TTPB24MEDICINALPLANTS.ppt

© 2013 American Society of Plant Biologists
The Past, Present and Future of
Medicinal Plants

Herbal
medicines
have been
used for
millennia
1000s of
plants have
medicinal
uses
More people in the world
depend on herbal medicines
than pharmaceutical
medicines
More than half of
the 150 most-
prescribed
medicines have at
least one compound
derived from plants
Credits: WHO photo by D. Henrioud; Mycelium101

Reprinted by permission from Macmillan Publishers Ltd from Last, R.L., Jones, A.D. and Shachar-Hill, Y. (2007). Towards the plant metabolome and beyond. Nat. Rev. Mol. Cell Biol. 8: 167-174.
Image provided by S. O’Connor, reprinted from Glenn, W.S., Runguphan, W. and O’Connor, S.E. (2013) Recent progress in the metabolic engineering of alkaloids in plant systems. Curr. Opin. Plant Biol. (in press).
Traditional knowledge now can be
augmented with modern approaches
Metabolomics to
identify medicinally
active compounds
Metabolic engineering to
increase their production
and diversity

Lecture Outline
• Historical uses of plants as medicines
• From 1800 to the present
• Quest for active compounds
• The best of both
• Plant-based medicines, present and
future
• Health care for all

People have used plants as
medicines since pre-history
Chemicals preserved in 50,000
year old Neanderthal teeth
suggest medicinal plants such
as chamomile were eaten
Reprinted from Wadley, L., Sievers, C., Bamford, M., Goldberg, P., Berna, F. and Miller, C. (2011). Middle stone age bedding construction and
settlement patterns at Sibudu, South Africa. Science. 334: 1388-1391 with permission from AAAS. CSIC Comunicación; Köhler’s medicinal plants
77,000 year-old South African
Cryptocarya woodii
leaves used for bedding – this
plant is toxic to mosquitoes

University of Virginia, and Mexiclore; Powell, J. W. Seventh Annual Report of the Bureau of
Ethnology. Washington: Government Printing Office, 1891. Page 159; Mycelium101
Historical records are scarce, but evidence suggests that cultures
around the world have used plants as medicines for thousands of years
South America: The Badianus
Manuscript, or Aztec Herbal
(1552), written and illustrated by
two Aztec men, Martín de la Cruz
and Juan Badiano
North America: Ojibwa midewiwin
preparing herbal medicine
Persia: Ibn Sina, also
known as Avicenna,
c. 1000 AD, wrote “The
Book of Healing” and “The
Canon of Medicine”
Healers who use
traditional herbal
remedies are the
major health
providers
throughout much
of sub-Saharan
Africa

Written records of medicinal plants
date back 4000 years
NIH – Images from the history of medicine; Beijing Digital Museum of TCM;
Sumerian and Egyptian
texts from more than 3500
years ago describe the use
of medicinal plants
The use of herbal medicines
in China and India date back
at least 4000 years
These ancient texts mention hundreds of
plants including aloe, peppermint, opium,
willow, wormwood and many more

Greek herbals remained in use
through the middle ages
Historia Plantarum
by Theophrastus
~200 BC
This edition printed 1644
De Materia Medica
by Pedanius Dioscorides
~50 AD
This edition copied ~500 AD
Biodiversity heritage library

1500: Liber de arte distillandi
simplicia et composita
NIH and BHL
“The same water withdryueth the
spottys in the face / whan it is often
wasshed and rubbed therwith / and
let drye agayne by hym selfe”
Water of white lilies:
A manual for distilling herbs
was published in 1500 by
Hieronymus Brunschwig
(English translation, 1527)
The book contains
instructions for how make
and use plant extracts

The “Doctrine of Signatures”:
Form reveals purpose
Image credits: Wellcome Library, AndonicO, Wellcome Library, London
"That to which a sign
belongs, to it also the effect
belongs; and that to which
the effect belongs, equally
to it the sign belongs; and
those which lack the signs
also lack the effects”
G. della Porta (~1600)
Are pomegranates
good for your teeth?
Are walnuts
brain food?
Will daisies cure
eye problems?

Apothecaries and physic gardens
used and cultivated medicinal plants
Botanic Garden
Leiden University 1625
National Library of Medicine, NLM, NLM, Orto Botanica di Padova
The oldest existing
botanical garden was
founded in Padua, 1545

Discovery of cardiac glycosides
from foxglove, Digitalis purpura
“We shall sooner obtain the end proposed if we take up
the subject as altogether new and, rejecting the fables of
the ancient herbalist, build only upon the basis of
accurate and well considered experiments’
William Withering (1741 – 1799)
English botanist and doctor, he wrote
the first book to apply Linnaean
taxonomy to British flora. He applied
modern, rational methods to the
study of folk medicines

1785 “An Account of the Foxglove,
and Some of its Medical Uses”
Krikler, D.M. (1985). The foxglove, “the old woman from Shropshire” and William Withering. Journal of the American College of Cardiology. 5: 3A-9A; Lee, M.R. (2001) William Withering (1741–
1799): A Birmingham Lunatic. Proc. R. Coll. Physicians Edinb. 31: 77-83. Wilkins, M.R., Kendall, M.J. and Wade, O.L. (1985). William Withering and digitalis, 1785 to 1985. BMJ. 290: 7-8.
“…this medicine was
composed of twenty or more
different herbs; but ….the
active herb could be no
other than the Foxglove”
Digoxin, one of several
cardiac glycosides
isolated from foxglove.
Withering spent years
investigating optimal
preparations and doses
of foxglove leaves for
the treatment of heart
conditions

