Recent Advances in Polyphenol Research, Volume 4

Acknowledgments vii

Contributors xvii

Preface xix

1 Monolignol Biosynthesis and its Genetic Manipulation: The Good, the Bad, and the Ugly 1
Richard A. Dixon, M.S. Srinivasa Reddy, and Lina Gallego-Giraldo

1.1 Introduction 2

1.2 Function and distribution of lignin in plants 2

1.3 Targets for modification of lignin biosynthesis 5

1.3.1 Gene targets 1. Biosynthetic enzymes 5

1.3.1.1 L-phenylalanine ammonia-lyase (PAL) 6

1.3.1.2 Cinnamate 4-hydroxylase (C4H) 6

1.3.1.3 4-coumarate: coenzyme-A ligase (4CL) 6

1.3.1.4 Enzymes of the coumaroyl shikimate shunt 7

1.3.1.5 Caffeoyl-CoA 3-O-methyltransferase (CCoAOMT) 7

1.3.1.6 Ferulate 5-hydroxylase (F5H) 8

1.3.1.7 Caffeic acid 3-O-methyltransferase (COMT) 8

1.3.1.8 Cinnamoyl-CoA reductase 8

1.3.1.9 Cinnamyl alcohol dehydrogenase (CAD) 9

1.3.2 Gene targets 2. Transcription factors 9

1.4 Impacts of lignin modification through targeting of the monolignol biosynthetic pathway 9

1.4.1 L-phenylalanine ammonia-lyase (PAL) 10

1.4.2 Cinnamate 4-hydroxylase (C4H) 10

1.4.3 4-coumarate: coenzyme-A ligase (4CL) 11

1.4.4 Hydroxycinnamoyl-CoA: shikimate hydroxycinnamoyl transferase (HCT) 13

1.4.5 4-coumaroyl shikimate 3'-hydroxylase (C3'H) 14

1.4.6 Caffeoyl CoA 3-O-methyltransferase (CCoAOMT) 15

1.4.7 Ferulate 5-hydroxylase (F5H) 17

1.4.8 Caffeic acid O-methyltransferase (COMT) 18

1.4.9 Cinnamoyl-CoA reductase (CCR) 20

1.4.10 Cinnamyl alcohol dehydrogenase (CAD) 22

1.5 Impacts of lignin modification through targeting of TFs 23

1.5.1 NAC master switches 24

1.5.2 MYB repressors of monolignol biosynthesis 24

1.5.3 WRKY repressors of lignification in pith 24

1.6 Monolignol pathway modification and plant growth 25

1.7 Conclusions: it isn't all that bad! 26

References 27

2 Perturbing Lignin Biosynthesis: Metabolic Changes in Response to Manipulation of the Phenylpropanoid Pathway 39
Nickolas A. Anderson and Clint Chapple

2.1 Introduction 40

2.1.1 Cell wall-bound phenylpropanoids 40

2.1.2 Soluble phenylpropanoids 43

2.2 Changes in metabolism associated with phenylpropanoid-pathway disruptions 44

2.2.1 Phenylalanine ammonia-lyase (PAL) 44

2.2.2 Cinnamate 4-hydroxylase (C4H) 45

2.2.3 4-coumarate: CoA ligase (4CL) 46

2.2.4 Hydroxycinnamoyl-coenzyme A: shikimate/quinate hydroxycinnamoyltransferase (HCT)/p-coumaroyl shikimate 3'-hydroxylase (C3'H) 46

2.2.5 Cinnamoyl CoA reductase (CCR) 47

2.2.6 Ferulate 5-hydroxylase (F5H) 48

2.2.7 Caffeic acid/5-hydroxyferulic acid O-methyltransferase (COMT)/caffeoyl CoA 3-O-methyltransferase (CCoAOMT) 49

2.2.8 Cinnamyl alcohol dehydrogenases (CAD) 50

2.3 Atypical lignins 50

2.4 Dwarfism 51

2.5 Conclusions 52

References 52

3 Function, Structure, and Evolution of Flavonoid Glycosyltransferases in Plants 61
Keiko Yonekura-Sakakibara and Kazuki Saito

