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Chemical Biology

Forcing Fungi to Make Stranger Compounds

Natural products come up around here fairly often, as sources of chemical diversity and inspiration. Here’s a paper that combines them with another topic (epigenetics) that’s been popular around here as well, even if there’s some disagreement about what the word means.
A group of Japanese researchers were looking at the natural products derived from a fungus (Chaetomium indicum). Recent work has suggested that fungi have a lot more genes/enzymes available to make such things than are commonly expressed, so in this work, the team fed the fungus an HDAC inhibitor to kick its expression profile around a bit. The paper has a few references to other examples of this technique, and it worked again here – they got a significantly larger amount of polyketide products out of the fermentation, included several that had never been described before.
There have been many attempts to rejigger the synthetic machinery in natural-product-producing organisms, ranging from changing their diet of starting materials, adding environmental stresses to their culture, all the way to manipulating their actual
genomic sequences directly. This method has the advantage of being easier than most, and the number of potential gene-expression-changing compounds is large. Histone deacetylase inhibitors alone have wide ranges of selectivity against members of the class, and then you have the reverse mechanism (histone actyltranferase), methyltransferase and demethylase inhibitors, and many more. These should be sufficient to produce weirdo compounds a-plenty.

4 comments on “Forcing Fungi to Make Stranger Compounds”

  1. paperclip says:

    This really is fascinating stuff. Time and again it is seen that fungi in the lab produce just a fraction of the compounds that their genomes suggest they are capable of making. The next great antibiotic could be locked away in one of those fungi. HDAC inhibitors seem to pry out a couple more compounds sometimes, but not everything. Although researchers are trying to find out the rhyme and reason to it all, for now the best thing is to try anything you can think of to induce a fungus to produce more.

  2. Anonymous says:

    Thanks for the updated picture!
    I love how your color changes with the surroundings – are you sure you’re not part chameleon?
    And thanks for blogging so prolifically – it’s always interesting to read!

  3. simpl says:

    How far off is a yeast-based production of atorvastatin?

  4. Aspergil says:

    I’m a fungal molecular biologist that works on secondary metabolites. As you state, there are several studies that use this chemical induction approach to get fungi to express many of their normally silent secondary metabolite genes. Now that we have genome sequences for many fungi, we can see that there are far more secondary metabolite genes than there are defined products. People in the field have been going after these genes with promoter replacements and heterologous expression hosts. This work is rapidly accelerating compound discovery and will only get faster in the future. I would argue that yeast-based production is not as efficient as production in filamentous fungi. Genetic manipulation in filamentous fungi is far more advanced than most people are aware of. There is very little difference in genetic manipulation of yeasts and filamentous fungi.

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