Scientists Mimic Fungal Process to Create Novel Medicines

Since Alexander Fleming's unintentional 1928 discovery of penicillin, fungi have been a treasure trove of medicinal compounds for almost a century. They have offered remedies for a variety of illnesses, including cancer, organ rejection, high cholesterol, and infections.

The method by which fungi produce some of their most powerful substances is still unknown, though. This is particularly true for cyclopentachromone, a crucial component of fungal products whose derivatives have demonstrated potential for anti-inflammatory and anti-cancer effects, among other therapeutic benefits.

Reading Nature’s Instructions

Although chemists have made strides in producing chromone derivatives in the laboratory, it has proven challenging to accurately and consistently replicate the molecule's unique structure.

It is very easy to wind up with a version where the chemical bonds are not in the right place, or the structure is flipped.”

Sherry Gao, Presidential Penn Compact Associate Professor and Study Senior Author, University of Pennsylvania

Members of the Gao Lab explain in a study published in the Journal of the American Chemical Society how they were able to decipher nature's instructions, specifically the genes of the mold Penicillium citrinum, which is frequently found on citrus fruits, to find an enzyme that had not been previously identified that catalyzes the formation of compounds that contain cyclopentachromones.  

Nature has had billions of years to develop pathways for creating these compounds. Now we can borrow nature’s tools to develop and study these compounds further, which could potentially lead to the development of new pharmaceuticals.”

Sherry Gao, Presidential Penn Compact Associate Professor and Study Senior Author, University of Pennsylvania

A Molecular Puzzle

One of cyclopentachromone's distinguishing features is its unique structure, which consists of three carbon rings, two with six carbons and one with five. This set of rings serves as the structural basis for many bioactive compounds, much like the scaffold used to build a building.

But one of the known chemical precursors of cyclopentachromone has an extra carbon, creating three identically sized rings. It has never been explained exactly how nature transforms that chemical into one with a different ring structure, even though those rings are typically stable.

Identifying the genes that coded for the enzyme at play required methodically turning P. citrinum genes on and off until the pathway was broken.

It was like having to test hundreds of light switches to see which one operates a particular bulb.”

Qiuyue Nie, Postdoctoral Fellow and Study First Author, University of Pennsylvania

The scientists found that another intermediate compound, 2S-remisporine A, which is generated by the recently discovered enzyme IscL, has a sulfur atom that hangs off one side of the three-ring structure, resembling a truck hitch.

From Mold to Medicine

Cycloopentachromone's medicinal versatility stems from its high degree of reactivity. The carbon-sulfur bond in 2S-remisporine A can combine with a wide range of other groups to produce a diverse array of molecules, much like a truck can pull a variety of attachments, from wagons to boats.

Nie said, “This intermediary compound is highly reactive. The carbon-sulfur bond can react with different sulfur donors to produce a lot of new compounds.”

The reason 2S-remisporine A has never been completely identified before is that it is extremely reactive and will combine with different molecules, including itself.

Nie said, “We could never invent how to make such a reactive intermediate compound. We had to learn how nature makes it, then leverage those enzymatic tools ourselves.”

To further develop the use of fungal compounds in medicine, the researchers hope that future research will explore this recently identified pathway using the genetic map that directs it.

Gao said, “Nature has an incredible toolbox. This paper shows us how one of those tools is made.”