For nearly a century, since Alexander Fleming's accidental discovery of penicillin in 1928, fungi have been a goldmine for drugs. They have provided cures for a wide selection of ailments, from infections and high cholesterol to organ rejection and even cancer.
However, the method by which fungi synthesize a few of their most potent compounds stays elusive. This is very true of cyclopentachromone, a crucial constructing block in fungal products whose derivatives have shown promise for fighting cancer and reducing inflammation, amongst other medicinal properties.
Reading Nature's Instructions
Although chemists have made progress in making chromone derivatives within the laboratory, accurately and reliably duplicating the precise structure of the molecule has proven difficult. “It's very easy to wind up with versions where the chemical bonds are not in the right place, or the structure is flipped,” says Sherry Gao, Penn Compact Associate Professor of Chemical and Biomolecular Engineering (CBE) and Chair in Bioengineering. BE).
In a brand new paper, members of the Gao lab describe how they interpreted nature's instructions—that's, K genes, commonly found on citrus fruits—to find a previously unreported enzyme. which catalyzes the formation of cyclopentachromone-containing compounds. .
“Nature has had billions of years to develop pathways to make these compounds,” says Gao, senior creator of the paper. “We can now borrow nature's tools to develop and further study these compounds, potentially leading to the development of new pharmaceuticals.”
A molecular puzzle
Part of what makes cyclopentachromone unique is its specific structure, which incorporates three carbon rings, two with six carbons, and one with five carbons. Like the scaffolding used to erect a constructing, this series of rings provides the structural basis for a lot of bioactive molecules.
However, the known chemical precursor of cyclopentachromone has an additional carbon, forming three rings of the identical size. Exactly how nature transforms this chemical with different ring structures, when such rings are normally stable, has never been explained before.
Elucidating this process requires systematically turning genes on and off until the pathway is disrupted, clarifying which genes code for the enzyme to operate. “It was like checking hundreds of light switches to see which one turns on a particular bulb,” says Qiuyue Nie, a postdoctoral fellow in Gao's lab and first creator of the paper.
As the researchers discovered, a unique intermediate compound, 2S-remisporine A, produced by the newly identified enzyme, IscL, has a sulfur atom hanging off one side of a three-ring structure, much like that of Trk. Occurs on the back. .
From mold to medicine
This high degree of reactivity is the source of cyclopentachromone's medicinal versatility: just as a truck can tow many differing types of attachments, from wagons to boats, the carbon-sulfur bond in 2S-remisporine A may be utilized by a gaggle of other groups. Can be found with a wide selection. Creating a various array of molecules. “This intermediate compound is highly reactive,” Nee says. “The carbon-sulfur bond can react with different sulfur donors to produce many new compounds.”
The indisputable fact that 2S-remisporine A could be very reactive and can mix with various molecules, even itself, explains why this precursor has never been fully identified before. “We've never been able to figure out how to make such a reactive intermediate compound,” Nee says. “We had to learn how nature makes it, then take advantage of these enzymatic tools ourselves.”
The researchers hope that future work will give you the chance to follow this newly discovered pathway using a genetic map that guides them to further develop using fungal compounds in medicine. “Nature has an incredible toolbox,” says Gao. “This paper shows us how to build one of those tools.”