Tài liệu BIOCHEMICAL TARGETS OF PLANT BIOACTIVE COMPOUNDS A pharmacological reference guide to sites of action and biological effects doc

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Contents
List of tables
Preface
1
Plant defensive compounds and their molecular targets
I.
I
Introduction
I
1.2 Organization and scope ofthe book
2
1.3 Descr$tion of the tables
3
1.4 Using the tables
6
1.5
The structural diversiiy of plant defensive compounds
6
1.6
Plant alkaloids
8
1.7
Plantphenolics
21
1.8 Plant te9enes
33
1.9 Other plant compounds 44
2
Biochemistry
-
the chemistry of life
2.1 Introduction
-
water-based l$ 52
2.2 Protein structure 53
2.3
Engmes and
ligand-binding proteins
58
2.4
Metabolic strategies
66
2.5
Inhibition of biochemical processes by plant defensiue compounds
85
3
Neurotransmitter- and hormone-gated ion channels
3.1
Introduction
-
electrical signalling in excitable cells
86
3.2
Ionotropic neurotransmitter receptors
-
neurotransmitter-gatedzon
channels
88
3.3
Structure and function of ionotropic receptors
88
4
Ion pumps, ligand- and voltage-gated ion channels
4.1
Introduction
123
4.2
Ion pumps
123
4.3 Voltage-gated Nui channels 125
4.4 Ligand-regulated and voltage-gated
K'+
channels 126
4.5 Voltage-gated
Ca" channels 126
vi
Contents
4.6 Ligand-gated Ca" channels 126
4.7 Chloride transport and voltage-regulated chloride channels 127
5
Plasma membrane
G
protein-coupled receptors
5.1 Introduction
-
signalling via heterotrimeric Gproteins 157
5.2
G
protein-coupled hormone and neurotransnzitter receptors 158
5.3 Hormones and neurotransmitters acting via G protein-coupled receptors 159
5.4 Activation of
spec$c G protein-coupled receptors 160
5.5
Leucocyte and inzamnzation-related G protein-linked receptors 162
5.6 Other
G
protein-coupled receptors 164
6
Neurotransmitter transporters and converters
6.1 Introduction 231
6.2 Synthesis of neurotransmitters 232
6.3 Release of
neurotransmittersjonz synaptic vesicles 233
6.4 Re-uptake
of
neurotransnzitters into neurons and synaptic vesicles
233
6.5 Neurotransmitter degradation 233
7
Cyclic nucleotide-, ca2+
-
and nitric oxide-based signalling
7.1 Introduction 253
7.2
~a" and calmodulin-dependent engymes 254
7.3
Ad~yiyl cyclase 255
7.4 Manbrane-bound and soluble
guanyiyl cyclases 255
7.5
Nitric oxide synthesis 256
7.6
Cyclic AMP- and cyclic GMP-dependentprotein kinases 257
7.7 Protein kinase honzologies and
phosphoprotein phosphatases 257
7.8 Cyclic nucleotide
phosphodiesterases 258
8
Signal-regulated protein kinases
Introduction 295
Cyclic
AMP-dependent protein kinase 296
Cyclic
GMP-dependent protein kinase 29 7
Protein kinase
C 298
Ca2+ -calnzodulin-dependent protein kinases 298
AMP-dependent protein
kinase 299
Receptor
!yrosine kinases 300
Protein kinase
B
301
Cytokine activation oftheJAK'/STATpathw(/~ 302
Cell cycle control 303
Receptor
serine/threonine kinases 303
Other protein kinases 303
Phosphoprotein phosphatases 304
9 Gene expression, cell division and apoptosis
9.1 Introduction 339
9.2
Regulation of gene expression in
prokaryotes 339
9.3 Regulation of
transcr$tion in eukaryotes 340
9.4
MA processing and translation 342
9.5 Control of translation 342
9.6 Protein processing and post-translational
mody5cation 343
9.7 Protein targeting 343
9.8 Cell division and apoptosis 344
9.9
HIVI
infection and
HIVI
replication 345
9.10 Plant compounds
intefering with gene expression 345
Contents
vii
339
10 Taste and smell perception, pheromones and semiochemicals
10.1 Introduction 396
1 0.2 Sweet taste receptors 39
7
10.3 Bitter taste receptors 397
10.4
Saliy taste perception 398
10.5 Sour taste perception 398
10.6
Umami jplutamate taste perception) 398
10.7 Odorant perception 398
10.8 Animal pheronzones and other animal bioactives produced
by
plants 399
10.9 Other plant senziochemicals
affecting aninzal behaviour 399
10.10
Odoriferous animal metabolites of ingestedplant compounds 399
11 Agonists and antagonists of cytosolic hormone receptors
11.1 Introduction 452
11.2 Steroid hormones 452
11.3
Non-steroid cytosolic hormone receptor ligands 453
11.4 Plant bioactives affecting cytosolic receptor-mediated
signalling 454
12 Polynucleotides, polysaccharides, phospholipids and membranes 487
