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Isopenicillin N synthase (IPNS) catalyzes a key step in the biosynthesis of the important beta-lactam antibiotics penicillins and cephalosporins. Density-functional calculations with the B3LYP functional are used to propose a detailed mechanism for this reaction. The results support the general scheme outlined from experimental observations, with formation of a four-membered beta-lactam ring followed by formation of a five-membered thiazolidine ring. However, an alternative mechanism for the heterolytic O-O bond cleavage and beta-lactam ring formation steps is proposed. The former part involves protonation of the distal oxygen by an iron-bound water ligand. This mechanism highlights the strong similarities that exist between IPNS and other enzymes of the 2-histidine-1-carboxylate family, especially pterin-dependent amino acid hydroxylases and alpha-keto acid-dependent dioxygenases. Both activation of the cysteine beta-C-H bond by an iron-bound superoxo radical and activation of the valine beta-C-H bond by a ferryl-oxo species show reaction barriers close to the experimentally measured one. These results are in agreement with kinetic isotope experiments that suggest both C-H bond activation steps to be partially rate limiting. The ring formation sequence is determined by the relative strengths of the two C-H bonds. Only the ferryl-oxo intermediate is capable of activating the stronger valine beta-C-H bond.

biochemistry

The Mechanism for Isopenicillin N Synthase from Density-Functional Modeling Highlights the Similarities with Other Enzymes in the 2-His-1-carboxylate Family