Contributors p. xiii
Preface p. xix
1 Determinants of Vitamin K Status in Humans Sarah L. Booth and Ala Al Rajabi p. 1
I Introduction p. 2
II Assessment of Vitamin K Status p. 2
III Nongenetic Determinants p. 5
IV Genetic Determinants p. 14
V Conclusions and Future Directions p. 16
Acknowledgments p. 17
References p. 17
2 VKORC1 and the Vitamin K Cycle Andrea A. Garcia and Pieter H. Reitsma p. 23
I Vitamin K Cycle: Limiting Step of Carboxylation p. 24
II VKOR: Is It a Complex? p. 27
III VKORC1 in Clinical Practice p. 29
IV Conclusion p. 31
Acknowledgment p. 31
References p. 32
3 The Vitamin K Cycle Johannes Oldenburg and Milka Marinova and Clemens Muller-Reible and Matthias Watzka p. 35
I Introduction p. 36
II Vitamin K Biosynthesis p. 37
III Vitamin K Cycle p. 39
IV Physiological Role of Vitamin K Dependent Proteins p. 44
V Clinical Phenotypes Related to the Vitamin K Pathway in Man p. 47
VI Conclusions and Perspectives p. 53
Acknowledgments p. 54
References p. 54
4 Structure, Function, and Mechanism of Cytosolic Quinone Reductases Mario A. Bianchet and Sabri Bora Erdemli and L. Mario Amzel p. 63
I Introduction p. 64
II Quinone Reductase Type 1 p. 65
III Quinone Reductase Type 2 p. 77
IV Disclaimer p. 79
References p. 79
5 Quinone Oxidoreductases and Vitamin K Metabolism Xing Gong and Ramana Gutala and Anil K. Jaiswal p. 85
I Vitamin K and Vitamin K Cycle p. 86
II Quinone Oxidoreductases p. 87
III Quinone Oxidoreductases and Reduction of Vitamin K to Hydroquinone p. 91
IV Quinone Oxidoreductases and Metabolic Detoxification or Activation of Vitamin K p. 93
V Quinone Oxidoreductases and Anticancer Effects of Vitamin K p. 95
VI Future Perspectives p. 96
Acknowledgments p. 96
References p. 96
6 Structure and Function of Vitamin K Epoxide Reductase Jian-Ke Tie and Darrel W. Stafford p. 103
I Introduction p. 104
II Purification of VKOR p. 106
III Mechanism of Vitamin K Epoxide Reduction Catalyzed by VKOR p. 110
IV Identification of the Active Site of VKOR p. 115
V Warfarin Inhibition of VKOR p. 117
VI Membrane Topology of VKOR p. 122
VII Conclusion p. 124
References p. 125
7 Vitamin K-Dependent Carboxylation Kathleen L. Berkner p. 131
I Vitamin K-Dependent Protein Function p. 132
II Vitamin K Forms p. 134
III Mechanism of Carboxylation p. 135
IV Functional Regions of the Carboxylase p. 138
V Vitamin K Reduction Is Required for Carboxylation in Tissue p. 142
VI Carboxylation Interfaces with Secretion p. 144
VII The Capacity of Vitamin K-Dependent Protein Carboxylation Is Limited in Cultured Cells p. 146
VIII Summary p. 148
References p. 149
8 Vitamin K-Dependent [gamma]-Glutamylcarboxylation: An Ancient Posttranslational Modification Pradip K. Bandyopadhyay p. 157
I Introduction p. 158
II Reviews p. 159
III [gamma]-Carboxylation Reaction p. 159
IV Vitamin K Cycle p. 161
V Mechanism of [gamma]-Carboxylation p. 162
VI Proposed Topology of [gamma]-Glutamyl Carboxylase p. 162
VII Substrate Recognition (Propeptide) p. 163
VIII Structure-Function Relationship p. 164
IX Expression of GGCX During Development p. 166
X Gla-Containing Proteins and [gamma]-Carboxylase in Urochordate p. 166
XI Drosophila [gamma]-Glutamyl Carboxylase p. 167
XII [gamma]-Carboxylated Peptides in Conus p. 167
XIII Conus [gamma]-Glutamyl Carboxylase p. 174
XIV Future Prospects p. 175
Acknowledgments p. 177
References p. 177
9 Vitamin K-Dependent Actions of Gas6 Lola Bellido-Martin and Pablo Garcia de Frutos p. 185
I Introduction p. 186
II Gas6 Structure p. 186
III Cellular Effects of Gas6 p. 187
IV Interaction with TAM Receptor Molecules and Signal Transduction in the Gas6/TAM Ligand/Receptor System p. 191
V Role of the Gas6/TAM System in Vascular Biology p. 194
VI Gas6 in Innate Immunity: A Modulator of the Inflammatory Response p. 195
VII Further Functions of Gas6/TAM Receptors in Cellular Homeostasis p. 197
VIII Overlapping Functions of Gas6 and Protein S p. 197
IX The Implications of Vitamin K in Gas6 Function p. 199
