin K metabolizing enzymes of normal and warfarin-resistant rat liver. Biochemistry 1982; 21: 2406-11.
    CrossrefPubMedSearch in Google Scholar
  • 58 Wallin R, Martin LF. Vitamin K-dependent carboxylation and vitamin K metabolism in liver. Effects of warfarin. J Clin Invest 1985; 76: 1879-84.
    CrossrefPubMedSearch in Google Scholar
  • 59 Bell RG. Metabolism of vitamin K and prothrombin synthesis: anticoagulants and the vitamin K-epoxide cycle. Fed Proc 1978; 37: 2599-604.
    PubMedSearch in Google Scholar
  • 60 Hirsh J, Ginsberg JS, Marder VJ. Anticoagulant therapy with coumarin agents. In: Hemostasis and Thrombosis: Principles and Clinical Practice. Colman RW, Hirsh J, Marder VJ, Salzman EW. editors. Philadelphia: J. B. Lippincott; 1994
    Search in Google Scholar
  • 61 Bell RG, Matschiner JT. Vitamin K activity of phylloquinone oxide. Arch Biochem Biophys 1970; 141: 473-6.
    CrossrefPubMedSearch in Google Scholar
  • 62 Diuguid DL, Rabiet MJ, Furie BC, Liebman HA, Furie B. Molecular basis of hemophilia B: a defective enzyme due to an unprocessed propeptide is caused by a point mutation in the factor IX precursor. Proc Natl Acad Sci USA 1986; 83: 5803-7.
    CrossrefPubMedSearch in Google Scholar
  • 63 Stanley TB, Wu SM, Houben RJ, Mutucumarana VP, Stafford DW. Role of the propeptide and gamma-glutamic acid domain of factor IX for in vitro carboxylation by the vitamin K-dependent carboxylase. Biochemistry 1998; 37: 13262-8.
    CrossrefPubMedSearch in Google Scholar
  • 64 Morris DP, Stevens RD, Wright DJ, Stafford DW. Processive post-translational modification. Vitamin K-dependent carboxylation of a peptide substrate. J Biol Chem 1995; 270: 30491-8.
    CrossrefPubMedSearch in Google Scholar
  • 65 Stenina O, Pudota BN, McNally BA, Hommema E, Berkner KL. Tethered processivity of the vitamin K-dependent carboxylase: factor IX is efficiently modified in a mechanism which distinguishes gla’s from glu’s and which accounts for comprehensive carboxylation in vivo. Biochemistry 2001; 40: 10301-9.
    CrossrefPubMedSearch in Google Scholar
  • 66 Kurachi K, Davie EW. Isolation and characterization of a cDNA coding for human factor IX. Proc Natl Acad Sci USA 1982; 79: 6461-4.
    CrossrefPubMedSearch in Google Scholar
  • 67 Foster DC, Rudinski MS, Schach BG, Berkner KL, Kumar AA, Hagen FS, Sprecher CA, Insley MY, Davie EW. Propeptide of human protein C is necessary for gamma-carboxylation. Biochemistry 1987; 26: 7003-11.
    CrossrefPubMedSearch in Google Scholar
  • 68 Jorgensen MJ, Cantor AB, Furie BC, Brown CL, Shoemaker CB, Furie B. Recognition site directing vitamin K-dependent gamma-carboxylation resides on the propeptide of factor IX. Cell 1987; 48: 185-91.
    CrossrefPubMedSearch in Google Scholar
  • 69 Pan LC, Price PA. The propeptide of rat bone gamma-carboxyglutamic acid protein shares homology with other vitamin K-dependent protein precursors. Proc Natl Acad Sci USA 1985; 82: 6109-13.
    CrossrefPubMedSearch in Google Scholar
  • 70 Handford PA, Winship PR, Brownlee GG. Protein engineering of the propeptide of human factor IX. Protein Eng 1991; 04: 319-23.
    CrossrefPubMedSearch in Google Scholar
  • 71 Huber P, Schmitz T, Griffin J, Jacobs M, Walsh C, Furie B, Furie BC. Identification of amino acids in the gamma-carboxylation recognition site on the propeptide of prothrombin. J Biol Chem 1990; 265: 12467-73.
    PubMedSearch in Google Scholar
  • 72 Furie B, Furie BC. Molecular basis of vitamin K-dependent gamma-carboxylation. Blood 1990; 75: 1753-62.
