A new enzyme may help the development of anti-cancer drugs

Many of the drugs we use to treat cancer and infectious diseases are—or are derived from—natural substances, but it’s hard to know how nature collects them.

In a further study of the environment, Rice University chemist Xue Gao and his team mapped all the processes that marine fungi use to produce 21R-citrinadin A, a complex molecule with anticancer properties.

Meanwhile, Gao and colleagues discovered a new enzyme, CtdY, which is the only one of its kind known to break the amide bond, according to new research published in Journal of the American Chemical Society.

“CtdY belongs to a large family of enzymes known as cytochrome P450s that perform a variety of functions and are being studied for industrial and pharmaceutical applications,” Gao said. “However, none of the P450s identified so far can break the amide bond.

“Amide bonds are found in all proteins—they’re what link amino acids together. They’re the most important, most stable type of bond.”

The enzyme’s ability to cleave amide bonds may make it a useful tool for the development of new drugs.

“The fact that CtdY can do this is amazing,” said Qiuyue Nie, a postdoctoral researcher in Gao’s lab who is one of the study’s lead authors. “It holds great promise for the pharmaceutical industry,” he said.

This enzyme is known not only because it can break the most stable bonds, but also because it does so because of the complex structure of cells.

“You want to keep the whole system and just want to break a single, hard-to-break contract ⎯ this is a real and difficult task,” Gao said.

When CtdY breaks the amide bond-which has a 3D circular shape-a group of seven other enzymes intervene to complete the assembly of the 21R-citrinadin A molecule.

“When they open the ring, all the other enzymes can do oxidation and put oxygen-hydrogen groups in a very precise way,” Gao said. “It’s like CtdY brings home a Christmas tree, and then these other enzymes get together to decorate it.”

Gao’s lab has been working for years to uncover all the mechanisms involved in the production of 21R-citrinadin A, which has been shown to be effective against leukemia in rats and throat cancer cells, according to Shuai Liu, a Rice postdoctoral fellow. the researcher who is the co-director of the study.

The newly identified enzyme is one of several discovered by Gao’s lab that can perform one useful function such as controlling chirality and facilitating the Diels-Alder reaction.

“This is a complete story,” Gao said. “We used gene knockout, heterologous expression, mutagenesis studies, enzymology and so on to solve almost every step in the biosynthesis of this compound. More than 20 enzymes are assembled and coordinated to make a molecule. I find it interesting that enzymes work together in this. process of making a molecule this is very difficult.