Contributors .................................................. xvi
Preface ........................................................ xx
1. Plant Phenolics - Secondary Metabolites with Diverse
Functions .................................................... 1
Vincenzo Lattanzio, Paul A. Kroon, Stephane Quideau
and Dieter Treutter
1.1. Secondary metabolism in the interactions between
plants and their environment ............................ 1
1.2. Function and use of plant phenolics ..................... 5
1.2.1. UV sunscreens .................................... 6
1.2.2. Phenolics as signal compounds .................... 6
1.2.3. Phenolics as pigments ............................ 8
1.2.4. Phenolics and plant growth ....................... 9
1.2.5. Phenolics and plant defense ..................... 11
1.2.5.1. Fungal pathogens ....................... 13
1.2.5.2. Phenolics and plant-insect
interactions ........................... 17
1.2.6. Plant phenolics and health ...................... 22
1.3. Note ................................................... 24
1.4. References ............................................. 24
2. Lignification: are Lignins Biosynthesized via simple
Combinatorial Chemistry or via Proteinaceous Control
and Template Replication? ................................... 36
John Ralph, Gösta Brunow, Philip J. Harris, Richard
A. Dixon, Paul F. Schatz and Wout Boerjan
2.1. Introduction ........................................... 36
2.2. The current theory ..................................... 37
2.3. Is there a need for a new theory? ...................... 37
2.3.1. The challenge hypothesis (proteinaceous
control and template replication) ............... 38
2.3.2. Has the challenge hypothesis become
a theory? ....................................... 38
2.4. Are criticisms of the current theory valid? ............ 38
2.4.1. Lignification as a biochemical anomaly .......... 38
2.4.2. The (3-ether frequency anomaly .................. 39
2.4.3. 'Obligatory' linkages? .......................... 40
2.5. Is there anything wrong with the dirigent
hypothesis? ............................................ 40
2.5.1. Monomer substitution ............................ 40
2.5.1.1. Has monomer substitution been
disproven? ............................. 41
2.5.1.2. Malleability of lignification: what
makes a good monolignol substitute? .... 43
2.5.2. 'Well-defined primary structure' ................ 45
2.5.2.1. Sequencing of lignin oligomers ......... 45
2.5.2.2. Monomer-independent sequences .......... 46
2.5.2.3. The 'urgent need to sequence lignin
primary structure' ..................... 47
2.5.3. Lignins' racemic nature ......................... 47
2.5.3.1. The'number of isomers'problem .......... 48
2.5.4. Comments on template replication ................ 48
2.5.5. Polymer branching ............................... 49
2.6. Why the new hypothesis is not in contention ............ 50
2.7. Is lignification a biochemical anomaly? ................ 51
2.7.1. Ferulate dehydrodimerization is
combinatorial ................................... 51
2.7.2. Polysaccharide primary structure is NOT
absolutely dictated ............................. 51
2.8. Summary comments on the dirigent/replication
hypothesis ............................................. 52
2.9. Conclusions ............................................ 53
2.10.Notes .................................................. 55
2.11.References ............................................. 58
3. Flavonoid-Protein Binding Processes and their Potential
Impact on Human Health ...................................... 67
Olivier Dangles and Claire Dufour
3.1. Introduction ........................................... 67
3.2. Biologically relevant chemical properties of
flavonoids ............................................. 68
3.3. Binding processes prior to absorption .................. 71
3.4. Binding processes involved in flavonoid
bioavailability ........................................ 72
3.4.1. Absorption and conjugation ...................... 72
3.4.2. Transport in plasma ............................. 73
3.4.3. Tissue distribution and cellular metabolism ..... 73
3.5. Binding processes involved in the potential health
effects of flavonoids .................................. 74
3.5.1. Inhibition of enzymes involved in ROS
production ...................................... 74
3.5.2. Modulation of the redox properties of
flavonoids by binding to proteins ............... 76
3.5.3. Inhibition of protein kinases ................... 78
3.5.4. Inhibition of cytochrome P450 enzymes ........... 79
3.5.5. Regulation of gene expression ................... 80
3.6. Conclusion ............................................. 83
3.7. References ............................................. 83
4. Methods for Synthesizing the Cocoa-Derived Oligomeric
Epi-Catechins - Observations on the Anticancer Activity
of the Cocoa Polyphenols .................................... 88
Alan P. Kozikowski and Werner Tüchnantel
4.1. Introduction ........................................... 88
4.2. Synthesis of procyanidins .............................. 89
4.2.1. General chemical properties of cocoa
procyanidins .................................... 89
4.2.2. Earlier synthetic work .......................... 91
4.2.3. The synthesis of benzyl-protected building
blocks .......................................... 92
4.2.4. Inter-flavan bond formation using benzyl-