Acknowledgment p. 200
References p. 200
10 Vitamin K[subscript 2]-Mediated Apoptosis in Cancer Cells: Role of Mitochondrial Transmembrane Potential Toshiko Shibayama-Imazu and Toshihiro Aiuchi and Kazuyasu Nakaya p. 211
I Introduction p. 212
II Growth-Inhibitory Effect of Vitamin K[subscript 2] p. 213
III Induction of Differentiation of Leukemia Cells by Vitamin K[subscript 2] p. 213
IV Induction of Apoptosis by Vitamin K[subscript 2] in Human Cancer Cells p. 214
V Association with Reduced Mitochondrial Membrane Potential ([Delta Psi]m) p. 217
VI Conclusion p. 221
References p. 222
11 VKORC1: A Warfarin-Sensitive Enzyme in Vitamin K Metabolism and Biosynthesis of Vitamin K-Dependent Blood Coagulation Factors Reidar Wallin and Nadeem Wajih and Susan M. Hutson p. 227
I Introduction p. 228
II The Vitamin K-Dependent [gamma]-Carboxylation System p. 231
III Genetics of Warfarin Resistance p. 241
IV Future Perspectives p. 242
References p. 242
12 Warfarin Therapy: Influence of Pharmacogenetic and Environmental Factors on the Anticoagulant Response to Warfarin Virginie Siguret and Eric Pautas and Isabelle Gouin-Thibault p. 247
I Introduction p. 248
II Vitamin K and Vitamin K Antagonists and Blood Coagulation p. 249
III Pharmacology of Warfarin p. 251
IV Influence of Environmental Factors on the Anticoagulant Response to Warfarin p. 253
V Influence of Pharmacogenetics on the Anticoagulant Response to Warfarin p. 257
VI Conclusion p. 261
References p. 261
13 Vitamin K and Thrombosis Geno J. Merli and James Fink p. 265
I Introduction p. 266
II Pharmacology of Vitamin K p. 266
III Therapeutic Uses of Vitamin K p. 269
IV Patients with Major Hemorrhage p. 271
V Patients Without Bleeding but Prolonged INR p. 271
VI New Physiologic Functions of Vitamin K p. 274
VII Warfarin Effects on Vitamin K p. 275
VIII Summary p. 276
References p. 276
14 Congenital Bleeding Disorders of the Vitamin K-Dependent Clotting Factors A. Girolami and R. Scandellari and M. Scapin and S. Vettore p. 281
I Introduction p. 283
II Congenital Prothrombin (Factor II) Deficiency p. 285
III Congenital Factor VII Deficiency p. 303
IV Congenital Factor IX Deficiency (Hemophilia B) p. 318
V Congenital Factor X Deficiency p. 329
VI Combined Congenital Deficiency of FII, FVII, FIX, FX p. 347
VII Deficiency of Protein Z p. 354
VIII Conclusions p. 355
References p. 357
15 Role of Growth Arrest-Specific Gene 6 in Diabetic Nephropathy Hidenori Arai and Kojiro Nagai and Toshio Doi p. 375
I Introduction p. 376
II Role of Gas6 in STZ-Induced Diabetic Rats p. 377
III In Vitro Effect of Gas6 in Mesangial Cells p. 381
IV Role of the Akt Pathway in Diabetic Nephropathy p. 382
V High Glucose Induces Mesangial Hypertrophy Via Gas6/Axl In Vitro p. 386
VI Study Using Gas6-Knockout Mice p. 388
VII Conclusions p. 389
Acknowledgments p. 391
References p. 391
16 Vitamin K and Bone Health in Adult Humans Susanne Bugel p. 393
I Introduction p. 394
II Vitamin K Intake and Bone Health p. 397
III Reasons for the Inconsistent Results p. 405
IV Vitamin K Recommendations p. 408
V Anticoagulation Treatment and Risk of Osteoporosis p. 409
VI Interactions Between Vitamin K and Vitamin D p. 410
VII Discussion and Conclusion p. 411
References p. 411
17 Diagnosis of Osteoporosis with Vitamin K as a New Biochemical Marker C. Heiss and L. M. Hoesel and U. Wehr and S. Wenisch and I. Drosse and V. Alt and C. Meyer and U. Horas and M. Schieker and R. Schnettler p. 417
I Introduction p. 418
II The Important Role of Vitamin K in Bone Metabolism p. 421
III Biochemical Markers as Indices of Bone Turnover p. 428
Acknowledgments p. 429
References p. 429
18 Hepatocellular Carcinoma and Vitamin K Toshihiko Mizuta and Iwata Ozaki p. 435
I Introduction p. 435
II Antitumor Effects of VK p. 436
III Mechanism of Growth Inhibition of HCC Cells by VK2 p. 437
IV Analysis of Tumor Recurrence Suppression Following Liver Cancer Treatment p. 439
V Future Tasks p. 440
References p. 440
Index p. 443