12.1 Introduction 487
12.2
Po~ynucleotides 488
12.3
Poiysaccharides and 01ip.osaccharides 489
12.4
Phosphol$ids and membranes 490
13 Inhibitors of digestion and metabolism
13.1 Introduction 51 7
13.2
Giycohydrolases 51 7
13.3 Proteases 518
13.4
Giyco&sis and tricarboxylic acid cycle 522
13.5 Mitochondria1 electron transport and oxidative
phospho~ylation 522
13.6
Gluconeogenesis 523
13.7 Solute translocation 524

viii
Contents
14
Anti-inflammatory, antioxidant and antidiabetic plant compounds
14.1 Introduction 595
14.2 Adhesion and movement of
inzammatocy leucocytes 596
14.3
Chemokines 596
14.4
Phagocytosis 597
14.5
Kinins, ~ytokines, platelet activating factor and eicosanoids 598
14.6 Plant-derived
anti-inJamnzatory conqounds 599
14.7 Diabetes
nzellitus and plant antidiabetic compounds 599
14.8
Summary 601
Appendix: structures of key parent and representative compounds
Bibliography
Compound index
Plant genus index
Plant
common names index
Subject index
Abbreviations
Tables
Nicotinic acetylcholine receptor agorlists and antagonists
Iorlotropic y-aminobutyric acid and
benzodiazepirle receptors
Iorlotropic glutamate,
glycirle and serotonin receptors
Sigma
and vanilloid receptors
Ca'+-A~Pase, Hf, K+-ATPase and Naf, Kf -ATPase
Voltage-gated Na+ channel
Ligand- and voltage-gated
K+
channels
Voltage-
and ligand-gated Ca2+ channels and ~a+ /Ca2+ antiporter
CFTR, voltage-gated
C1 channels and Naf -K+-'LC1 co-transporter
Adenosine receptors
Muscarinic
acetylcholirle receptor
Adrenergic receptors
Dopamine receptors
Metabotropic
GABA(B)-, glutamate- and serotonin-receptors
Opiate receptors
Leucocyte- and inflammation-related G protein-coupled receptors
Other G protein-linked receptors
G protein-interacting plant compounds
Synthesis of
rleurotransmitters
Release of neurotransmitters from syrlaptic vesicles
Re-uptake of neurotransmitters into
neurons and synaptic vesicles
Acetylcholinesterase
Morloamirle oxidase
Degradation of other neurotransmitters
Calmodulirl
Adenylyl cyclase and guanylyl cyclase
Nitric oxide synthesis
Cyclic nucleotide phosphodiesterases
Eukaryote protein
kirlases
Activation of protein kirlase
C
by ~lant-derived phorbol esters
Receptor
tyrosine kinase-mediated signalling
Phosphatidylirlositol 3-kinase
Phosphoproteirl phosphatases
Ribosome-inactivating polynucleotide aminoglycosidases
Protein synthesis
x
Tables
DNA-dependent RNA and DNA synthesis and topoisomerases
Dihydrofolate reductase and thymidylate synthetase
HIV-
1
integrase and HIV-
1
reverse transcriptase
Actin, histone acetylase, histone deacetylase, cell division and tubulin
Apoptosis-inducing plant compounds
Sweet plant compounds
Bitter plant compounds
Sour (acid) tasting plant compounds
Odorant plant compounds
Animal pheromones and defensive agents occurring in plants
Some further plant-derived semiochemicals
Odoriferous human products of ingested plant compounds
Agonists and antagonists of cytosolic steroid hormone receptors
Cytosolic non-steroid hormone receptor agonists and antagonists
Polynucleotide-binding compounds
Lectins and polysaccharide hydrolases
Non-protein plant compounds permeabilizing membranes
Plant proteins directly or indirectly perturbing membranes
Inhibition of glycosidases by plant non-protein compounds
Plant a-amylase inhibitor
(aAI) proteins
Plant
polygalacturonase-inhibiting
proteins
Inhibition of proteases by plant non-protein compounds
Inhibition of proteases by plant proteins
Oxidative phosphorylation and photophosphorylation
Multidrug resistance, glucose and other transporters
Various enzymes
Plant lipoxygenase and cyclooxygenase inhibitors
Antioxidant free radical scavengers
Pro-oxidant compounds
Antioxidant enzyme induction and pro-inflammatory blockage
Aldose reductase and aldehyde reductase inhibitors
Plant compounds with hypoglycaemic, antidiabetic and/or insulinotropic
effects
Preface
Plants defend themselves from other organisms by elaborating bioactive chemical
defences. This is the essential basis of the use of herbal medicines that still represents a
major therapeutic resort for much of humanity However, at the outset, it must be stated that
any plant that is not part of our evolved dietary cultures is potentially dangerous.