3.1 Introduction 61

3.2 UDP-dependent glycosyltransferases 63

3.2.1 Functional identification of flavonoid UGTs 63

3.2.1.1 Flavonoid 3-O-glycosyltransferases 63

3.2.1.2 Flavonoid 7-O-glycosyltransferases 63

3.2.1.3 Flavonoid glycosyltransferases that glycosylate the sugar moiety attached to a flavonoid aglycone 67

3.2.1.4 Flavonoid 3'-O-glycosyltransferase 69

3.2.1.5 Flavonoid C-glycosyltransferase 69

3.2.2 3D structures of flavonoid UGTs 70

3.2.3 Functional evolution in UGTs 72

3.2.3.1 Functional evolution in flavonoid UGTs 74

3.3 Glycoside hydrolase-type glycosyltransferases 75

3.3.1 Functional identification of flavonoid GH1-type glycosyltransferases 75

3.3.1.1 Anthocyanin 5/7-O-glycosyltransferases 75

3.3.1.2 Anthocyanin 3-O-6''-O-coumaroylglucoside: glucosyltransferase 76

3.3.2 The reaction mechanism of GH1-type glycosyltransferases 78

3.4 Conclusions 78

References 78

4 The Chemistry and Chemical Ecology of Ellagitannins in Plant-Insect Interactions: From Underestimated Molecules to Bioactive Plant Constituents 83
Juha-Pekka Salminen

4.1 Introduction 84

4.2 Definitions and chemical structures of hydrolyzable tannins 85

4.3 Biosynthetic pathways of hydrolyzable tannins in plants 87

4.3.1 Tannin biosynthetic pathways have many branching points that affect the flux of biosynthetic energy towards different tannins 90

4.3.2 Biosynthesis of gallic acid, galloylglucoses, and gallotannins 91

4.3.3 Biosynthesis of ellagitannins 92

4.4 Distributions of different types of tannin in plants 94

4.5 Tannins in plant-herbivore interactions 98

4.5.1 General aspects of tannins and plant-herbivore interactions 98

4.5.2 The tannin oxidation hypothesis and its verification in plant-herbivore interactions 102

4.5.3 The ease of oxidation of individual ellagitannins can be predicted by their chemical structures and chromatographic properties 104

4.5.4 Other factors that may affect ellagitannin activities against insect herbivores 107

4.6 Conclusions 108

Acknowledgments 109

References 109

5 Diverse Ecological Roles of Plant Tannins: Plant Defense and Beyond 115
C. Peter Constabel, Kazuko Yoshida, and Vincent Walker

