Fueled by New Chemistry, Algorithm Mines Fungi for Useful Molecules

A newly described type of chemistry in fungi is both surprisingly common and likely to involve highly reactive enzymes, two traits that make the genes involved useful signposts pointing to a potential treasure trove of biological compounds with medical and chemical applications.

It was also nearly invisible to scientists until now.

In the last 15 years, the hunt for molecules from living organisms — many with promise as drugs, antimicrobial agents, chemical catalysts and even food additives — has relied on computer algorithms trained to search the DNA of bacteria, fungi and plants for genes that produce enzymes known to drive biological processes that result in interesting compounds.

“The field kind of hit a wall in the early 2000s, when the discovery process was to extract things from fungi and see what those extracts did. But we kept rediscovering the same things,” says Grant Nickles, a graduate student in the lab of Nancy Keller, professor of medical Microbiology and immunology. “As we learned more about the genes that make these cool natural products, we designed algorithms that could search for them, find targets and make the process much more efficient.”

That method also hit a wall of sorts because the algorithms only had eyes for certain types of genes.

“The main algorithms made to find natural products work great, but they are focused on genes related to three canonical backbone enzymes,” says Keller. “There have been incremental improvements to those algorithms, but you can only search the same genomes for similar genes so many times before you are, again, rediscovering the same things.”

In 2005, a community of researchers sequenced the genome of Aspergillus fumigatus, a fungus that can infect people with compromised immune systems.

“The first sequence made the hairs on my arms rise,” Keller says. “There were so many clusters of genes of the type that make these backbone enzymes that produce interesting secondary metabolites. I said, ‘Oh! There’s a lot more natural products in fungi than we ever could have guessed.’”

In subsequent research, Keller’s lab uncovered at least one cluster of genes involved in biochemical processes reliant on a backbone enzyme called isocyanide synthase, which is not one of the three “canonical” enzymes known to be common chemical workhorses across bacteria and fungi.

Source: wisc.edu

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