From 1800 to the present: Quest for
active compounds
Taxus breviola,
Pacific yew
1966 - Taxol purified from
Pacific yew (Taxus breviola)
1820 – Quinine
purified from
Cinchona tree
(Cinchona spp)
1820s - Salicin
was isolated
from willow
bark
eventually to
become
“aspirin”
1805 – Morphine
purified from opium
poppy
(Papaver
somniferum)

Which is “better”, a plant extract or
the purified compound?
Traditional
Natural
Safer
Scientific
Pure
Safer
No “middleman”,
often cheaper
Multifactorial
effects can
be beneficial
Single defined
compound, no
unknowns
Overharvesting and
supply shortages
are problems
Synthetic forms can
preserve wild
plants, provide
consistent supply
Batch-to-batch
variation can be
a problem
Prohibitively
expensive for many
Consistent,
precise
dosages

Morphine, a powerful narcotic
analgesic alkaloid from poppy
Photo courtesy of Toni Kutchan, Donald Danforth Plant Science Center
The pain-relieving properties of
opium have been known for
millennia
Opium is the dried latex from the
seed capsule of the poppy, and
contains many pharmacologically
active alkaloids including morphine,
codeine, noscapine and thebaine morphine
codeine
thebaine
noscapine

Morphine is the best and the worst
of drugs - effective but addictive
US National Institute of Drug Abuse; UNODC, World Drug Report 2012 (United Nations publication, Sales No. E.12.XI.1)
Morphine and related opioids are
extremely effective pain relievers, but also
highly addictive. Prolonged use affects the
activity or amount of neurotransmitter
receptors, causing a chemical dependency

Making a safer poppy for licit, but
not illicit, purposes
Reprinted by permission from Macmillan Publishers Ltd: Millgate, A.G., Pogson, B.J., Wilson, I.W., Kutchan, T.M., Zenk, M.H., Gerlach, W.L., Fist, A.J. and Larkin, P.J. (2004). Analgesia: Morphine-pathway block
in top1 poppies. Nature. 431: 413-414. See also Hagel, J.M. and Facchini, P.J. (2010). Dioxygenases catalyze the O-demethylation steps of morphine biosynthesis in opium poppy. Nat. Chem. Biol. 6: 273-275.
The thebaine oripavine poppy 1 (top1) variety
accumulates thebaine and oripavine, but not
morphine or codeine. These poppies can be used
as precursors for synthetic opioid production, but
carry “little risk of diversion for illicit purposes”
Wild type extract
top1 extract

Antimalarials: quinine and
artemisinin
Hay, S.I., et al., (2009) PLoS Med 6(3): e1000048. doi:10.1371/ journal.pmed.1000048 Image by Ute Frevert; false color by Margaret Shear. Photo credit: CDC
Malaria kills and debilitates millions of
people each year, and accounts for
20% of childhood deaths. It is caused
by a mosquito-transmitted protozoan.
Quinine and artemisinin are
effective antimalarial drugs

Image credits: Köhler; CDC, H. Zell
Cinchona tree bark contains quinine,
which kills Plasmodium
Cinchona bark was brought to Europe from
Peru in the 17th century. Quinine was
purified from it in 1820. Synthesis is very
difficult and too expensive, so cinchona
trees remain the source of the drug

Artemisia annua produces
artemisinin, an effective antimalarial
Artemisinin
Artemisia has been used
by Chinese herbalists for
thousands of years. In
1972 the active ingredient,
artemisinin, was purified
Artemisia annua
Photo credit: www.anamed.net; Reprinted by permission from Macmillan Publishers Ltd. From Van Noorden, R. (2010) Demand for malaria drug soars. Nature 466: 672 – 673.
Demand for artemisinin
exceeds supply

Several approaches are being used
to increase artemisinin production
Reprinted from Graham, I.A., et al. and Bowles, D. (2010). The genetic map of Artemisia annua L. identifies loci affecting yield of the antimalarial drug artemisinin. Science. 327: 328-331 with permission from AAAS; Reprinted
by permission from Macmillan Publishers Ltd from Ro, D.-Ket al and Keasling, J.D. (2006). Production of the antimalarial drug precursor artemisinic acid in engineered yeast. Nature. 440: 940-943; see also Westfall, P.J. et al .
and Paddon, C.J. (2012). Production of amorphadiene in yeast, and its conversion to dihydroartemisinic acid, precursor to the antimalarial agent artemisinin. Proc. Natl. Acad. Sci. 109: E111-E118. Covello, P.S. (2008). Making
artemisinin. Phytochemistry. 69: 2881-2885. Lévesque, F. and Seeberger, P.H. (2012). Continuous-Flow Synthesis of the Anti-Malaria Drug Artemisinin. Angewandte Chemie International Edition. 51: 1706-1709.
Genetic approach: Identify
genes that increase production
for breeding strategy
Semisynthetic
approach: Introduce
plant genes into
metabolically
engineered yeast
Both methods have
advantages, and its
been said that both
are needed to ensure
adequate supply