    PubMedSearch in Google Scholar
  • 73 Bristol JA, Furie BC, Furie B. Propeptide processing during factor IX biosynthesis. Effect of point mutations adjacent to the propeptide cleavage site. J Biol Chem 1993; 268: 7577-84.
    PubMedSearch in Google Scholar
  • 74 Ware J, Diuguid DL, Liebman HA, Rabiet MJ, Kasper CK, Furie BCBF, Stafford DW. Factor IX San Dimas. Substitution of glutamine for Arg-4 in the propeptide leads to incomplete gamma-carboxylation and altered phospholipid binding properties. J Biol Chem 1989; 264: 11401-6.
    PubMedSearch in Google Scholar
  • 75 Bristol JA, Freedman S, Furie BC, Furie B. Profactor IX: the propeptide inhibits binding to membrane surfaces and activation by factor XIa. Biochemistry 1994; 33: 14136-43.
    CrossrefPubMedSearch in Google Scholar
  • 76 Price PA, Fraser JD, Metz-Virca G. Molecular cloning of matrix Gla protein: implications for substrate recognition by the vitamin K-dependent gamma-carboxylase. Proc Natl Acad Sci USA 1987; 84: 8335-9.
    CrossrefPubMedSearch in Google Scholar
  • 77 Engelke JA, Hale JE, Suttie JW, Price PA. Vitamin K-dependent carboxylase: utilization of decarboxylated bone Gla protein and matrix Gla protein as substrates. Biochim Biophys Acta 1991; 1078: 31-4.
    CrossrefPubMedSearch in Google Scholar
  • 78 Vermeer C, Soute BA, Hendrix H, de Boer-van den Berg MA. Decarboxylated bone Gla-protein as a substrate for hepatic vitamin K-dependent carboxylase. FEBS Lett 1984; 165: 16-20.
    CrossrefPubMedSearch in Google Scholar
  • 79 Houben RJ, Jin D, Stafford DW, Proost P, Ebberink RH, Vermeer C, Soute BA. Osteocalcin binds tightly to the gamma-glutamyl carboxylase at a site distinct from that of the other known vitamin K-dependent proteins. Biochem 1999; 341: 265-9.
    CrossrefPubMedSearch in Google Scholar
  • 80 Suttie JW. Synthesis of vitamin K-dependent proteins. FASEB J 1993; 07: 445-52.
    CrossrefPubMedSearch in Google Scholar
  • 81 Rich DH, Lehrman SR, Kawai M, Goodman HL, Suttie JW. Synthesis of peptide analogues of prothrombin precursor sequence 5-9. Substrate specificity of vitamin K-dependent carboxylase. J Med Chem 1981; 24: 706-11.
    CrossrefPubMedSearch in Google Scholar
  • 82 Ulrich MM, Furie B, Jacobs MR, Vermeer C, Furie BC. Vitamin K-dependent carboxylation. A synthetic peptide based upon the gamma-carboxylation recognition site sequence of the prothrombin propeptide is an active substrate for the carboxylase in vitro. J Biol Chem 1988; 263: 9697-702.
    PubMedSearch in Google Scholar
  • 83 Hubbard BR, Jacobs M, Ulrich MM, Walsh C, Furie B, Furie BC. Vitamin K-dependent carboxylation. In vitro modification of synthetic peptides containing the gamma-carboxylation recognition site. J Biol Chem 1989; 264: 14145-50.
    PubMedSearch in Google Scholar
  • 84 Zhang L, Castellino FJ. Role of the hexapeptide disulfide loop present in the gamma-carboxyglutamic acid domain of human protein C in its activation properties and in the in vitro anticoagulant activity of activated protein C. Biochemistry 1991; 30: 6696-704.
    CrossrefPubMedSearch in Google Scholar
  • 85 Zhang L, Jhingan A, Castellino FJ. Role of individual gamma-carboxyglutamic acid residues of activated human protein C in defining its in vitro anticoagulant activity. Blood 1992; 80: 942-52.
    PubMedSearch in Google Scholar
  • 86 Wu SM, Soute BA, Vermeer C, Stafford DW. In vitro gamma-carboxylation of a 59-residue recombinant peptide including the propeptide and the gamma-carboxyglutamic acid domain of coagulation factor IX. Effect of mutations near the propeptide cleavage site. J Biol Chem 1990; 265: 13124-9.
