Exploring Natural Products Diversity: A Co-evolutionary Perspective

1. The many and changing ideas to explain existence and the chemical diversity of Natural Products Is it all the result of co-evolution?

2. 1. Humans have seemingly been obsessed with NPs. Discuss the biological issues that you consider to be relevant to the analysis of that obsession. 2. Natural scents, colours and flavours are of great commercial importance. How easy has it been for breeders to maipulate the content of these valuable products? Is that expected to change?

3. At the end of this lecture you should appreciate: • why some natural phenomena encourage scientists to devise a great many, diverse explanations • what kinds of explanations were proposed to explain NP diversity and why each proposal had strengths and weaknesses • why academic compartmentation hindered thinking - those working on NPs in microbes rarely spoke to those working on NPs in plants • the currently accepted paradigm

4. Subjectfragmentation

5. Thefragmentation of the study of NPs Microbiologists interested in antibiotics Entomologists interested in plant-insect interactions Plant pathologists interested in plant-fungal interactions Plant biologists thinking about plant-plant interactions Zoologists thinking about animal food preferences Chemists thinking about NPs structures Biochemists thinking about enzymes making NPs

6. Wasteproducts? Plants lack an excretion system so how do they get rid of waste? Plants unlike animals make Natural Products. So maybe Natural Products are made as a way of getting rid of waste? Alkaloids could function as nitrogen waste products like urea in mammals. But do microbes and plants make waste? Why would they? Why would evolution come up with so many varied ways of doing it and keep changing the routes?

7. Fortuitous. There is no reason …. It is just chance .. Afterall look at “junk DNA” … why must there be a reason for everything? Popular with some microbiologist but what would the selective advantage be to the producer? Biochemists and chemists were happy with this idea because they were not really that fussed about evolution. But many biologists found this idea offensive. Costs without benefits are rarely beneficial. Any exceptions?

8. Relics of previous specific uses One famous microbiologist claimed that the potency of the antibiotics, and the fact that so many acted via an inhibition of protein or RNA synthesis, suggested that these chemicals were once used by bacteria as regulators but the regulation methodology had become redundant and these were relics. Why would this relic remain and not others when billions of years have passed. Why would animals have got rid of them but not plants?

9. Inventive metabolism Zahner, a microbiologist, argued that Natural Product metabolism was needed to try out new branches of biochemistry. Thus the actual NPs were not important as such but the “testing” of new enzymes was handy. How came some organisms manage without such “testing”? What are they testing for?

10. Alkaloids could act as nitrogen storage resevoirs for use by the plant in nitrogen limiting situations. What about NPs that were not alkaloids? What is wrong with storing nitrogen in proteins – seed storage proteins are common and some plants even make odd amino acids to store N in a form that is hard for other organisms to access

11. Secondary metabolites could serve as growth regulators. Gross argued that there are so many weird processes going on in plants that many new “hormones” were awaiting discovery and NPs would turn out to be very important in this role. But most plants share much of their physiology and developmental patterns (variations on common themes not different themes) so why has evolution kept changing the controlling chemicals. Do we need 500,000 new regulators?

12. Secondary metabolites may be used to help the plant maintain ionic balance, especially when the roots take up ions from the soil. And microbes? Why did evolution come up with so many variants? Would NPs really help? Not how it happens.

13. Chemical warfare (or more usefully chemical interactions between organisms) • As Demain (1995) said: • "It has always amazed me that the importance of chemical compounds in ecological interactions between plant versus herbivore, insect versus insect, and plant versus plant has been universally accepted, but the importance of antimicrobials in microbial interactions has been almost universally denied"

14. Constituitive vs inducible chemicals Phytoalexins

16. Plant – insect interactions … Fraenkel (1959) • Erlich, P.R. and P.H. Raven • 1964. Butterflies and plants: a study in coevolution. Evolution 18:586-608 • Looked at patterns of host-plant use by butterflies. Ex. Umbelliferae (Apiaceae)/Swallowtail butterflies Proposed a 5 step process • 1. Random genetic event – plant produces novel compound by chance • 2. Novel compound renders plant less suitable host plant • 3. Plant freed from herbivore pressure, can undergo evolutionary radiation in new adaptive zone • 4. Random genetic event – insect evolves resistance to compound • 5. Able to exploit previously unavailable resource, adapted insect enters new adaptive zone and undergoes its won evolutionary radiation • Janzen 1980 argues for more restricted definition. Change in one species, in response to selection imposed by another species, followed by a change in the second species in response to the change in the first. Coevolution is a reciprocal process

17. ..“Volatile metabolites of Lycopersicon species are of interest because of their roles in tomato flavour and in host defense against arthropod herbivores ..” (Colby et al., 1998).

18. Plant – insect interactions • Negative • Deterrents • Feeding • Oviposition • Toxins • Positive • Oviposition • Feeding • Parasitism enhancers

19. "In some scientific circles it is something of a sport to theorize about function, often with the intent of finding one overriding axiom true for all secondary metabolism. Speculations range from the notion that they are waste products or laboratory artefacts, to the concept that they are neutral participants in en evolutionary game, to ideas of chemical weaponry and signalling." • Bennett, 1995