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Pharmaceuticals

Kicking Enzymatic Aspartame Process Into Higher Gear

Enzyme-substrate structures reveal mechanism of key aspartame production reaction

by Stu Borman
April 21, 2014 | APPEARED IN VOLUME 92, ISSUE 16

The mechanism of an industrially important but sluggish protease-catalyzed reaction has been determined in a study that also suggests how it could be improved (ACS Med. Chem. Lett. 2014, DOI: 10.1021/ml500101z). The research also points the way toward improving other industrially promising protease reactions, which often have poor substrate-binding affinities and excessive reaction times. About 10% of the artificial sweetener aspartame produced worldwide each year is made with the protease thermolysin, which catalyzes a reaction in which an aspartate and a phenylalanine ester are combined to form a chiral aspartame precursor. Crystal structures of the reaction’s substrate-enzyme complexes have now been obtained by Gabriel Birrane of Beth Israel Deaconess Medical Center, in Boston; Balaji Bhyravbhatla of Xtal BioStructures, in Natick, Mass.; and Manuel A. Navia, now at Oxford Bioscience Partners, in Boston. The structures reveal that the aspartate binds preferentially at the phenylalanine ester binding site. This inhibits the reaction because the aspartate has to move to its own binding site before the reaction can proceed. The work could guide the selection of alternative substrates or enzyme modifications that might increase reaction efficiency.

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