The hypothesis
The hypothesis is composed of two parts.
1.
The identification of a fundamental constraint in the evolution of
metabolic processes leading to the synthesis of Natural Products -
potent, specific biological activity is a rare property for a molecule
to possess.
The reason why pharmaceutical companies invest
in large screening programmes to find useful biological activity is
because most molecules tested do not possess any potent biological
activity against any one target. The low frequency of potent, specific
biological activity is a consequence of the specificity of
ligand/binding site interactions. Any form of biological activity is
based on the more fundamental biomolecular
activity - the ability of any chemical
structure to bind reversibly to a specific protein.
Organisms that gain increased fitness by making
and exploiting molecules with biomolecular activity must face the same
constraint. Any mutation that results in the organism making a new
chemical has a very low probability of increasing the fitness of the
mutant because the very great majority of new chemicals will possess no
potent biomolecular activity of any kind. The low frequency of evolving
new molecules with potent, beneficial biomolecular activity places very
severe constraints on the evolution of the biochemical pathways leading
to such products.
2. A proposal as to how
secondary metabolism might have evolved with such a constraint -
including a prediction as to the metabolic traits that would expected
to minimize the effects of these constraints
How do organisms generate sufficient chemical
diversity to enhance their chances of finding the rare beneficial
chemical? How do organisms retain the capacity to generate new chemical
diversity when individual compounds or pathways become redundant? The
Screening Hypothesis proposes that certain metabolic traits (matrix
pathways, non-enzymic transformations, branched pathways, shared
pathways and enzymes with a broad substrate tolerance) would all help
increase generation and retention of chemical diversity.
Some consequences of the hypothesis
- One should not expect all naturally made
chemicals to have a role in the organisms that make them. Many will
have no role and will never have had any role in the organisms in which
they are found. Many chemicals will simply have been made because the
metabolic machinery capable of their production has a benefit for the
producer. If only one product that those pathways can produce has a
beneficial biological activity, the pathways will be sustained if the
costs of possessing that capacity is sustainable. This is akin to the immune
system in animals where most antibodies possess no beneficial
properties but the ability to make a great diversity of antibodies at
low cost is highly beneficial.
- One should not assume that some biological
activity found in a screening trial conducted by humans has any
significance to the role of the chemical in the organism that produces
it. If organisms are producing chemical diversity they must inevitably
produce chemicals with structures that will possess fortuitous
biological activity in non-target organisms.
- The metabolic traits predicted by the
screening hypothesis will sometimes make it hard to precisely
genetically manipulate the “secondary product”
pathways leading to Natural Products. For example, it is proposed that
in order to enhance the production and retention of chemical diversity,
many enzymes involved in secondary product biosynthesis will have low
substrate specificity. Consequently, if a new enzyme is introduced into
an organism to cause the production of a new secondary product, there
is high probability that existing enzymes in the transformed organism
will further elaborate the new product to produce more novel chemical
diversity.
- Some of the metabolic traits predicted (for
example low substrate specificity) might be usefully exploited in
biotransformation and bioremediation studies.
- The flux of carbon through secondary
metabolite pathways must have been very large throughout the period of
life on earth. The metabolic traits predicted by the Screening
Hypothesis may have played a part in encouraging the microbial
catabolism of this huge amount of chemical diversity. The world has
never been a clean place chemically hence organisms must have the
capacity to survive and thrive in the presence of chemical diversity.
Most synthetic chemicals released into the environment will be
substrates for enzymes that can transform them and maybe many NPs.
- Organisms with a varied diet must ingest many
Natural Products hence they must possess mechanisms to keep the
concentration of many varied chemicals at low enough concentration to
reduce their effect. These mechanisms will be available to reduce the
concentration of synthetic chemicals in the body.
When these ideas were first advanced they were
regarded as verging on heresy. However in the last decade a very large
amount of evidence has been published which is consistent with the
predictions of the model. But the hypothesis is there to argued about.
Please engage us in debate. We cannot think of any simple experiment
that could disprove the hypothesis - the model is based on a metabolic
flexibility that makes it robust to some challenges. However, we really
do enjoy thinking about the model’s strengths and weaknesses.
We would welcome being made aware of evidence which supports or
contradicts the predictions. We would also welcome evidence as to the
frequency of biological activity/biomolecular activity in collections
of chemicals. There must be masses of data in the files of screening
companies which would be valuable - we don't need to know the identity
of the compounds, or even the exact screen being used, but we could
usefully use information about the frequency of activity, especially if
the screen was conducted at different concentrations.
Want to know more? Try reading the FAQs or indeed the papers
listed. Thanks.
Richard
D Firn
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