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Plant Physiol, January 2001, Vol. 125, pp. 58-60
Ecological Arsenal and Developmental Dispatcher. The
Paradigm of Secondary Metabolism
Toni M.
Kutchan*
Leibniz-Institut für Pflanzenbiochemie, Weinberg 3, 06120 Halle, Germany
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PLANTS PRODUCE A LARGE NUMBER OF CHEMICALS OF DIVERSE
STRUCTURE AND CLASS |
Mankind has been exploiting plant
chemicals in the form of potions and poisons for thousands of years.
The attitude toward the physiological significance of this plethora of
small molecules is reflected in the terminology that was assigned to
them: secondary metabolites. Less flattering terms were also assigned:
waste products, metabolic leftovers, and excrement. Two schools of
thought concerning the function of secondary metabolites had developed
into the 1970s. Prominent personalities such as Miriam Rothschild, an
amateur naturalist in England, were proponents of a critical ecological function for secondary metabolites such as cardiac glycosides, cannabinoids, anthocyanins, and pyrrolizidine alkaloids. On the other
side were followers of Kurt Mothes, a charismatic professor of plant
biochemistry in East Germany who held the opinion that substances such
as alkaloids have "no special physiological meaning" and that
"many people apparently cannot live without the idea that everything
in Nature has a purpose." That being said, how far have we come since 1975?
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SECONDARY METABOLITES CAN BE KEY PLAYERS IN THE INTERACTION BETWEEN
PLANTS AND THEIR ENVIRONMENT |
Pioneering work published by the likes of Miriam Rothschild (13),
Jeffrey Harborne (The University of Reading), Tom Eisner, and Jerry
Meinwald (Cornell University) established a new field of study and
coined its name, "chemical ecology." It is now accepted that there
is an integral interaction between plants and their environment and
that species-specific secondary metabolites are key players in this
interaction. For example, the pigments that are produced in flower
petals, "signatures" of mixtures of anthocyanins or betalains,
determine in part how effectively a flower will be pollinated. In
another form of interaction, juvenile forms of insects have become
specialized to feed on poisonous plants. In fact, some insects can have
an out right predilection for poisonous food plants. The protection
proffered is 2-fold: Poisonous plants are avoided by large herbivores
and the insects accumulate toxic plant secondary metabolites such as
cardiac glycosides and pyrrolizidine alkaloids that serve to protect
them in later stages of development. To further demonstrate function,
the research group of Hans Grisebach (Freiburg University) showed that
secondary metabolites have a role in plant defense. Phenylpropanoids
were found to accumulate in soybean in response to treatment with
pathogens (19). This then linked the field of secondary metabolism to phytopathology.
In recent years a discovery of the function of secondary metabolites in
the interaction with symbionts, rather than pathogens, was made that
was biochemically clearly verifiable. A groundbreaking observation by
the group of Sharon Long (Stanford University) demonstrated that the
flavone luteolin exuded from roots of alfalfa serves as a signal that
activates rhizobial nodulation genes and therefore plays an integral
role in root colonization (12).
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SECONDARY METABOLITES CAN ALSO BE SIGNAL COMPOUNDS INVOLVED
IN PLANT DEVELOPMENT |
One of the classical secondary metabolites, methyl jasmonate
(familiar as the scent of jasmine), is now recognized as part of a
signal transduction chain that begins with the membrane associated fatty acid  -linolenic acid and results in pleiotropic effects ranging from defense gene activation to mechanotransduction, tuber formation, and plant senescence, among others (18). Using Arabidopsis mutants demonstrating dwarfism and defects in light-regulated development, another class of secondary metabolites, the
brassinosteroids, has been found to have a role in the regulation of
plant development (9, 16). A role for flavonols in functional pollen
development was demonstrated using antisense chalcone synthase petunia
plants and chalcone synthase mutant maize plants (10, 17). Plants that could not produce flavonols were male sterile, defective in pollen germination and tube growth, but the sterility could be overcome by
addition of the flavonol aglycones kaempferol or quercetin to mature
pollen at pollination. With the discovery of physiological roles for
secondary metabolites such as jasmonates, brassinosteroids, and
flavonols in critical processes in plant growth and development, the
chapter in scientific history that relegated secondary metabolites to
being flukes of nature effectively came to an end.
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IF SECONDARY METABOLITES HAVE A DEFINITE AND EVOLVED ROLE IN THE
LIFE CYCLE OF A PLANT, THEN SPECIFIC ENZYMES SHOULD UNDERLIE THEIR
FORMATION |
This was another point of contention encompassing two opposing
hypotheses: Enzymes of primary metabolism fortuitously catalyze the
formation of secondary metabolites, or enzymes specific to the
biosynthesis of secondary metabolites have arisen during the course of
evolution. Pioneers of the enzymology of plant secondary metabolism,
such as Eric E. Conn (University of California, Davis) and Hans
Grisebach began to demonstrate that specific enzymes, such as Phe
ammonia lyase of phenylpropanoid biosynthesis, did exist. However,
higher plants have a relatively sluggish rate of expression of
secondary metabolism, and steady-state concentrations of biosynthetic
enzymes are low. In addition, large amounts of tannins and other
phenolics that accumulate in plants interfere with the extraction of
active enzymes. A breakthrough in the study of the enzymology of
secondary metabolite formation came with the establishment of plant
cell suspension cultures that produce quantities of secondary
metabolites that match or surpass those levels found in plants. These
experiments in the research group of Meinhart H. Zenk (Bochum
University, University of Munich) went on to show with the discovery
and purification of more than 80 new substrate-specific enzymes of
phenylpropanoid and alkaloid anabolism that the dogma that assigned
secondary metabolites as mistakes or a simple play of primary
metabolism was incorrect (20).