Commercial herbal medicinal preparations approved by expert regulatory authorities have a
significant place in mainstream conventional medicine and in complementary medicine.
The first and last message of this book on the biochemical targets of bioactive plant con-
stituents is that use of herbal preparations for medicinal purposes should only occur subject
to expert medical advice. In the language of popular culture,
DO NOT TRY THIS AT
HOME!
This book arose from
40
years as a student, researcher and academic teacher in biochem-
istry, a discipline fundamentally informed by both chemistry and physiology. This book
is aimed at a very wide readership from biomedical researchers and practitioners to a
wide range of scientifically literate lay persons. Lay readers (notably high school and
university students and graduates) would range from everyone following public media
reports and discussions on health, environmental and other scientific matters to potential
readers of popular generalist scientific journals such as
Scientzjc American
or
New Scientkt.
The scientific readership would include researchers, professionals, practitioners, teachers
and industry specialists in a wide range of disciplines including the life sciences,
ecology, nursing, naturopathy, psychology, veterinary science, paramedical disciplines,
medicine, complementary medicine, chemistry, biochemistry, molecular biology, toxicology
and pharmacology
This book condenses a huge body of information in a succinct and user-friendly way
Ready access to a goldmine of key chemical structure/plant source/biochemical
target/physiological effect data from a huge scientific literature is via a Plant Common
names index, a Plant genus index and a Compound index. Such information is obviously
useful for biomedical and other science specialists. The introductory chemical and biochem-
ical summaries will be very useful to students in these and allied disciplines. However, at
a universal, everyday level, one can also use the book to readily find out about the nature and
targets of bioactive substances in what you are eating at a dinner party Further, plants and
their constituents play an important part in human culture and the bed-time or aeroplane
reader will find a wealth of interesting snippets on the historical, literary, artistic and general
cultural impact of plant bioactive substances.
Many people have variously helped and encouraged me in this project, most notably my
wife, Zareena, my children Daniel, Michael and Susannah, my mother and siblings, recent
xii
Preface
research collaborators, colleagues who have given computing and scientific advice and
further colleagues and other professionals who have read specific chapters.
I
must gratefully
acknowledge the profound influence of my late father, Dr John Polya. Any deficiencies of
this book are simply due to me and have occurred despite such helpful interactions.
Dr Gideon Polya
Department of Biochemistry, La Trobe University
Bundoora, Melbourne, Australia
August
2002
1
Plant defensive compounds and
their molecular targets
1.1
Introduction
Higher plants are sessile and are consumed by motile organisms, namely other eukaryotes
and prokaryotes. Plants defend themselves by physical barriers including cell walls at the cel-
lular level, by the waxy cuticle of leaves and by bark
and thorns at the macroscopic level.
Plants also defend themselves from
fungal and bacterial pathogens and animal herbivores
by elaborating a variety of bioactive secondary metabolites and defensive proteins. There
may be as
marly as 100,000 different kinds of plant defensive compounds of which about
30,000
have been isolated and structurally characterized. Biochemical targets have been
determined
in vitro
or
in viuo
for some thousands of the defensive compounds isolated to date.
The word "target" is
being used rather broadly and loosely here to encompass the molec-
ular sites of interaction demonstrated for such compounds. However, the demonstrated
binding of a plant
compound to a protein
in vitro
or
in viuo
does not necessarily mean that this
particular interaction is actually the critical site of action of the defensive compound.
Further, a particular defensive compound may
have multiple molecular sites of action and
may well
have synergistic effects with other such compounds. This book is concerned with
the biochemical targets of plant defensive compounds.