Reprinted from Horwitz, S.B. (2003). Personal Recollections on the Early Development of Taxol. Journal of Natural Products. 67: 136-138, copyright American Chemical Society.
See also Jennewein, S.J. and Croteau, R.C. (2001). Taxol: biosynthesis, molecular genetics, and biotechnological applications. Applied Microbiology and Biotechnology. 57: 13-19 .
Taxus breviola,
Pacific yew
Taxol was discovered
through a random
screening project
Taxol is an effective
anticancer drug because it
stabilizes microtubules, and
blocks cell division
Taxol - “It’s the kind of
structure that only a tree would make’’

Taxol’s success as a therapeutic
agent threatened the Pacific yew
Methods for taxol
synthesis were
worked out in 1994,
but they are far too
expensive
Photo credit : Dave Powell USDA
In the 1980s
thousands of
trees were being
killed and
stripped of their
bark for taxol
extraction
Currently, taxol is produced
semisynthetically, from a
precursor harvested from the
needles of Taxus baccata
(European Yew) that occurs at
much higher levels than taxol.
Branches can be harvested
from trees annually without
sacrificing the tree
Another taxol -production
method uses cultured
plant cells

Camptothecin, an antitumor drug
from the happy tree, xi shu
Irinotecan
Camptothecin
Topotecan
Natural product – too
toxic for therapeutic use
Semisynthetic derivatives – used in
the treatment of many cancers
The same project led
to camptothecin, from
Camptotheca
acuminata,
the “happy tree” 喜树

Camptothecins block DNA
replication via topoisomerase
Reprinted by permission from Macmillan Publishers Ltd from Pommier, Y. (2006). Topoisomerase I inhibitors: camptothecins and beyond. Nat. Rev. Cancer. 6: 789-802.
Camptothecin arrests
cancer cell growth by
targeting topoisomerase I,
and identified a new
cellular target for
chemotherapy agents

Vinca alkaloids, a fortuitous find
Vinblastine
Vincristine
Noble, R.L. (1990). The discovery of the vinca alkaloids—chemotherapeutic agents against cancer. Biochem. Cell Biol. 68: 1344-1351. Roepke, J., Salim, V., Wu, M., Thamm, A.M.K., Murata, J., Ploss, K., Boland, W.
and De Luca, V. (2010). Vinca drug components accumulate exclusively in leaf exudates of Madagascar periwinkle. Proc. Natl. Acad. Sci. USA. 107: 15287-15292. Photo credit titanium22; figure © gtang
Vinca alkaloids bind
free tubulin dimers and
interfere with
microtubule assembly,
therefore blocking cell
division
Periwinkle initially was used to treat diabetes. Animal
studies revealed that the plant extract is toxic to white
blood cells, and is an effective treatment for cancer of
white blood cells such as lymphoma
Madagascar
periwinkle,
Catharanthus
roseus

Summary – medicinal compounds
from plants
The medicinal properties of
some plants can be traced to
a single active compound,
which can be purified or
synthesized and precisely
prescribed
These single purified
compounds have specific
actions; they are “magic
bullets” that affect a very
specific target
Not all medicinal plants can
be purified to a single active
compound
As an example opiates specifically
target opiate receptors
National Institute on Drug Abuse

Not all conditions will be treatable
by single compounds
Some chronic diseases are
pleiotropic in nature and unlikely to
be treated by a single compound:
AIDS
Diabetes
Metabolic syndrome
Obesity
Alzheimer’s
Disease
Many traditional medicines are
composed of several plants –
perhaps some of their effects
arise from multiple factors
acting together?

The best of both: Plant-based
medicines, present and future
Traditional medicines
Untested plants
New
Drug
Identification of
clinical efficiency,
optimization and
standardization
Screening
for bioactivity
Identification of
active compound(s)
or fractions
Direct to consumer
Via healer
Regulatory
approval
Mark de Fraeye, Wellcome Images N0027823; Rkitko

Medicines from traditional Chinese
medicine
Yinxingye
Xuanshen
Beijing Digital Museum of Traditional Chinese Medicine
Scrophularia spp.
(figwort root)
Bilobalide
Qinghao
Artemisia annua
Artemisinin, for
the treatment of
malaria
Ginkgo biloba
May help slow memory decline in the
elderly. Terpenoids including ginkgolides
and bilobalides are thought to be involved
Used in the treatment
of arthritis, several
compounds seem to
contribute including
iridoid glycosides

Medicines from Ayurveda, traditional
Indian medicine
Curcumin (haridra)
from tumeric
(Curcuma longa),
thought to have
many benefits
See Mukherjee, P.K. and Wahile, A. (2006). Integrated approaches towards drug development from Ayurveda and other Indian system of medicines. J. Ethnopharmacol. 103: 25-35.
Withfarin A, a compound with
diverse functions including
anti-cancer activity,
Withania somnifera
(ashwagandha)
Senna glycosides,
used as laxatives and
dieters’ tea, from
Senna alexandrina