    PubMedSearch in Google Scholar
  • 87 Furie BC, Ratcliffe JV, Tward J, Jorgensen MJ, Blaszkowsky LS, DiMichele D, Furie B. The gamma-carboxylation recognition site is sufficient to direct vitamin K-dependent carboxylation on an adjacent glutamate-rich region of thrombin in a propeptide-thrombin chimera. J Biol Chem 1997; 272: 28258-62.
    CrossrefPubMedSearch in Google Scholar
  • 88 Stanley TB, Humphries J, High KA, Stafford DW. Amino acids responsible for reduced affinities of vitamin K-dependent propeptides for the carboxylase. Biochemistry 1999; 38: 15681-7.
    CrossrefPubMedSearch in Google Scholar
  • 89 Olivera BM. Conus venom peptides, receptor and ion channel targets, and drug design: 50 million years of neuropharmacology. Mol Biol Cell 1997; 08: 2101-9.
    CrossrefPubMedSearch in Google Scholar
  • 90 Olivera BM, Rivier J, Clark C, Ramilo CA, Corpuz GP, Abogadie FC, Mena EE, Woodward SR, Hillyard DR, Cruz LJ. Diversity of Conus neuropeptides. Science 1990; 249: 257-63.
    CrossrefPubMedSearch in Google Scholar
  • 91 McIntosh JM, Olivera BM, Cruz LJ, Gray WR. Gamma-carboxyglutamate in a neuroactive toxin. J Biol Chem 1984; 259: 14343-6.
    PubMedSearch in Google Scholar
  • 92 Lirazan MB, Hooper D, Corpuz GP, Ramilo CA, Bandyopadhyay P, Cruz LJ, Olivera BM. The spasmodic peptide defines a new conotoxin superfamily. Biochemistry 2000; 39: 1583-8.
    CrossrefPubMedSearch in Google Scholar
  • 93 Bandyopadhyay PK, Colledge CJ, Walker CS, Zhou LM, Hillyard DR, Olivera BM. Conantokin-G precursor and its role in gamma-carboxylation by a vitamin K-dependent carboxylase from a Conus snail. J Biol Chem 1998; 273: 5447-50.
    CrossrefPubMedSearch in Google Scholar
  • 94 Bush KA, Stenflo J, Roth DA, Czerwiec E, Harrist A, Begley GS, Furie BC, Furie B. Hydrophobic amino acids define the carboxylation recognition site in the precursor of the gamma-carboxyglutamic-acid-containing conotoxin epsilon-TxIX from the marine cone snail Conus textile. Biochemistry 1999; 38: 14660-6.
    CrossrefPubMedSearch in Google Scholar
  • 95 Yamada M, Kuliopulos A, Nelson NP, Roth DA, Furie B, Furie BC, Walsh CT. Localization of the factor IX propeptide binding site on recombinant vitamin K dependent carboxylase using benzoylphenylalanine photoaffinity peptide inactivators. Biochemistry 1995; 34: 481-9.
    CrossrefPubMedSearch in Google Scholar
  • 96 Sugiura I, Furie B, Walsh CT, Furie BC. Profactor IX propeptide and glutamate substrate binding sites on the vitamin K-dependent carboxylase identified by site-directed mutagenesis. J Biol Chem 1996; 271: 17837-44.
    CrossrefPubMedSearch in Google Scholar
  • 97 Kuliopulos A, Cieurzo CE, Furie B, Furie BC, Walsh CT. N-bromoacetylpeptide substrate affinity labeling of vitamin K dependent carboxylase. Biochemistry 1992; 31: 9436-44.
    CrossrefPubMedSearch in Google Scholar
  • 98 Kuliopulos A, Nelson NP, Yamada M, Walsh CT, Furie B, Furie BC, Roth DA. Localization of the affinity peptide-substrate inactivator site on recombinant vitamin K-dependent carboxylase. J Biol Chem 1994; 269: 21364-70.
    PubMedSearch in Google Scholar
  • 99 Maillet M, Morris D, Gaudry M, Marquet A. The active site region of the vitamin K-dependent carboxylase includes both the amino-terminal hydrophobic and carboxy-terminal hydrophilic domains of the protein. FEBS Lett 1997; 413: 1-6.
    CrossrefPubMedSearch in Google Scholar
  • 100 Brenner B. Hereditary deficiency of vitamin K-dependent coagulation factors. Thromb Haemost 2000; 84: 935-6.
