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Breaking bonds: a new enzyme to help drug discovery

‘Breaking bonds: a new enzyme to help drug discovery’ – Written by Charlotte Harrison, Science Writer.

Amide bonds are strong and difficult to break. They link amino acids together and are also found in the chemical precursors that are needed to make many therapeutic drugs. Cleaving them in the lab often requires harsh reaction conditions and is unselective. 

A new paper from researchers at Rice University has identified a new enzyme called CtdY, which is the only one of its kind known to break amide bonds. The enzyme’s ability to cleave amide bonds could make it a useful tool for creating new drugs. 

Complex assembly 

The enzyme CtdY is a P450 enzyme. It was discovered as part of the researchers’ efforts to map out the series of enzyme-catalysed reactions used by a marine fungus to produce 21R-citrinadin A. That molecule is large and complex, yet has promising anticancer properties.  

The researchers used gene knockout, heterologous expression, mutagenesis studies and enzymology to solve almost every step in the biosynthesis of 21R-citrinadin A – a process that involves over 20 enzymes. 

During their investigations of a critical step in the biosynthesis pathway, they discovered CtdY, and characterized it further. 

Difficult task 

The CtdY enzyme is notable not only because it can break a highly-stable bond, but also because it does so within a very complex molecular structure – a very specific and difficult task. 

“The fact that CtdY can do this [task] is quite remarkable,” said the authors in a press release. “It holds significant promise for the pharmaceutical industry,” they said. 

Once CtdY breaks the amide bond within the ring structure of the precursor molecule, a group of seven other enzymes step in to complete the assembly of the 21R-citrinadin A molecule. 

“Once [CtdY] opens the ring, all the other enzymes are able to perform oxidation and install oxygen-hydrogen groups in a highly precise way,” said the authors. “It’s like CtdY brings the Christmas tree home, and then these other enzymes come together to decorate it.” 

Overall, the discovery of CtdY could offer a cleaner, greener and more precise way to catalyse reactions commonly used in drug discovery.  

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