Drawing by Gracia Lam and reprinted by permission from Macmillan Publishers Ltd: from Xu, Z. (2011) One step at a time. Nature 480:
S90 – S92, and Gilbert, N. (2011). Herbal medicine rule book. Can Western guidelines govern Eastern herbal traditions? Nature 480: S98.
Identification of clinical
efficiency, optimization
and standardization
Identification of
active compound(s)
or fractions
Traditional medicines can be used
traditionally, or can benefit from
standardization. They also can be
sources for new drug discovery
Drugs and therapies
from traditional
medicines

Herb Common Name
黃苓 Huang Qin
Baical skullcap root,
Scutellaria, Scute
大棗 Da Zao Jujube, Chinese date
白芍 Bai Shao
White peony root,
Chinese peony
炙甘草 Zhi Gan Cao
Honey prepared
licorice, Chinese
licorice
Huang Qin Tang – from TCM to
clinical trials
Callaway, E. (2010) How an 1,800-year-old herbal mix heals the gut. Nature News.
Huang Qin Tang has been
used to treat nausea for
nearly 2000 years. It is
made from four plants,
each of which is needed
for its activity

A formulation of Huang Qin Tang
called PHY906 is in clinical trials
From Lam, W., Bussom, S., Guan, F., Jiang, Z., Zhang, W., Gullen, E.A., Liu, S.-H. and Cheng, Y.-C. (2010). The four-herb Chinese medicine PHY906 reduces chemotherapy-induced gastrointestinal toxicity. Sci. Transl.
Med. 2: 45ra59, with permission from AAAS. Liu, S.-H. and Cheng, Y.-C. (2012). Old formula, new Rx: The journey of PHY906 as cancer adjuvant therapy. J. Ethnopharmacol. 140: 614-623 with permission from Elsevier.
Rats treated with the
chemotherapy agent CPT-11
experienced damage to their
intestinal epithelium and death
With the addition of
PHY906, the toxic
effects were greatly
reduced

Ginseng (Panax spp.) – is it a
panacea?
Ginseng (Panax spp.) is the most widely
used and one of the most highly valued
herbal medicines, and is believed to have
many benefits. There are several species
that have different properties and values
100 year old
wild ginseng
root sold for
$250,000
300 year old
ginseng root
sold for
$400,000

The composition of ginsenosides in
ginseng is variable
Briskin, D.P. (2000). Medicinal plants and phytomedicines. Linking plant biochemistry and physiology to human health. Plant Physiol. 124: 507-514; William M. Brown Jr., bugwood..org
Age and growth
conditions affect
the biochemical
properties of the
plant and extract

Ephedra (ma huang), use and abuse
Ephedra sinica
(ma huang)
麻黃
See Abourashed, E.A., El-Alfy, A.T., Khan, I.A. and Walker, L. (2003). Ephedra in perspective – a current review. Phytother. Res.
17: 703-712; NCCAM; Univ. Maryland Med. Center; Beijing Digital Museum of Traditional Chinese Medicine
ephedrine
• Its use and abuse as a performance
enhancer and weight-loss agent is thought
to have contributed to many deaths
• Since 2004 its sale in the US has been
severely restricted
Ephedra dilates the bronchial
passages of the lungs and relieves
asthma and respiratory problems
It also stimulates
the heart and
metabolic rates

21st century science can be applied
to ancient medicines
Reprinted from Liu, S.-H. and Cheng, Y.-C. (2012). Old formula, new Rx: The journey of PHY906 as cancer adjuvant therapy. J. Ethnopharmacol. 140: 614-623 with permission from Elsevier.
What are the active
compounds?
What are optimal
dosages?
What biochemical
pathways do they
affect in the patient?
What side effects
can arise?

Standardizations and quality
assurances of herbal medicines
See Betz, J., Fisher, K., Saldanha, L. and Coates, P. (2007). The NIH analytical methods and reference materials program for dietary supplements. Analytical and Bioanalytical
Chemistry. 389: 19-25. Cordell, G.A. and Colvard, M.D. (2012). Natural Products and Traditional Medicine: Turning on a Paradigm. Journal of Natural Products. 75: 514-525.
In the United States, it is estimated that there is only
a 50:50 chance of selecting an authentic product
containing both the correct species and correct plant
component at an appropriate strength
How can quality
be assured?
Quality refers to
identity, purity
and strength.
DNA barcoding to assess species identity
Biological assays for effectiveness
Mass spectroscopy to assess
composition
Analytical tests for common contaminants
(e.g. heavy metals, pesticides)

Over-the-counter herbal medicines
Many people are exploring the
use of herbs and other
alternatives to Western medicine.
Many of these are sold over-the-
counter as dietary supplements
Percentage of
people who have tried
complementary or
alternative medicines
Drug Botanical Name
Echinacea Echinacea species
Garlic Allium sativum
Goldenseal Hydratis canadensis
Ginseng Panax species
Gingko Ginkgo biloba
Saw palmeto Serenoa repens
St. John’s wort Hypericum species
Kava kava Piper methysticum
10 best selling OTC herbal
medicines

