Figure 1: Enzyme complex showing nocardicin G (dark blue) positioned next to the 3-ACP group (green) in the enzyme active site. Reprinted with permission from Ref 1. Copyright 2026 American Chemical Society
Key details in the enzyme-driven biosynthesis of a natural molecule with potent antibiotic activity have been revealed by chemists at RIKEN1. This discovery has the potential to enable a swathe of new antibiotics to be developed, which are urgently needed to counter the increasing emergence of drug-resistant bacterial superbugs.
Dubbed 'nocardicin A', the powerful natural antibiotic is produced by a soil-dwelling bacterium which biosynthesizes it in an unusual way.
Its anti-microbial activity seems to depend on a side chain in the molecule that consists of an amino group attached to a carboxy-containing propyl functional group (3-ACP).
The origin of the side chain is a ubiquitous biomolecule known as S-adenosyl-L-methionine (SAM). SAM donates the side chain in an enzyme-mediated reaction with nocardicin G, a precursor to nocardicin A.
But SAM is much better known as a donor of methyl groups. The mechanism by which the enzyme transfers 3-ACP rather than a methyl group to make nocardicin A had been unclear, says Takayoshi Awakawa of the RIKEN Center for Sustainable Resource Science.
While the enzyme structure could be obtained by computational analysis, explaining how it transfers 3-ACP from SAM to nocardicin G required X-ray structural analysis-something that no-one had been able to do until now.
Awakawa's team was able to capture the first X-ray structure of the enzyme complex at the point when 3-ACP was poised to transfer to nocardicin G.
"Our analysis has revealed how nocardicin G is anchored to the enzyme via a network of amino acid residues and water molecules," Awakawa says.
Notably, the enzyme aligns with nocardicin G so that its reactive site is closer to SAM's 3-ACP group than to its methyl group, which favors 3-ACP transfer (Fig. 1).
This structural and mechanistic insight could facilitate the discovery of new antibiotics. By modifying the enzyme's structure to accept other substrates beside nocardicin G, researchers should be able to produce a range of potential medicines with the 3-ACP group attached.
"We showed that, when commercially available antibiotics such as amoxicillin and cefadroxil were used as substrates, 3-ACP-modified products were detected," Awakawa says.
The team is also exploring converting enzymes that promote SAM methyl transfer into enzymes that promote 3-ACP transfer instead.
"Methylating enzymes are very common," Awakawa says. "By altering their activity to become 3-ACP transferase enzymes, we can modify compounds with diverse structures to create new antibiotics and other useful compounds with superior biological activity."
Takayoshi Awakawa and his coworkers have uncovered the structural basis for 3-amino-3-carboxypropyl (3-ACP) transfer in the biosynthesis of nocardicin. © 2026 RIKEN
