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Enzyme ping-pong provides pointers for new antibiotics

‘Enzyme ping-pong provides pointers for new antibiotics’ Written by Charlotte Harrison, Science Writer 

The specialized lipoproteins in bacteria are attractive targets for antibiotic drug discovery because of the lack of human counterparts. A new paper in Science Advances has produced high-resolution structural insights into a key bacterial lipoprotein enzyme, which will likely aid the rational design of new antibiotics.

Ping-pong reaction

The bacterial enzyme N-acyltransferase is a 57-kDa protein found in Gram-negative bacteria. The enzyme is the final one in the bacterial lipoprotein synthesis pathway, and is proposed to act by a ping-pong mechanism; that is, it catalyzes the acetylation of small molecules through a double displacement reaction.

In the current study, the researchers used X-ray crystallography and cryo-electron microscopy to determine the discrete structural states of the enzyme that occur as the N-acyltransferase reaction proceeded.

They obtained nine structures within the resolution range of 2.4–3.1 Å, which captured the enzyme in three states: the apo (substrate-free), Michaelis (substrate intermediate) and product complex states. The structures provided information on how N-acyltransferase engages with and transforms two substrates, and also produces and releases two products by a double-displacement mechanism.

Overall, the researchers showed that N-acyltransferase has a single active site that has evolved to sequentially bind substrates — in a way that meets structural and chemical criteria — so that the reactive parts are orientated next to the catalytic residues.

Antibiotic target

The authors note that the study validates the ping-pong mechanism and explains the molecular basis for the substrate promiscuity of N-acyltransferase. More importantly, though, they note that their findings should facilitate the structure-informed design of antibiotics with minimal off-target effects.

“New drugs are therefore badly needed and, while the journey can be a long one from providing a structural blueprint like this to developing a new drug, the precision to which we have resolved this potential target paints something of a ‘bullseye’ on that target,” said lead author Martin Caffrey in a press release.

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