5.1 Introduction 115

5.2 Overview of tannin structure and function in defense 116

5.2.1 Structural diversity and distribution 116

5.2.2 In vitro biochemical activities 119

5.2.3 Old and new views on tannins in defense 120

5.2.4 The antimicrobial nature of tannins 122

5.3 Tissue localization and ecological function 124

5.3.1 Distribution of tannins in vegetative tissues 125

5.3.2 Tannins in seeds and fruit 126

5.3.3 Ecology of fruit tannins 127

5.4 Tannins in plant-soil-environment interactions 129

5.4.1 Tannin distribution and stability in soil 129

5.4.2 Impact of tannins on soil nitrogen cycling and microbial activity 130

5.4.3 Interaction with community and ecosystem processes 131

5.4.4 Tannins and other plant stress adaptations 133

5.5 Conclusions 134

Acknowledgments 134

References 134

6 Epigenetics, Plant (Poly)phenolics, and Cancer Prevention 143
Clarissa Gerhauser

6.1 Introduction 143

6.2 Influence of polyphenols on DNA methylation 145

6.2.1 DNA methylation in normal and tumor cells 145

6.2.2 Inhibition of DNMTs in vitro 145

6.2.3 Inhibition of DNA methylation in cellular systems and in vivo 147

6.2.3.1 Quercetin 147

6.2.3.2 Nordihydroguaiaretic acid (NDGA) 147

6.2.3.3 Resveratrol 158

6.2.3.4 Apple polyphenols 159

6.2.3.5 Black raspberry polyphenols 159

6.3 Influence of polyphenols on histone-modifying enzymes 160

6.3.1 Acetylation of histones and non-histone proteins 161

6.3.1.1 Anacardic acid 161

6.3.1.2 Curcumin 165

6.3.1.3 Garcinol 166

6.3.1.4 Gallic acid 167

6.3.1.5 Delphinidin 167

6.3.2 Deacetylation by HDACs and sirtuins 168

6.3.2.1 Inhibition of HDAC activity 168

6.3.2.2 Modulation of sirtuin activity 168

6.3.3 Histone methylation marks 171

6.3.3.1 Histone lysine methylation 171

6.3.3.2 Histone lysine demethylation 171

6.4 Influence of noncoding miRNAs on gene expression 172

6.5 Chemopreventive polyphenols affecting the epigenome via multiple mechanisms 173

6.5.1 (-)-epigallocatechin 3-gallate (EGCG) and green-tea polyphenols (GTPs) 173

6.5.1.1 DNA methylation 174

6.5.1.2 Histone-modifying enzymes (HATs, HDACs, HMTs) 178

6.5.1.3 miRNAs 181

6.5.2 Genistein and soy isoflavones 183

6.5.2.1 DNA methylation 183

6.5.2.2 Influence on histone acetylation and methylation 189

6.5.2.3 miRNAs affected by isoflavones 192

6.6 Conclusions 195

6.6.1 DNA methylation 195

6.6.2 Histone-modifying enzymes 195

6.6.3 miRNAs 196

6.6.4 Summary 196

References 196

7 Discovery of Polyphenol-Based Drugs for Cancer Prevention and Treatment: The Tumor Proteasome as a Novel Target 209
Fathima R. Kona, Min Shen, Di Chen, Tak Hang Chan, and Q. Ping Dou

7.1 Introduction 209

7.2 Secondary metabolites of plants 210

7.3 Plant polyphenols and their analogs 211

7.3.1 Classification and bioavailability of plant polyphenols 211

7.3.2 Tea and tea polyphenols 212

7.3.3 Targeting of the tumor proteasome by tea polyphenols 216

7.3.4 EGCG analogs as proteasome inhibitors 217

7.3.4.1 Peracetate and other prodrugs of EGCG 219

7.3.4.2 Fluoro-substituted EGCG analogs 222

7.3.4.3 Para-amino substituent on the D ring 222

7.3.4.4 Bis-galloyl derivatives of EGCG 223

7.3.4.5 Methylation-resistant (-)-EGCG analogs 223

7.3.5 Other molecular targets of tea polyphenols 224

7.3.5.1 AMPK activation 224

7.3.6 Proteasome inhibitory action of other plant polyphenols 225

7.4 Natural polyphenols in reversal of drug resistance 226

7.4.1 Mechanisms of tumor drug resistance 226

7.4.2 The ubiquitin-proteasome pathway in drug resistance 226

7.4.3 EGCG and overcoming drug resistance 227

7.4.4 Genistein and overcoming drug resistance 228

7.4.5 Curcumin and overcoming drug resistance 228

7.4.6 Clinical trials using polyphenols and chemotherapy 229

7.5 Conclusions 231

Acknowledgments 231

References 231

8 Flavonoid Occurrence, Bioavailability, Metabolism, and Protective Effects in Humans: Focus on Flavan-3-ols and Flavonols 239
Luca Calani, Margherita Dall'Asta, Renato Bruni, and Daniele Del Rio