protected building blocks ....................... 94
4.2.5. Establishment of inter-flavan bond
stereochemistry ................................. 97
4.2.6. Further developments ........................... 102
4.3. Anticancer activity ................................... 105
4.4. Acknowledgments ....................................... 109
4.5. References ............................................ 109
5. Gene Discovery and Metabolic Engineering in
the Phenylpropanoid Pathway ................................ 113
Luzia V. Modolo, Yongzhen Pang, Li Tian and Richard
A. Dixon
5.1. Introduction .......................................... 113
5.2. Biosynthesis and functions of isoflavones ............. 113
5.3. Dietary sources of isoflavones ........................ 115
5.4. Metabolic engineering of isoflavones .................. 115
5.4.1. Metabolic engineering by ectopic expression
of IFS ......................................... 115
5.4.2. Structural biology-assisted design and
metabolic engineering with an artificial
bifunctional IFS enzyme ........................ 116
5.5. Gene discovery in the proanthocyanidin biosynthetic
pathway ............................................... 117
5.5.1. Structural genes for PA biosynthesis ........... 118
5.5.2. Regulatory genes for PA biosynthesis ........... 121
5.6. Metabolic engineering of PAs in plants ................ 122
5.7. Glycosyltransferases for modification of
phenylpropanoid compounds - in vitro biochemistry
and in vivo function .................................. 123
5.7.1. UGTs active with non-flavonoid phenolic
compounds ...................................... 124
5.7.2. Glycosylation of flavonoid compounds ........... 128
5.7.3. Problems for the functional annotation of
UGTs ........................................... 130
5.8. Concerted strategies for metabolic engineering ........ 131
5.9. References ............................................ 132
5.10.Abbreviation list of the pathway genes ................ 138
6. Recent Advances in the Molecular Biology and Metabolic
Engineering of Flavonoid Biosynthesis in Ornamental
Plants ..................................................... 139
Kevin M. Davies, Huaibi Zhang and Kathy E. Schwinn
6.1. Introduction .......................................... 139
6.2. Metabolic engineering of flavonoid production in
flowers ............................................... 142
6.2.1. Engineering yellow flower colors ............... 143
6.2.2. Engineering blue flower colors ................. 144
6.3. Anthocyanic vacuolar inclusions ....................... 149
6.4. Regulation of anthocyanin biosynthesis ................ 152
6.5. Concluding comments ................................... 157
6.6. References ............................................ 158
7. Recent Advances in the Field of Anthocyanins - Main
Focus on Structures ........................................ 167
Øyvind M. Andersen
7.1. Introduction .......................................... 167
7.2. Anthocyanidins ........................................ 168
7.3. Anthocyanidin equilibrium forms ....................... 178
7.4. New anthocyanin glycosides ............................ 181
7.5. New anthocyanin acylglycosides ........................ 183
7.6. Flavonoid complexes including at least one
anthocyanidin subunit ................................. 187
7.7. Metalloanthocyanins ................................... 188
7.8. Biosynthesis and molecular biology .................... 189
7.9. Anthocyanin localization in plant cells ............... 191
7.10.Acknowledgments ....................................... 192
7.11.Notes ................................................. 192
7.12.References ............................................ 193
8. Salicylic Acid and Induced Plant Defenses .................. 202
Jean-Pierre Metraux, Elisabeth Lamodiere, Jeremy
Catinot, Olivier Lamotte and Christophe Garcion
8.1. Induced resistance and phenolics ...................... 202
8.2. The biosynthesis of SA ................................ 203
8.3. The network of signaling and the action of SA ......... 205
8.4. Conclusions ........................................... 207
8.5. Acknowledgment ........................................ 207
8.6. References ............................................ 207
9. Phenols and the Onset and Expression of Plant Disease
Resistance ................................................. 211
Ray Hammerschmidt and Samantha I. Hollosy
9.1. Introduction .......................................... 211
9.2. Biosynthetic origins of defense-associated phenolic
compounds ............................................. 212
9.3. Phenolic compounds as preformed defenses .............. 212
9.3.1. Resistance of onion bulbs ...................... 213
9.3.2. Fusarium wilt of carnation ..................... 214
9.3.3. Mango fruit and AIternaria ..................... 214
9.3.4. Regulation of preformed antifungal
compounds by phenols in avocado ................ 214
9.3.5. Chlorogenic acid and the infection of stone
fruit by Monilinia ............................. 215
9.4. Active defense ........................................ 215
9.5. Localized defenses .................................... 216
9.5.1. Phenolic phytoalexins .......................... 216
9.5.2. Phenolic structural defenses ................... 218
9.5.3. Plant phenols and induced disease
resistance ..................................... 219