    Thieme ConnectPubMedSearch in Google Scholar
  • 101 Brenner B, Sanchez-Vega B, Wu SM, Lanir N, Stafford DW, Solera J. A missense mutation in gamma-glutamyl carboxylase gene causes combined deficiency of all vitamin K-dependent blood coagulation factors. Blood 1998; 92: 4554-9.
    PubMedSearch in Google Scholar
  • 102 Mutucumarana VP, Stafford DW, Stanley TB, Jin DY, Solera J, Brenner B, Azerad R, Wu SM. Expression and characterization of the naturally occurring mutation L394R in human gamma-glutamyl carboxylase. J Biol Chem 2000; 275: 32572-7.
    CrossrefPubMedSearch in Google Scholar
  • 103 Spronk HM, Farah RA, Buchanan GR, Vermeer C, Soute BA. Novel mutation in the gamma-glutamyl carboxylase gene resulting in congenital combined deficiency of all vitamin K-dependent blood coagulation factors. Blood 2000; 96: 3650-2.
    PubMedSearch in Google Scholar
  • 104 Sout BA, Mutucumarana VP, Jin D-Y, Stafford DW. Unpublished observations. 2001
    PubMedSearch in Google Scholar
  • 105 Knobloch JE, Suttie JW. Vitamin K-dependent carboxylase. Control of enzyme activity by the “propeptide” region of factor X. J Biol Chem 1987; 262: 15334-7.
    PubMedSearch in Google Scholar
  • 106 Soute BA, Ulrich MM, Watson AD, Maddison JE, Ebberin RH, Vermeer C. Congenital deficiency of all vitamin K-dependent blood coagulation factors due to a defective vitamin K dependent carboxylase in Devon Rex cats. Thromb Haemost 1992; 68: 521-5.
    Thieme ConnectPubMedSearch in Google Scholar
  • 107 Presnell SR, Tripathy A, Lentz BR, Jin D-Y, Stafford DW. A novel fluorescence assay to study the propeptide interaction with gamma-glutamyl carboxylase. Biochemistry 2001; 40: 11723-33.
    CrossrefPubMedSearch in Google Scholar
  • 108 Rehemtulla A, Roth DA, Wasley LC, Kuliopulos A, Walsh CT, Furie B, Furie BC, Kaufman RJ. In vitro and in vivo functional characterization of bovine vitamin K-dependent gamma-carboxylase expressed in Chinese hamster ovary cells. Proc Natl Acad Sci USA 1993; 90: 4611-5.
    CrossrefPubMedSearch in Google Scholar
  • 109 Zhu A, Zheng X, Ginsburg D. Characterization of the mouse gamma-carboxylase genomic locus and its promoter, Genbank. Accession number: NM019802; 2000.
    PubMed
  • 110 Begley GS, Furie BC, Czerwiec E, Taylor KL, Furie GL, Bronstein L, Stenflo J, Furie B. A conserved motif within the vitamin K-dependent carboxylase gene is widely distributed across animal phyla. J Biol Chem 2000; 275: 36245-9.
    CrossrefPubMedSearch in Google Scholar
  • 111 Stanley TB, Stafford DW, Olivera BM, Bandyopadhyay PK. Identification of a vitamin K-dependent carboxylase in the venom duct of a Conus snail. FEBS Lett 1997; 407: 85-8.
    CrossrefPubMedSearch in Google Scholar
  • 112 Li T, Yang C-T, Jin D, Stafford DW. Identification of a drosophila Vitamin K-dependent gamma-glutamyl carboxylase. J Biol Chem 2000; 275: 18291-6.
    CrossrefPubMedSearch in Google Scholar
  • 113 Walker CS, Shetty RP, Clark KA, Kazuko SG, Letsou A, Olivera BM, Bandyopadhyay PK. On a potential global role for vitamin K-dependent gamma-carboxylation in animal systems: Evidence for a gamma-glutamyl carboxylase in drosophila. J Biol Chem 2001; 276: 7769-74.
    CrossrefPubMedSearch in Google Scholar
  • 114 Martinez MB, Harvey SB, Higgins LA, Krick T, Shen L, Kisiel W, Foster DC, Brown T, Evans TC, Shah AM, Nelsestuen GL. Undercarboxylation of Vitamin K-dependent proteins: occasionally severe, possibly universal. In: Proceedings of the 49th ASMS Conference on Mass Spectrometry and Allied Topics; 2001. Chicago, Illinois:
    Search in Google Scholar
  • 115 Magnusson S, Sottrup-Jensen L, Petersen TE, Morris HR, Dell A. Primary structure of the vitamin K-dependent part of prothrombin. FEBS Lett 1974; 44: 189-93.
