For nearly a century, fungi have been a treasure trove of life-saving medicines.
From Alexander Fleming’s discovery of penicillin in 1928 to treatments for cholesterol, infections, cancer, and more, fungi continue to play a vital role in medicine.
However, the way fungi create some of their most powerful compounds has remained a mystery—until now.
A new study from the Gao Lab at the University of Pennsylvania reveals how fungi produce a key medicinal molecule called cyclopentachromone.
This molecule forms the foundation for many compounds with promising anti-cancer and anti-inflammatory properties.
The findings, published in the Journal of the American Chemical Society, uncover a previously unknown enzyme that catalyzes the creation of cyclopentachromone, bringing scientists closer to developing new pharmaceuticals inspired by nature.
Cyclopentachromone is unique because of its complex structure: three carbon rings, two with six carbons and one with five. This structure acts as a scaffold, supporting various bioactive molecules.
One of the biggest challenges in studying cyclopentachromone has been replicating its structure in the lab. “It’s easy to end up with a molecule where the bonds are in the wrong places, or the structure is flipped,” explains Dr. Sherry Gao, senior author and professor at Penn.
To understand how fungi produce cyclopentachromone, the team studied the genes of Penicillium citrinum, a mold commonly found on citrus fruits. They identified a specific enzyme, called IscL, that plays a key role in the process.
The research was like solving a molecular puzzle. The team systematically turned different genes in P. citrinum on and off to figure out which ones controlled the enzyme’s activity.
“It was like testing hundreds of light switches to find the one that turns on a specific bulb,” says Qiuyue Nie, a postdoctoral fellow and the study’s first author.
Their experiments revealed that IscL produces an intermediate compound called 2S-remisporine A. This compound features a highly reactive carbon-sulfur bond, which allows it to combine with many other molecules.
The reactive nature of 2S-remisporine A explains why cyclopentachromone is so versatile as a medicinal compound. The carbon-sulfur bond acts like a hitch on a truck, allowing the molecule to attach to various groups and form new compounds.
“This intermediary compound is highly reactive and can combine with different sulfur donors to create a wide variety of molecules,” Nie explains.
Because of its reactivity, 2S-remisporine A has been challenging to identify—until now. The team’s work shows how nature produces this elusive molecule and provides tools to harness its potential.
By understanding how fungi naturally create cyclopentachromone, scientists can use this knowledge to design new drugs. The Gao Lab’s discovery offers a roadmap for studying fungal compounds and developing pharmaceuticals that leverage nature’s own processes.
“Nature has had billions of years to perfect these pathways,” says Gao. “We’re learning to borrow these tools to create and study compounds that could lead to new medicines.”
The researchers hope to use their findings to advance fungal-based therapies and discover new applications for cyclopentachromone and its derivatives.
“This paper shows us how one of nature’s incredible tools is made,” Gao adds. “The possibilities for medicine are exciting.”
The study also involved contributions from researchers at East China Normal University and several members of Penn Engineering. Their work highlights the potential of fungi to inspire breakthroughs in modern medicine, turning ancient natural processes into cutting-edge solutions.
Source: University of Pennsylvania.