9.6. Responses of the induced plant ........................ 220
9.6.1. Induced resistance in green bean and C.
lindemunthianum ................................ 220
9.6.2. Acibenzolar-S-methyl mediated induced
resistance ..................................... 220
9.6.3. Plant growth-promoting rhizobacteria and
induced resistance ............................. 220
9.6.4. Silicon as a modulator of defense and
phenolic compounds ............................. 221
9.7. Chemical induction of phenolic compounds and
resistance ............................................ 221
9.7.1. Structural phenolic compounds and induced
resistance ..................................... 221
9.7.2. Antioxidant activity of phenolic compounds
and plant defense .............................. 222
9.8. Phenols and defense: a multitude of roles ............. 222
9.9. Acknowledgment ........................................ 223
9.10.References ............................................ 223
10.Bioactivity, Absorption, and Metabolism of Anthocyanins .... 228
Giuseppe (Joe) Mazza and Colin D. Kay
10.1.Introduction .......................................... 228
10.1.1. Structural characteristics .................... 228
10.2.Bioactivity ........................................... 229
10.2.1.Antioxidant activity ........................... 230
10.2.2.Anti-inflammatory effects ...................... 233
10.2.3.Anti-atherogenic effects ....................... 233
10.2.4.Anticarcinogenic effects ....................... 234
10.2.5.Antibacterial and antiviral activity ........... 235
10.2.6.Neuroprotective effects ........................ 235
10.2.7.Prevention of obesity .......................... 235
10.2.8.Gastric protective effects ..................... 236
10.2.9.Improvement of vision .......................... 236
10.3.Absorption of anthocyanins ............................ 236
10.3.1.Variability of absorption ...................... 239
10.3.1.1.Variations in dosage .................. 239
10.3.1.2.Chemical structure of the
anthocyanins .......................... 240
10.3.1.3.Food matrix ........................... 241
10.3.1.4.Analytical methodology ................ 241
10.3.2.Elimination .................................... 242
10.3.3.The concentration of anthocyanins in human
blood and urine is very low .................... 243
10.3.4.Suggested mechanisms of anthocyanin
absorption ..................................... 243
10.3.5.Structural transformations of anthocyanins ..... 245
10.4.Metabolism of anthocyanins ............................ 247
10.4.1.Human studies .................................. 247
10.4.2.Animal studies ................................. 251
10.4.2.1.Rat studies .................................. 251
10.4.2.2.Pig studies .................................. 252
10.4.3.Potential mechanisms of anthocyanin
metabolism ..................................... 252
10.5.Conclusions ........................................... 254
10.6.References ............................................ 254
11.Bioavailability, Metabolism, and Bioactivity of Food
Ellagic Acid and Related Polyphenols ....................... 263
Francisco A. Tomas-Barberan, Maria Teresa Garcia-
Conesa, Mar Larrosa, Begona Cerda, Rocio Gonzalez-
Barrio, Maria Jose Bermudez-Soto, Antonio Gonzalez-
Sarrias and Juan Carlos Espin
11.1.Introduction .......................................... 263
11.2.Ellagitannins and ellagic acid as examples of
bioactive polyphenols ................................. 264
11.3.Evaluation of antioxidant activity in vitro ........... 265
11.4.Biological activity associated to ellagitannin-
rich food intake; clinical studies .................... 265
11.5.Questions arising after the demonstration of
the large antioxidant activity in vitro and the
biological activity associated with the intake
of ellagitannin-rich food ............................. 266
11.5.1.Bioavailability and metabolism of
ellagitannins and ellagic acid and
distribution of the metabolites in different
tissues ........................................ 267
11.5.2.Evaluation of the biological activity of
ellagitannin metabolites produced in vivo ...... 269
11.6.Conclusion ............................................ 275
11.7.Acknowledgments ....................................... 275
11.8.References ............................................ 275
12.Multiplicity of Phenolic Oxidation Products in Apple
Juices and Ciders, from Synthetic Medium to Commercial
Products ................................................... 278
Sylvain Guyot, Stephane Bernillon, Pascal Poupard
and Catherine M.G.С. Renard
12.1.Introduction .......................................... 278
12.2.Preparation and characterization of the
caffeoylquinic acid o-quinone solution ................ 281
12.3.Incubation of caffeoylquinic acid o-quinone in
model solutions ....................................... 282
12.3.1.Incubation of caffeoylquinic acid o-quinone
with caffeoylquinic acid ....................... 282
12.3.2.Incubation of caffeoylquinic acid o-quinone
with (-)-epicatechin ........................... 285
12.4.LC-MS analysis of oxidation products in commercial
apple beverages ....................................... 288
12.5.Conclusions ........................................... 290
12.6.Acknowledgments ....................................... 290
12.7.References ............................................ 290
13.Phytoestrogens in Drug Discovery for Controlling Steroid