Reprinted by permission from Macmillan Publishers Ltd: from Schmidt, B.M., Ribnicky, D.M., Lipsky, P.E. and Raskin, I. (2007). Revisiting the ancient concept of
botanical therapeutics. Nat Chem Biol. 3: 360-366. See also FDA (2004) Guidance for Industry. Botanical Drug Products (FDA, DC, June 2004).
Flow chart and outcomes for the
commercialization of medicines
from plants. It’s more expensive to
be approved as a “drug” than a
dietary supplement, but the
financial gains can be much higher

Regulator’s main
concern – is the
product safe as sold?
Consumer has
responsibility to
ensure that it is used
appropriately
Limited oversight of OTC herbal
medicines (supplements)
“The Food and Drug Administration
suggests that you consult with a health
care professional before using any
dietary supplement”

Echinacea, cure for the common
cold?
Globally, sales of Echinacea-
based products exceed $320
million
Echinacea products
(Echinacea spp.) are
among the top selling
herbal medicines
They are thought to
promote the immune
system and deter
respiratory infections, but
do they work?
MAYBE
“Echinacea probably has only a small
beneficial effect. Individual choices
should be guided by personal health
values and preferences…”
-Barrett et al., 2010.
See Barrett, B., Brown, R., Rakel, D., Mundt, M., Bone, K., Barlow, S. and Ewers, T. (2010).
Echinacea for treating the common cold: A randomized trial. Ann. Internal Medicine. 153: 769-777.

How can we know
which plants are good
candidates for drugs?
Ray Carruthers, USDA

Bioprospecting: Drugs and
medicines found by plant screening
Plant samples
are collected and
extracted
Chemical assays
Biological
assays
Heydrienne; Jim Gathany, CDC image 7282;

Collecting and selecting plants to
screen
Reprinted by permission from Macmillan Publishers Ltd from Dalton, R. (2000). Political uncertainty halts bioprospecting in Mexico. Nature. 408: 278-278; Manfred Mielke USDA; Poppy photos by Forest and Kim Starr; Bonobo by Kabir Bakie
Random collecting
With indigenous guides
Zoopharmacognosy – many
animals have been observed to
self-medicate by eating
pharmacologically active plants
By family - Certain
plant families, such
as Papaveraceae
are rich in medicinal
compounds

Medicinal compounds are unequally
distributed in plant families
Zhu, F., Qin, C., Tao, L., Liu, X., Shi, Z., Ma, X., Jia, J., Tan, Y., Cui, C., Lin, J., Tan, C., Jiang, Y. and Chen, Y. (2011). Clustered
patterns of species origins of nature-derived drugs and clues for future bioprospecting. Proc. Natl. Acad. Sci. 108: 12943-12948.
Plant families associated with drug-
production are indicated in green,
and red indicates families with
endangered species
Solanaceae (tobacco,
nightshade, peppers) Papavaraceae
(poppy)
Taxaceae
(Pacific yew)
Apocynaceae (periwinkle)
Myrtaceae
(eucalyptus, clove)

Guilt by association – drug
discovery by relatedness
Saslis-Lagoudakis, C.H., Savolainen, V., Williamson, E.M., Forest, F., Wagstaff, S.J., Baral, S.R., Watson, M.F., Pendry, C.A. and Hawkins, J.A. (2012). Phylogenies reveal predictive
power of traditional medicine in bioprospecting. Proc. Natl. Acad. Sci. 109: 15835–15840. See also Zhu, F., Qin, C., Tao, L., Liu, X., Shi, Z., Ma, X., Jia, J., Tan, Y., Cui, C., Lin, J.,
Tan, C., Jiang, Y. and Chen, Y. (2011). Clustered patterns of species origins of nature-derived drugs and clues for future bioprospecting. Proc. Natl. Acad. Sci. 108: 12943-12948.
Some plant families are more likely to have medicinal value. Plant
genera used medicinally in three indigenous cultures were mapped, and
some overlaps identified; good candidates for further study!

• Plants produce
>200.000
compounds
• Many of these
chemicals function
in defense
Classes of phytochemicals with
medicinal properties

Redrawn from Hartmann, T. (1996). Diversity and variability of plant secondary
metabolism: a mechanistic view. Entomologia Experimentalis et Applicata 80: 177-188.
Photo-
synthesis
Carbohydrate
metabolism
Alkaloids
Coumarins
Terpenoids:
e.g. Limonoids
Saponins
Pinene
Phenolic: e.g. Flavonoids; Salicylic acid; Lignins etc
Alkaloids
Three structural classes of
specialized metabolites
Although hugely
diverse, specialized
metabolites are derived
from a few dozen
highly versatile central
intermediates, which
are modified in lots of
different ways

Alkaloids are biosynthetically diverse;
most derive from amino acids
There are
approximately 2500
benzylisoquinoline
alkaloids (BIAs),
including morphine
Tropane alkaloids
include cocaine
The ~2000
monterpenoid
indole alkaloids
(MIAs) are derived
from strictosidine
Caffeine is a
purine alkaloid
Senecionine is
a pyrrolizidine
alkaloid

MIAs are mainly known from two
plants “Indian snakeroot” aka
Sarpagandha, and Madagascar
periwinkle
Monoterpenoid indole alkaloids
(MIAs) are derived from strictosidine
Reprinted from Loris, E.A., Panjikar, S., Ruppert, M., Barleben, L., Unger, M., Schübel, H. and Stöckigt, J. (2007). Structure-based engineering of strictosidine
synthase: Auxiliary for alkaloid libraries. Chem. Biol. 14: 979-985 with permission from Elsevier; Forest and Kim Starr; Vinayaraj
Rauwolfia
serpentina
Catharanthus
roseus

