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Penicillin’s building enzyme briefly releases a bond to iron

X-ray snapshots caught fleeting structures in the enzyme that builds penicillin’s rings. Sulfur temporarily detached from iron before the bond returned as a ring formed. The peer-reviewed experiments also traced the role of water molecules around the reaction centre, giving a more detailed account of chemistry that was difficult to reconstruct from the finished molecule.

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A tiny clear crystal on a metal sample holder between laboratory instrument components, with a fine nozzle directed toward it.

A fleeting bond change appears during ring formation

Researchers captured transient structures in the enzyme that builds penicillin’s core. The peer-reviewed structural study followed a reaction whose intermediate stages had previously escaped direct observation.[1], [2]

Isopenicillin N synthase, the enzyme that assembles the antibiotic’s two rings, uses iron and oxygen to transform a three-amino-acid starting molecule. In an early intermediate, sulfur detached from the iron centre. The bond returned with formation of a single beta-lactam ring. Earlier descriptions had expected sulfur to remain attached throughout this stage.[1]

Short X-ray pulses follow a reaction in microcrystals

The team exposed oxygen-free enzyme microcrystals to oxygen and examined selected reaction times with a free-electron laser. Crystallography located atoms; spectroscopy probed iron’s electronic state. A deuterium-labelled starting molecule slowed one step enough to help capture a ring-containing intermediate. Some measurements contained mixtures of structures rather than one isolated intermediate.[1]

Changing the water network changes the reaction product

Mutation experiments examined a hydrogen-bond network containing three active-site water molecules. One variant formed a hydrated aldehyde in solution instead of the usual two-ring product; another stalled the reaction early. Crystal and solution results sometimes differed, since crystal packing constrains movement. The proposed water-mediated pathway also rests on spectroscopy and calculations for fleeting steps that were not directly imaged.[1]

References

  1. News sourceNature CatalysisX-ray snapshots capture unexpected steps in penicillin formation↩1↩2↩3↩4
  2. News sourceSLAC National Accelerator LaboratoryX-ray snapshots capture fleeting steps in penicillin formation↩
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