This treatise has been designed to address a
very wide audience ranging from scientifically
literate lay people to researchers in many disciplines
and health professionals. Plant products
have had a huge impact on the way in which different human societies have developed, espe-
cially
over the last twelve thousand years since the advent of agriculture. Thus, the evolution
of specific day-length and temperature requirements for plant development meant adapta-
tion of specific plants to particular latitudes. Accordingly, exploitation of "useful" plants
(and of domesticatable animals feeding upon them) would
have spread rapidly on an
East-West axis. This contributed to the technological and military dominance of cultures of
the Eurasian axis in the colonial era (as opposed to those of the North-South
long axis con-
tinents of Africa and the Americas) (Diamond, 1997).
Particular
plant products have had a massive impact on human populations and cultures
in recent centuries as evidenced by the
slave trade to the Americas (for the purposes of coffee,
sugar and cotton production), colonial conquest in the East (opium, indigo, tea, cotton
and
preservative spices), African subjugation (slavery, cocoa, rubber and timber) and temperate
colonization (grain, cotton, timber and herbivore production). Notwithstanding the
European "Enlightenment", these economic expansions
and social reorganizations (both
domestic
and colonial) were accompanied by horrendous abuses connected with war and
famine (problems that are continuing today in the "New World Order").
Plants
provide a bulk supply of carbohydrate (typically as seed or tuber starch) to support
the global human population that now totals
6
billion as compared to an estimated
1
million
2
1.
Plant defensive compounds and their molecular targets
hunter-gatherers before the advent of agriculture-based civilization twelve thousand years
ago. However, plants also provide humanity with a variety of bioactive constituents used for
their taste, preservative, psychotropic or medicinal properties. Notwithstanding synthetic
sweeteners, non-plant preservatives and an explosion of psychotropic drugs and other phar-
maceuticals, plants are still major sources of such ameliorative and protective agents.
While
the "Western" pharmaceutical global market reached a value of US8354 billion in 2000,
the total global herbal medicine market is currently about US830 billion. Herbal medicine
remains a major core recourse for the impoverished majority of the world's population.
Herbal medicinal traditions can be traced back to our primate forebears. Thus, parasite-
infected chimpanzees make recourse to particular plants, which they evidently associate with
symptomatic relief. Human cultures in general have accumulated medicinal protocols based
on use of plants, major traditions including Chinese medicine and Indian
Ayurvedic herbal
medicine. As detailed in this book, in some instances, specific bioactive substances from med-
icinal plants (or derivatives of such compounds) have found application in conventional
medicine. Thus, the cardiotonic cardiac glycoside sodium pump (Naf, K+-ATPase)
inhibitors derived from the initial use for cardiac insufficiency of digitalis (dried leaves of the
foxglove,
DZpitalispurpureumn).
Determining the molecular sites of action of bioactive medicinal plant constituents is
clearly important for establishing the chemical and physiological basis for herbal medicinal
efficacy, for quality control of commercial herbal preparations and for the discovery of "lead
compounds" for synthetic (or semi-synthetic) pharmaceutical development. Of course, it
must be recognized that medicinal plant
efficacy may derive from complex synergistic effects
or even from quasi-placebo effects connected with the taste, mild effects and appearance of
the preparation.
While recognizing these possible "holistic" complications, in order to find
out how such preparations work, it is clearly important to initially isolate, structurally char-
acterize and define the biochemical targets of plant bioactive substances.
1.2
Organization and scope of the book
The book has been devised and organized so that it can be used by a wide range of people
as (a) a textbook, (b) a user-friendly reference and (c) as a comprehensive summary of the
biochemical pharmacology of plant compounds. This book focuses specifically on purified
plant compounds (secondary metabolites and proteins) and the molecular entities (princi-
pally proteins) with which they interact in the target microbial pathogens and animal herbi-
vores. In contrast, there are many essentially ethnobotanical books that variously deal with
medicinal and psychotropic plants, detailing the nature, distribution, physiological effects,
chemical components (where known) and cultural significance of such plants. In addition,
there are many books that deal with purified and characterized plant defensive components
from a chemical structure perspective. The Merck Index (Budavari, 2001) and the
Phytochemical Dictionary (Harborne and Baxter, 1993) are notable examples of such
chemical compendia that were particularly useful in the writing of this book and indeed are
very useful adjuncts to the present work (especially for the chemical structures of plant
compounds).
This first chapter deals with the structural diversity of plant defensive compounds. Chapter 2
provides a succinct but comprehensive summary of the essentials of biochemistry (the
chemistry of living things). This biochemical review provides a detailed background for
understanding the nature and function of the targets of plant defensive metabolites and pro-
teins. The remainder of the book summarizes (mainly in table form) a wealth of information