8.1 Introduction 240

8.2 Focus on flavan-3-ols and flavonols: chemical structures and dietary sources 240

8.2.1 Flavan-3-ols 240

8.2.2 Flavonols 243

8.3 Metabolism and bioavailability of flavonoids in humans 244

8.3.1 Flavan-3-ols 245

8.3.2 Flavonols 251

8.4 In vitro studies 255

8.4.1 Flavan-3-ols 256

8.4.1.1 Phase II metabolites 256

8.4.1.2 Microbe-derived metabolites 259

8.4.2 Flavonols 260

8.4.2.1 Phase II metabolites 260

8.4.2.2 Microbe-derived metabolites 265

8.5 In vivo studies 266

8.5.1 Cardiovascular and endothelial protection 267

8.5.1.1 Flavan-3-ols 267

8.5.1.2 Flavonols 268

8.5.2 Neuroprotection 269

8.5.2.1 Flavan-3-ols 269

8.5.3 Cancer prevention 269

8.5.3.1 Flavan-3-ols 269

8.5.3.2 Flavonols 270

8.6 Conclusions 271

References 272

9 Inhibition of VEGF Signaling by Polyphenols in Relation to Atherosclerosis and Cardiovascular Disease 281
Rebecca L. Edwards and Paul A. Kroon

9.1 Introduction 282

9.2 VEGF and VEGF signaling 282

9.3 VEGF signaling and angiogenesis 286

9.4 Angiogenesis and atherosclerosis 286

9.5 Polyphenols in foods and diets, and their absorption and metabolism 289

9.6 Effects of polyphenols on VEGF signaling, angiogenesis, and atherosclerosis 290

9.6.1 VEGF signaling 314

9.6.2 Angiogenesis 315

9.6.3 Atherosclerosis 315

9.7 Relationships between polyphenol consumption and CVD risk 316

9.7.1 Epidemiological studies 316

9.7.2 Intervention studies 318

9.8 Conclusions 319

Acknowledgments 320

References 320

10 Phenolic Compounds from a Sex-Gender Perspective 327
Ilaria Campesi, Annalisa Romani, Maria Marino, and Flavia Franconi

10.1 Introduction 328

10.2 Phenolic compound classification and molecular mechanisms 329

10.3 Sex-gender and the xenokinetics of phenolic compounds 330

10.4 Sex-gender differences in xenodynamics 333

10.5 Conclusions 334

References 334

11 Thermodynamic and Kinetic Processes of Anthocyanins and Related Compounds and their Bio-Inspired Applications 341
Fernando Pina

11.1 Introduction 342

11.2 Anthocyanins in aqueous solution 342

11.2.1 Step-by-step procedure for calculating rate and equilibrium constants 349

11.2.1.1 Step 1: determination of the equilibrium constant K'a 349

11.2.1.2 Step 2: determination of the equilibrium constant Ka 349

11.2.1.3 Step 3: determination of the equilibrium constant Kt and the respective rate constants 350

11.2.1.4 Step 4: determination of the hydration rate and equilibrium constants 350

11.2.1.5 Step 5: determination of the isomerization rate and equilibrium constants 350

11.2.1.6 Step 6: verification of the self-consistency of all the data 351

11.3 Influence of anthocyanin self-aggregation on the determination of rate and equilibrium constants 351

11.4 Photochromism: applications bio-inspired in anthocyanins 357

11.4.1 Systems lacking the cis-trans isomerization barrier 357

11.4.2 Systems exhibiting high cis-trans isomerization barriers 361

11.4.2.1 The concept of right-lock-read-unlock-erase optical memories 361

11.4.3 Styryl-1-benzopyrylium (styryl flavylium) and naphthoflavylium 362

11.4.4 Dye-sensitized solar cells based on anthocyanins 362

11.5 How to construct an energy-level diagram 364

11.6 How to calculate the mole-fraction distribution of a network species 367

References 368

12 Synthetic Strategies and Tactics for Catechin and Related Polyphenols 371
Ken Ohmori and Keisuke Suzuki

12.1 Introduction 371

12.2 Early synthetic work 375

12.3 Stereoselective approaches to flavan-3-ols 380

12.3.1 Synthesis of catechin-series (= 2,3-trans) derivatives 380

12.3.2 Synthesis of epi-series (= 2,3-cis) catechins 393

12.4 Conclusions 407

Abbreviations 407

Acknowledgments 408

References 408

Index 411