Both plants and animals produce functional secondary metabolites, either as a result of digestion and processing of food molecules or from biosynthetic pathways in the organism’s own body.
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The last few decades have witnessed the emergence of knowledge about the origin of many natural products from animals, which were made possible by symbiotic bacteria.
Even more recently, scientists have become aware that animal genomes do encode natural products that look very much like those produced by microbes.
Some of these products may be the result of the integration of bacterial genomes into the host chromosomes, but in many other cases, they come from a new type of biochemical pathway in animals.
What is biosynthesis?
Biosynthesis refers to a complex multistep process of converting substances (substrates), via the catalytic action of enzymes, into more complex products within living organisms.
Many of these reactions occur via processes called metabolic pathways, either within a single cell organelle or, more commonly, spread over multiple organelles.
The meaning of diversity
A compound is structurally diverse in the following situations:
- Appendage diversity allows different structural groups to be added around a common skeleton
- Functional group diversity allows different types of functional groups
- Stereochemical diversity permits variation in the way the different elements of the compound may interact with macromolecules concerning their orientation
- Scaffold (or skeletal) diversity, where the molecular skeleton itself is only one of many
For small molecules, the shape is the paradigm that determines their biological activity, because it offers a complimentary 3D binding surface that macromolecules can interact with. This means that ultimately, scaffold diversity holds a key place in the functional diversity of molecules.
Diversity-oriented synthesis (DOS) refers to the “deliberate, simultaneous and efficient synthesis of more than one target compound in a diversity-driven approach.”
Modern biotechnology coupled with biosynthesis can allow natural products to be synthesized within tested and proven industrial microbes.
To plan a DOS pathway, it is necessary to design a strategy with 5 or fewer steps for maximum efficiency, looking in the forward sense, where a simple material is a substrate for multiple structurally diverse small molecules.
Types of metabolic pathway
How do living organisms give rise to multiple chemical products? The answer is that there are metabolic pathways of different types.
The first type, which is more common, results in the formation of one specific product, or a few, at most.
However, the second type is designed to produce multiple and often very diverse biosynthetic products. These are the diversity-generating pathways and yield most of the small molecules within living organisms.
One such pathway is the tru pathway, where each successive step goes slower as the system becomes capable of producing different types of chemicals the further it proceeds. The enzymes within this pathway can catalyze multiple substrates using the same chemical reaction.
With this type of pathway, the intermediate products persist for a long time and therefore their levels accumulate over time.
This marks a fundamental difference between the tru pathway and what may be called conventional metabolic pathways. In the latter, the first step is rate-limiting and the intermediate compounds quickly degrade or are converted into the next reactant.
The Tru pathway – a symbol of biosynthetic diversity
The tru pathway is seen in cyanobacteria living symbiotically with coral reef animals. It can begin with any of an extremely broad range of substrates using the same sequence of identical enzymes. It can synthesize an enormous number of products with widely varying chemical structures.
The pathway begins with the first precursor peptide, TruE, being synthesized on the ribosome. Many TruE variants are known, both artificial and natural. It then moves through TruD and TruA enzymatic steps to be acted on by TruG and finally TruF1, to become an isoprene-bearing macrocycle.
The nature of this pathway is such that these enzymes can act on many different substrates. However, with the early part of the pathway, the enzymes can recognize large conserved sequences called recognition sequences.
As these sequences are cut during the progress of the reaction, they are missing from the final product. Enzymes at the later stages of the pathway meet substrates with very different structures.
The implications of biosynthetic diversity
In a typical enzymatic pathway, regulatory elements are modulated to achieve higher gene expression.
In the tru pathway, the addition of hydrogen sulfide modulates the activity of the enzyme, though the final amount of product and its lifetime remained constant. This is in contrast to the (typically) first rate-limiting step of most metabolic pathways.
The substrate flexibility allows the organism to rapidly produce new chemicals without having to shift the pathway, though each succeeding step becomes slower and more sluggish. This may represent a natural optimization technique in an organism presented with a threat or challenge.
In short, animal metabolites serve a host of purposes, whether protective, offensive or communicative. Though humans feed on chemicals synthesized by plants, they can also elaborate complex compounds such as corticosteroids, neurotransmitters, G-protein coupled ligands and prostaglandins.
DOS has also earned its place as a synthetic biology approach that is extremely valuable in handling the demands of generating new structurally diverse libraries of small molecules with bioactivity, even against traditionally undruggable or largely unchallengeable biological processes.
This can serve as a powerful method for identifying novel small molecules with potent biological activity.
- Tianero, M. D., et al. Metabolic model for diversity-generating biosynthesis. PNAS 2016; 113 (7) 1772-1777.https://doi.org/10.1073/pnas.1525438113. https://www.pnas.org/content/113/7/1772
- Gu, W., and Schmidt, E. W. Three principles of diversity-generating biosynthesis. Accounts of Chemical Research 2017 Oct 17; 50(10): 2569–2576. DOI: 10.1021/acs.accounts.7b00330. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433375/
- Torres, J. P., and Schmidt, E. W. The biosynthetic diversity of the animal world. Journal of Biological Chemistry 2019. DOI: 10.1074/jbc.REV119.006130. https://doi.org/10.1074/jbc.rev119.006130
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