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Structural Biology

X-rays show full-length P450 enzyme for first time

Structural details could help engineer new biocatalysts

by Laura Howes
May 29, 2020 | APPEARED IN VOLUME 98, ISSUE 21

 

09821-scicon5-figure1.jpg
Credit: Rey-Ting Guo and Chun-Chi Chen
The overall structure of CYP116B46 showing the heme domain (blue), reductase domain (green), and ferredoxin domain (silver). The bound ligands are shown as stick models with iron ions in red and sulfur ions in yellow.

The first-ever structure of a full-length P450 enzyme has been solved. Cells use these enzymes to synthesize hormones and metabolize drugs. Chemists would like to engineer them to carry out reactions such as toxin degradation and the tricky oxidations needed to produce some pharmaceuticals—but this has been difficult to do without the full crystal structure.

“It is an outstanding achievement to get the full-length enzyme,” says Sabine L. Flitsch, a professor of chemistry biology at the University of Manchester who wasn’t involved in the work. Many groups, including her own, have tried to solve these structures because of their potential usefulness as biocatalysts.

The structure of the P450 enzyme called CYP116B46, which is made by a thermophilic bacterium, was solved by a team at Hubei University led by Rey-Ting Guo and Chun-Chi Chen (Nat. Commun. 2020, DOI: 10.1038/s41467-020-16500-5). Chen says that until now, researchers like herself and Guo were only able to refer to partial structures, which limited their ability to engineer the enzyme. “Now we have the chance to engineer the reductase domain and the electron transfer path,” she says.

P450 enzymes have been difficult to map because they are challenging to crystallize. CYP116B46 is relatively stable, and Chen and Guo were able to put it through the X-ray crystallography process. The protein is made from a heme domain and a reductase domain containing flavin mononucleotide (FMN); the two sections are linked by a ferredoxin domain that contains an iron-sulfur cluster.

Guo and Chen say the structure shows that in this enzyme, the FMN is close enough to the iron-sulfur cluster to enable direct electron transfer, but the heme is too far from the cluster to allow for it. Instead, they suggest that the electron is shuttled along by different polar residues in the protein. Flitsch says this might help explain the low activity of the bacterial enzyme.

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