To be used industrially, an enzyme usually needs to undergo some surgery, for instance to resculpt its active site into a shape that will accept a range of chemical substrates. But the alterations that allow an enzyme to be more promiscuous can cripple its chemical activity. Researchers have now given the active site of an Escherichia coli aldolase a minimal makeover that enables it to handle a wider range of substrates without a loss in performance (ACS Catal. 2016, DOI: 10.1021/acscatal.5b02805). Aldolases catalyze a condensation reaction between two carbonyl compounds to form a β-hydroxy carbonyl product. Wolf-Dieter Fessner of the Technical University of Darmstadt, Pere Clapés of the Institute of Advanced Chemistry of Catalonia, and colleagues first identified key amino acid residues that could be altered to enlarge the enzyme’s binding pocket. They then used engineered E. coli to produce a range of mutant enzymes and tested them with various carbonyl substrates. The most successful mutant had two alanines in place of two leucines, which expanded the pocket to fit substrates containing up to seven carbon atoms, compared with only three for the original enzyme. Reactions pairing 3-hydroxypropanal with various hydroxyketones gave products with yields up to 89% with high stereoselectivity.