    CrossrefPubMedSearch in Google Scholar
  • 116 Zhang P, Suttie JW. Prothrombin Synthesis and Degradation in Rat Hepatoma (H-35) Cells: Effects of Warfarin. Blood 1994; 84: 169-75.
    PubMedSearch in Google Scholar
  • 117 Tokunaga F, Wakabayashi S, Koide T. Warfarin causes the degradation of protein C precursor in the endoplasmic reticulum. Biochemistry 1995; 34: 1163-70.
    CrossrefPubMedSearch in Google Scholar
  • 118 Price PA, Williamson MK. Substrate recognition by the vitamin K-dependent gamma-glutamyl carboxylase: identification of a sequence homology between the carboxylase and the carboxylase recognition site in the substrate. Protein Sci 1993; 02: 1987-8.
    CrossrefPubMedSearch in Google Scholar
  • 119 Suttie JW, Geweke LO, Martin S, Willingham AK. Vitamin K epoxidase: dependence of epoxidase activity on substrates of the vitamin K-dependent carboxylation reaction. FEBS Lett 1980; 109: 267-70.
    CrossrefPubMedSearch in Google Scholar
  • 120 Cheung A, Engelke JA, Sanders C, Suttie JW. Vitamin K-dependent carboxylase: influence of the “propeptide” region on enzyme activity. Arch Biochem Biophys 1989; 274: 574-81.
    CrossrefPubMedSearch in Google Scholar
  • 121 Cheung A, Suttie JW, Bernatowicz M. Vitamin K-dependent carboxylase: structural requirements for propeptide activation. Biochim Biophys Acta 1990; 1039: 90-3.
    CrossrefPubMedSearch in Google Scholar
  • 122 Li S, Furie BC, Furie B, Walsh CT. The propeptide of the vitamin K-dependent carboxylase substrate accelerates formation of the gamma-glutamyl carbanion intermediate. Biochemistry 1997; 36: 6384-90.
    CrossrefPubMedSearch in Google Scholar
  • 123 Chu K, Wu SM, Stanley T, Stafford DW, High KA. A mutation in the propeptide of factor IX leads to warfarin sensitivity by a novel mechanism. J Clin Invest 1996; 98: 1619-25.
    CrossrefPubMedSearch in Google Scholar
  • 124 Wu SM, Stanley B, Mutucumarana VP, Stafford DW. Characterization of the gamma-glutamyl carboxylase. Thromb Haemost 1997; 78: 599-604.
    Thieme ConnectPubMedSearch in Google Scholar
  • 125 Oldenburg J, Quenzel EM, Harbrecht U, Fregin A, Kress W, Muller CR, Hertfelder HJ, Schwaab R, Brackmann HH, Hanfland P. Missense mutations at Ala-10 in the factor IX propeptide: an insignificant variant in normal life but a decisive cause of bleeding during oral anticoagulant therapy. Br J Haematol 1997; 98: 240-4.
    CrossrefPubMedSearch in Google Scholar
  • 126 Yan SC, Grinnell BW, Wold F. Post-translational modifications of proteins: some problems left to solve. Trends Biochem Sci 1989; 14: 264-8.
    CrossrefPubMedSearch in Google Scholar
  • 127 Berkner KL. Expression of recombinant vitamin K-dependent proteins in mammalian cells: factors IX and VII. Methods Enzymol 1993; 222: 450-77.
    PubMedSearch in Google Scholar
  • 128 Camire RM, Larson PJ, Stafford DW, High KA. Enhanced gamma-carboxylation of recombinant factor X using a chimeric construct containing the prothrombin propeptide. Biochemistry 2001; 39: 14322-9.
    PubMedSearch in Google Scholar
  • 129 Soute BA, Vermeer C, De Metz M, Hemker HC, Lijnen HR. In vitro prothrombin synthesis from a purified precursor protein. III. Preparation of an acid-soluble substrate for vitamin K-dependent carboxylase by limited proteolysis of bovine descarboxyprothrombin. Biochim Biophys Acta 1981; 676: 101-7.
    CrossrefPubMedSearch in Google Scholar
  • 130 Tie J-K, Jin D-Y, Stafford DW. Unpublished observations. 2001
    PubMedSearch in Google Scholar