Alchivemycin A synthesized with help from enzymes

Alchivemycin A, a molecule produced by Streptomyces bacteria, has interesting antimicrobial properties that scientists would love to study for cues on how to make better antibiotics. But every previous attempt to assemble it in the lab was stymied by the molecule’s structural complexity. The trickiest bits include a highly oxidized macrocyclic core and an unusual 2H-tetrahydro-4,6-dioxo-1,2-oxazine (TDO) ring.

Now, Xiaoguang Lei of Peking University and coworkers have overcome the challenge by looking to nature. The researchers used enzymes from the molecule’s biosynthetic pathway to carry out three selective late-stage oxidations needed to finish the synthesis (Nat. Synth. DOI: 10.1038/s44160-024-00577-7). The team has been trying to make the molecule for a decade, and it’s exciting to have finally done it, Lei says in an email.

The 25-step synthesis relies on traditional chemical methods such as Suzuki coupling and nucleophilic substitution to assemble the macrocyclic skeleton. Then it’s the enzymes’ turn to add the finishing touches. The two epoxide-installing enzymes, AvmO2 and AvmO3, gave excellent yields right away despite the unnatural substrate, which Lei says was a pleasant surprise. The enzyme responsible for the final step, inserting an oxygen into a lactam to turn it into the elusive TDO ring, needed a little bit of extra engineering for efficiency. Switching a tyrosine for an arginine did the trick, getting the yield of the final step up to 85%.

Integrating enzymes into organic synthesis is becoming increasingly popular, so Lei and coworkers’ use of biocatalysis isn’t inherently novel, says Han Renata, who researches chemoenzymatic synthesis at Rice University, in an email. But he says this study is a well-executed illustration of how enzymes can help chemists tackle daunting targets.