When Humans Accidentally Invent Natural Products

Juvenile hormones are probably the single most important hormone in insects, playing crucial roles in development, especially in molting and metamorphosis. To underline their importance, a specific class of synthetic insectide, the insect growth regulators, is devoted only to messing around with juvenile hormone levels of target insects.

Two enzymes are involved in the natural deactivation of juvenile hormone: juvenile hormone esterase, and juvenile hormone epoxide hydrolase. A common method for insect growth regulators to act is by disrupting or mimicking these enzymes, thereby disrupting the insect’s physiology and natural life cycle, and leading to dangerously early moulting or metamorphosis, or to no moulting at all.

A particularly successful group of juvenile hormone epoxide hydrolase inhibitors are urea-based synthetic chemicals (Severson et al., 2002). A new paper by Nollmann et al. in press at ChemBioChem finds a very rare occurrence: natural analogues of these synthetic chemicals that are structurally extremely similar.

The analogs come from a pretty cool bacterium, Photorhabus luminescens. As the species name hints at, this is a bioluminescent bacterium, but that’s not the cool thing about it. It’s a well-known insect pathogen which teams up with the nematode Heterorhabditis bacteriophora, a fellow parasite of insects. The juvenile nematode gets into the insect innocently, and then proceeds to throw up all its endosymbionts, including P. luminescens, into the insect’s haemocoel (bloodstream). These proceed to produce a range of toxins, and the insect dies fairly quickly, providing massive amounts of nutrients necessary for the nematode’s growth and reproduction (Waterfield et al., 2009). The full scale of the interaction gets much more interesting (request and I will write a complete article on it!).

It turns out that one of the toxins that helps kill the insect was produced by P. luminescens is a natural copycat of a chemical we synthesised a few years ago to help kill insects.

While the implications for biotechnology are not so great – we already knew about urea-based inhibitors of that enzyme – there are three things that I like about this discovery:

  • It’s a subversion of the regular biotech pathway of finding natural products then mimicking them synthetically;
  • It speaks to how advanced biochemistry has become, that it can unwittingly converge on an effective chemical that otherwise took hundreds of years to evolve;
  • It provides a very good demonstration of the value of “useless” research. I often hear complaints about people studying insect diseases, always with the same gist: “We’re wasting money on studying sick insects instead of curing sick people“. No, we’re using money to find out how best to protect our crops so that people have something to eat instead of starving to death, thereby preventing mass population die-offs and allowing biomedical research to go on.

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