Benzylisoquinoline alkaloids (BIAs)
share a benzylisoqunoline structure
Reprinted from Liscombe, D.K., MacLeod, B.P., Loukanina, N., Nandi, O.I. and Facchini, P.J. (2005). Evidence for the monophyletic evolution of
benzylisoquinoline alkaloid biosynthesis in angiosperms. Phytochemistry. 66: 1374-1393 with permission from Elsevier; Richard Old, XID Services, Inc.
Benzylisoquinoline alkaloids (BIAs) are a
family of about 2500 compounds that are
all based on the elaboration of a simple
skeletal structure
Noscapine
Cough suppressant from
Papaver somniferum

Papaver somniferum
Coffee
Nicotiana tabacum
Alkaloids contain nitrogen and
include stimulants and narcotics
Coca
Caffeine
Nicotine
Cocaine
Morphine
Vincristine
Catharanthus
roseus

Terpenoids are diverse compounds
derived from isoprene units
Isoprene (C5)
Image sources: Calvero; Wilhelm Thomé; Forest & Kim Starr; Karan A. Rawlins, University of Georgia
Eucalyptol
Linalool
Many low-
molecular weight
terpenoids are
volatile, and
components of
essential oils
Limonene, a
monoterpene (C10) Farnesol, a
sesquiterpene
(C15)
Pinene
Isoprene

Terpenoids are diverse compounds
derived from isoprene units
Ginkgolide
Photo credit: Dave Powell, USDA Forest Service, Bugwood.org
Tetrahydro-
cannabinol (THC)
Cannibus
sativa
Ginkgo
biloba
Taxol
Taxus breviola
Ginsenoside
Panax
ginseng
Artemisia
annua
Artemisinin

Phenolics: flavonoids, anthocyanins
and related compounds
Curcumin from the spice turmeric
Genistein an
isoflavonoid
from soy beans
Epigallocatechin gallate
(EGCG), a flavonoid from
green tea
Syzygium aromaticum
Brian Arthur
Eugenol
Tannins Found in
tea, wine, nuts and
many plants

Most plant phenolics are products of
phenylpropanoid metabolism
From: Buchanan, B.B., Gruissem, W. and Jones, R.L. (2000) Biochemistry and Molecular Biology of Plants. American Society of Plant Physiologists.
Phenylalanine
Zingiber
officinale
Gingerol
Cyanidin-glucoside
Vitis
vinifera

-Omics, systems, semi-synthetic
methods and metabolic engineering
Reprinted from Schilmiller, A.L., Pichersky, E. and Last, R.L. (2012). Taming the hydra of specialized metabolism: how systems biology
and comparative approaches are revolutionizing plant biochemistry. Curr. Opin. Plant Biol. 15: 338-344, with permission from Elsevier.
High-throughput methods are
being used to identify genes,
proteins and metabolites found
in various medicinal plants
Candidate genes, proteins and
metabolites can be tested
through biochemistry, reverse
genetics and analysis of
natural variation
Large scale approaches also
suggest ecological roles and
evolutionary histories

High-throughput methods to identify
genes, intermediates and pathways
http://medicinalplantgenomics.msu.edu/index.shtml; http://metnetdb.org/mpmr/, http://www.phytometasyn.ca/, http://uic.edu/pharmacy/MedPlTranscriptome/, http://www.onekp.com/index.html
Goals of these projects
include:
To identify candidate
metabolites, pathway genes
and pathways
To introduce the synthetic
pathways into other
organisms (e.g. yeast)
To increase production
To identify novel derivatives
(See the links below for complete lists of species being investigated)
DNA –
Genomics
mRNA -
Transcriptomics
Protein -
Proteomics
Metabolites -
Metabolomics

Genomic sequences are only part of
the story…
Reprinted from Schilmiller, A.L., Pichersky, E. and Last, R.L. (2012). Taming the hydra of specialized metabolism: how systems biology and comparative
approaches are revolutionizing plant biochemistry. Curr. Opin. Plant Biol. 15: 338-344, with permission from Elsevier.
Specialized metabolites often
accumulate in only a few cell
types, and their synthesis is
regulated by the environment.
Furthermore, there can be large
variations amongst varieties
within the same species.
Therefore, a sequenced genome
is only one piece of the puzzle

Many enzymes and metabolites are
highly compartmentalized
Bird, D.A., Franceschi, V.R. and Facchini, P.J. (2003). A tale of three cell types: Alkaloid biosynthesis is localized to sieve elements in opium poppy. Plant Cell. 15: 2626-2635. See also Ziegler, J.
and Facchini, P.J. (2008). Alkaloid biosynthesis: Metabolism and trafficking. Annu. Rev. Plant Biol. 59: 735-769. Dai, X., Wang, G., Yang, D.S., Tang, Y., Broun, P., Marks, M.D., Sumner, L.W.,
Dixon, R.A. and Zhao, P.X. (2010). TrichOME: A comparative Omics database for plant trichomes. Plant Physiol. 152: 44-54. Schilmiller, A.L., Miner, D.P., Larson, M., McDowell, E., Gang, D.R.,
Wilkerson, C. and Last, R.L. (2010). Studies of a biochemical factory: Tomato trichome deep expressed sequence tag sequencing and proteomics. Plant Physiol. 153: 1212-1223.
Companion
cell
mRNA
protein
product
Sieve
element
Lactifer
* For example, in
morphine
biosynthesis, the
genes, proteins and
products are found in
different cell types;
The alkaloid
biosynthetic pathway
in Catharanthus
roseus is also highly
compartmentalized
Many specialized
metabolites accumulate in
trichomes, and trichome
–omics databases have
been developed to learn
more about these
“biochemical factories”