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DEDICATED, SPECIES-SPECIFIC BIOSYNTHETIC ENZYMES ARE PRESENT IN
PLANTS, BUT FROM WHERE DO THEY COME? |
The earliest identified enzymes of plant secondary metabolism were
of general phenylpropanoid metabolism, Phe ammonia lyase, 4-coumarate:CoA ligase, and chalcone synthase. Since their discovery they have also been the most intensely studied enzymes. The entry of
the area of plant secondary metabolism into the age of molecular genetics came in part with the isolation of the cDNAs encoding these
three enzymes by the groups of Rick Dixon (University of London), Chris
Lamb (Salk Institute), and Klaus Hahlbrock (Freiburg University) (3, 7, 15). This was followed within a few years by the isolation of the first
cDNAs of alkaloid biosynthesis, strictosidine synthase, of terpenoid
biosynthesis, 4S-limonene synthase, and of cyanogenic
glucoside biosynthesis, P-450Tyr by the groups of Toni Kutchan (University of Munich), Rod Croteau (Institute of Biological Chemistry, Pullman), and Birger Lindberg Møller (Royal Veterinary and Agricultural University, Copenhagen), respectively (1, 6, 8). Technological breakthroughs such as molecular cloning advanced
many research fields simultaneously and plant secondary metabolism was
included in this surge forward. Given knowledge of the complete amino
acid sequence of enzymes of secondary metabolism, insight can now been
gained into their evolutionary origin. Orthologs of some plant
secondary metabolite biosynthesis genes such as those encoding
cytochromes P-450, aldo-keto reductases, and methyltransferases exist
in organisms from widely unrelated kingdoms such as mammals and
bacteria. A strictosidine synthase-like gene has recently been found to
be strongly expressed in human brain (5). Inter-relatedness based on
primary amino acid sequences has been demonstrated between enzymes of
flavonoid and alkaloid anabolism. Plant polyketide synthases such as
chalcone synthase, stilbene synthase, and acridone synthase have
provided evidence for how small changes in gene evolution can lead to
diverse chemical structures such as the phenylpropanoid-derived chalcone and resveratrol,
and acridone alkaloids. Although the phylogeny of plant secondary
metabolites remains to be resolved, great progress is being made.
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SECONDARY METABOLISM IS A MUSE TO NEW CONCEPTS |
In the 1990s, secondary metabolism clearly emerged as a field of
research from which ideas were born that transcended plant sciences
into areas such as human health and materials engineering. In a study
of the enzymes involved in lignan/lignin biosynthesis in Forsythia, the
research group of Norman G. Lewis (Institute of Biological Chemistry,
Pullman) discovered a fundamentally new type of biomolecule, the
dirigent protein, which functions as a scaffold that determines the
chirality of a molecule after chemical transformation by an enzyme (2).
A tantalizing implication of these results is that one of our major
building materials, lignin, may be chiral.
The 5'-deoxyadenosyl radical derived from coenzyme
B12 is involved in an intramolecular migration in
the conversion of L-methylmalonyl CoA into succinyl CoA. In
mammals this step is part of the metabolism of certain amino acids and
odd chain-length fatty acids into Glc. Plants do not produce vitamin
B12 and it has been a long-standing question what
molecule takes the role of this cofactor in intramolecular migration
reactions. The answer has been provided very recently by the group of
János Rétey (University of Karlsruhe) who discovered that
during an intramolecular migration in the biosynthesis of the
anticholinergic alkaloid scopolamine in Jimson weed, 5'-deoxyadenosyl radical is formed from S-adenosyl-Met (11). This work has
defined a new role in plants for S-adenosyl-Met, known in
plant metabolism mainly as a major methyl group donor. It also
indicates how plants, similar to bacteria, have evolved to use a
cofactor that is structurally simpler than cobalamin to affect
intramolecular migration reactions.
One of the highest impact discoveries in secondary metabolism of the
last 10 years is the discovery and elucidation of the non-mevalonate
biosynthetic pathway to isoprenoids (4, 14). This breakthrough has
changed textbook knowledge that had long been accepted and
unchallenged. The pathway is currently being dissected by
simultaneously using plant and bacterial model systems. Although closure on the pathway will still take some years of research effort,
the impact of this knowledge will likely be far reaching to the field
of human medicine in the form of new treatments for bacterial- and
parasite-related diseases such as tuberculosis and malaria.
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WHAT THEN HAS CHANGED IN 25 YEARS? |
In the past 25 years we have transcended the view of plant
secondary metabolites as one of nature's meaningless waste products to
one in which secondary metabolites play critical roles in plant development and defense. They are no longer only fortuitously formed
chemicals that serve mankind as pharmaceuticals and pesticides. We now
understand that secondary metabolites can provide a local or a systemic
defense response to pathogen and herbivore attack. They have an
integral role in plant growth, development, symbiosis, and
reproduction. This list is certain to grow as we discover additional
important functions for secondary metabolites in the years to come.
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FOOTNOTES |
*
E-mail kutch{at}ipb-halle.de; fax 49-345-5582173.
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© 2001 American Society of Plant Physiologists
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PLANTS PRODUCE A LARGE...
SECONDARY METABOLITES CAN BE...