Biosynthesis ............................................... 293
Sampo Karkola, Annamaria Lilienkampf and Kristiina
Wähälä
13.1.Introduction .......................................... 293
13.2.Aromatase ............................................. 293
13.2.1.Natural phytoestrogens as aromatase
inhibitors ..................................... 295
13.2.1.1.Anti-aromatase activity of
phytoestrogens in human placental
microsome-based assays ................ 295
13.2.1.2.Anti-aromatase activity of
phytoestrogens in cell-based
assays ................................ 298
13.2.1.3.Anti-aromatase activity of
phytoestrogens in recombinant-
enzyme assays ......................... 299
13.2.1.4.The anti-aromatase activity of
various phytoestrogens ................ 299
13.2.2.The structure-activity relationship of
phytoestrogens ................................. 300
13.2.3.Phytoestrogens as lead compounds for
aromatase inhibition ........................... 301
13.3.17.β-Hydroxy steroid dehydrogenases and their
inhibition by phytoestrogens .................. 304
13.3.1.17β-HSDtypel ................................... 305
13.3.1.1.Binding of phytoestrogens to
17β-HSD1 .............................. 307
13.3.2.17β-HSD types 2 and 4 .......................... 307
13.3.3.Fungal Hp-HSDcl ................................ 308
13.3.3.1.Binding of phytoestrogens to
17p-HSDcl ............................. 309
13.3.4.17β-HSDtype 3 .................................. 310
13.3.5.17β-HSD type 5 ................................. 310
13.3.6.Phytoestrogens as lead compounds for
17β-HSD inhibitors ............................. 311
13.4.Conclusions ........................................... 312
13.5.Acknowledgments ....................................... 313
13.6.References ............................................ 313
14.Recent Advances in the Chemical Synthesis and
Biological Activity of Phenolic Metabolites ................ 317
Denis Barron
14.1.Introduction .......................................... 317
14.2.The different sites of generation of phenolic
metabolites ........................................... 318
14.2.1.The saliva ..................................... 318
14.2.2.The stomach .................................... 319
14.2.3.The small intestine ............................ 319
14.2.4.The colon ...................................... 320
14.2.5.The liver ...................................... 320
14.2.6.Metabolism at the target tissues or cells ...... 321
14.3.Nature of the metabolites of phenolic compounds ....... 321
14.3.1.Flavone and flavonol metabolites ............... 321
14.3.2.Flavanonone and flavanonol metabolites ......... 322
14.3.3.Flavan 3-ol metabolites ........................ 324
14.3.4.Ellagic tannin metabolites ..................... 324
14.3.5.Lignan metabolites ............................. 325
14.3.6.Isoflavone metabolites ......................... 325
14.3.7.Hydroxycinnamic acid metabolites ............... 326
14.3.8.Curcumin metabolites ........................... 327
14.3.9.Resveratrol metabolites ........................ 328
14.4.The chemical synthesis of phenolic conjugates ......... 328
14.4.1.The preparation of O-glucuronides .............. 329
14.4.2.The preparation of O-sulfates .................. 332
14.5.The biological properties of phenolic conjugates ...... 334
14.5.1.Antioxidant properties ......................... 334
14.5.1.1.Flavonol conjugates ................... 334
14.5.1.2.Flavone conjugates .................... 340
14.5.1.3.Flavanone conjugates .................. 340
14.5.1.4.Flavan 3-ol conjugates ................ 340
14.5.1.5.Isoflavone conjugates ................. 340
14.5.1.6.The case of the 7-O-conjugates ........ 341
14.5.2.Pro-oxidant properties ......................... 342
14.5.3.Interaction with signaling cascades ............ 343
14.5.4.Enzyme inhibition .............................. 344
14.5.4.1.Aldose reductase ...................... 344
14.5.4.2.β-glucuronidase ....................... 344
14.5.4.3.Xanthine oxidase ...................... 344
14.5.4.4.Glycerol p-phosphate dehydrogenase .... 345
14.5.4.5.Cyclooxygenase-2 ...................... 345
14.5.5.Effect on vascular function and
angiogenesis ................................... 345
14.5.6.Non-covalent binding to proteins ............... 345
14.5.7.Activity of microbial and tissular
metabolites .................................... 346
14.6.The cellular transport of phenolic conjugates ......... 346
14.6.1.Cellular efflux ................................ 346
14.6.2.Cellular uptake ................................ 347
14.7.Conclusions ........................................... 348
14.8.References ............................................ 350
15.Polyphenols and Gene Expression ............................ 359
Uwe Wenzel and Hannelore Daniel
15.1.Introduction .......................................... 359
15.2.The effects of polyphenols on the expression of
genes underlying detoxification mechanisms ............ 359
15.3.Polyphenols and the expression of genes underlying
cancer-relevant processes ............................. 363
15.4.The impact of polyphenols on the expression of
genes underlying atherosclerosis-relevant
processes ............................................. 369
15.5.References ............................................ 373
Index ......................................................... 379
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