In vitro synthesis is complicated by
natural products’ extensive chirality
Reprinted with permission from Feher, M. and Schmidt, J.M. (2002). Property Distributions: Differences between drugs, natural products, and molecules from combinatorial chemistry. J. Chem. Inf. Comput. Sci.
43: 218-227, copyright 2002 American Chemical Society. Facchini, P.J., Bohlmann, J., Covello, P.S., De Luca, V., Mahadevan, R., Page, J.E., Ro, D.-K., Sensen, C.W., Storms, R. and Martin, V.J.J. (2012).
Synthetic biosystems for the production of high-value plant metabolites. Trends Biotechnol. 30: 127-131. See also De Luca, V., Salim, V., Atsumi, S.M. and Yu, F. (2012). Mining the biodiversity of plants: A
revolution in the making. Science. 336: 1658-1661. Image source NASA.
Natural products have many chiral
centers that are hard to reproduce
synthetically. Engineered natural
systems can produce high yields of
compounds with appropriate
stereochemistry
Metabolic engineering of natural
systems is an important method for the
production of plant-derived medicines

Metabolic engineering can increase
yields and make novel compounds
A
B
C
D
E F
G H I
J
K
D
A
B
C
D
E F
G H I
J
K
D
A
B
C
D
E
F
G H
I
J
K
D
Once a biochemical
pathway is
identified, it can be
altered
Gene functions can be
silenced by RNAi, mutations,
viral-induced gene silencing
or natural variations
Gene functions can be
added or augmented by
environmental or
transgenic manipulations

The metabolic pathway can be
introduced into other organisms
A
B
C
D
E F
G H I
J
K
D A
B
C
D
E F
G H I
J
K
D
A
B
C
D
E F
G H I
J
K
D
Bacteria and yeast are widely used as
chemical factories for the production of
high value compounds, but plant cell
cultures are used also
A
B
C
D
E F
G H I
J
K
D

There are pros and cons to plant and
microbial cells
Reprinted by permission from Macmillan Publishers Ltd from Leonard, E., Runguphan, W., O'Connor, S. and Prather, K.J. (2009). Opportunities in metabolic
engineering to facilitate scalable alkaloid production. Nat. Chem. Biol. 5: 292-300.
Metabolic
engineering
Metabolic
engineering
Plant cells have pre-existing
transcription factors (tfs) and
intermediates, but also more
types of organelles. Over
(green)- or under (red)-
expression of genes can have
predicted or unintended
consequences
To produce a plant specialized
metabolite in yeast, often the
whole pathway must be
introduced (and engineered for
efficient expression in yeast),
and the necessary precursor (X)
provided.

Many medicinal metabolites have
been objects of pathway engineering
De Luca, V., Salim, V., Atsumi, S.M. and Yu, F. (2012). Mining the biodiversity
of plants: A revolution in the making. Science. 336: 1658-1661.
In bacteria and
yeast (black)
In yeast (blue)
In plants (green)
Rare non-opioid pain
reliever; higher desirable
candidate for engineering

Reprinted by permission from Macmillan Publishers Ltd from Keasling, J. (2008). From yeast to alkaloids. Nat Chem Biol. 4: 524-525; Hawkins, K.M. and
Smolke, C.D. (2008). Production of benzylisoquinoline alkaloids in Saccharomyces cerevisiae. Nat. Chem. Biol. 4: 564-573.
Example: Metabolic
engineering for
alkaloid production
in yeast
Black arrows indicate normal
pathway in plant cells. The
pathway engineered in yeast
used plant enzymes (red and
blue arrows) and a human
enzyme (purple) to produce
several important alkaloids

Metabolic engineering in plants and
plant cell cultures
Reprinted by permission from Macmillan Publishers Ltd from Roberts, S.C. (2007). Production and engineering of terpenoids in plant cell culture. Nat. Chem. Biol. 3: 387-395; Muñoz-Bertomeu, J., Arrillaga, I., Ros, R.
and Segura, J. (2006). Up-regulation of 1-ceoxy-d-xylulose-5-phosphate synthase enhances production of essential oils in transgenic spike lavender. Plant Physiol. 142: 890-900..
Enzymes affecting the production of
terpenoids, phenolics and alkaloids
have been enhanced or modified in cell
cultures and whole plants
As an example,
increasing the
production of the
terpenoid
precursor
isopentenyl
diphosphate
(IPP) can lead to
sweeter smelling
lavender 

Naturally decaffeinated coffee can
be made by RNAi-mediated silencing
Reprinted by permission from Macmillan Publishers Ltd. From Ogita, S., Uefuji, H., Yamaguchi, Y., Koizumi, N. and Sano, H. (2003). RNA interference: Producing decaffeinated coffee plants. Nature. 423: 823-823.
Extracts from plants
transformed with short
(black) and long (grey) RNA
interference constructs
7-methylxanthine
theobromine
caffeine
Theobromine
synthase
Caffeine
synthase
Transgenic silenced
plants produced less
theobromine and also
less caffeine than
controls
Theobromine synthase
was silenced in coffee
plants by RNA-
intereference

“Gilding the periwinkle” – enhancing
its diversity of alkaloid production
Reprinted by permission from Macmillan Publishers Ltd from Runguphan, W. and O'Connor, S.E. (2009). Metabolic reprogramming of periwinkle plant culture. Nat. Chem. Biol. 5: 151-153.
Example 1. A point mutation (V214M) in
strictosidine synthase expands its substrate
specificity so it accepts halogenated
substrates, leading to the production of
novel, halogenated products. The additional
substrates and products are shown in blue

“Gilding the periwinkle” – enhancing
its diversity of alkaloid production
Reprinted by permission from Macmillan Publishers Ltd from Runguphan, W., Qu, X. and O'Connor, S.E. (2010). Integrating carbon-halogen bond formation into medicinal plant metabolism. Nature. 468: 461-464.
Example 2. Introducing bacterial
tryptophan-modifying enzymes (red) means
that new strictosidine synthase substrates
are produced in vivo (and new products)

Recognizing the value of and
protecting biodiversity
Lew Diehl, Bugwood.org; http://www.cites.org
Goldenseal (Hydrastis canadensis) is being
seriously overharvested and is on the CITES
(Convention on International Trade in
Endangered Species) list of threatened plants
Worldwide, between 50,000 and
80,000 flowering plants are used
medicinally. Of these, at least
15,000 may face extinction due to
overharvesting and habitat loss.

"Peru offers a
branch of
cinchona to
Science”
In past centuries, explorers,
scientists and botanists freely
collected materials without
compensating the people
whose lands they were
studying
This sense of entitlement is
evident in this illustration

See Cordell, G.A. (2000). Biodiversity and drug discovery — a symbiotic relationship. Phytochem. 55: 463-480; Blaustein, R. (2006) Genetic resources and the convention on biological diversity. BioScience. 56: 560-
563 (Photo by Phyllis Coley); Kursar, T.A., Cabellero-George, C.C., Capson, T.L., Cubilla-Rios, L., Gerwich, W.H., Gupta, M.P., Ibañez, A., Linington, R.G., McPhail, K.L., Ortega-Barría, E., Romero, L.I., Solis, P.N.,
and Coley, P.D. (2006) Securing economic benefits and promoting conservation through bioprospecting. BioScience 56: 1005-1012; Convention on Biological Diversity – Nagoya Protocol on Access and Benefit-sharing.
The Convention on
Biological Diversity asks
for the “fair and equitable
sharing of the benefits
arising out of the utilization
of genetic resources”
Can bioprospecting and equitable
sharing promote conservation?
In other words, compensate
people who are good stewards of
biodiversity for their stewardship

Health care for all
Credit: Theresia Hofer, Mark de Fraeye Wellcome Images
Throughout much of the world, herbal
medicines are the foundation of
healthcare. Can science improve
healthcare as dispensed in its
traditional manner?

The World Health Organization
provides invaluable information
Photo credits: World Health Organization
Since 1999, WHO has
published 116 monographs
on selected medicinal plants
Each monograph
includes
information about
the plant’s
appearance,
synonyms,
chemical
constituents,
medicinal uses,
cautions, and
references

Medicine’s future draws from
Western and traditional medicines
World Health Organization; Adapted from Cheng, Y.-C. (2011) Why and how to globalize traditional Chinese medicine. J. Tradit. Complement. Med. 1: 1 - 4.
The two systems of traditional and Western medicine need not
clash…. they can blend together in a beneficial harmony, using
the best features of each system, and compensating for certain
weaknesses in each
Dr Margaret Chan, Director General of WHO
Traditional Knowledge
Zoopharmacognosy
Phytochemical studies
In vitro assays
GC-MS
Genomics and
metabolomics
Best
practices

Summary
Plants produce many
chemicals that can
benefit human health
Traditional and modern
methods can each
contribute to finding
and optimizing the use
of these
phytochemicals
Drawing by Gracia Lam and reprinted by permission from Macmillan Publishers
Ltd: from Xu, Z. (2011) One step at a time. Nature 480: S90 – S92

Future directions
Western
medicine
Traditional
medicine
Ethnobotany
Phyto-
chemistry
Medicinal
plants
Finding, optimizing
and using plant-
based medicines to
treat human
ailments requires
many types of
expertise
Finding new drugs
to treat emerging
diseases and
chronic diseases is
of particular interest

TTPB24MEDICINALPLANTS.ppt

Recommended

Recommended

More Related Content

Similar to TTPB24MEDICINALPLANTS.ppt

Similar to TTPB24MEDICINALPLANTS.ppt (20)

Recently uploaded

Recently uploaded (20)

TTPB24MEDICINALPLANTS.ppt