SCHEDULED MAINTENANCE
Enzymatic hydrolysis of l-azetidine-2-carboxylate ring opening†
*b
Abstract
The L-proline analogue, L-azetidine-2-carboxylate (L-AZC), is of considerable interest both from biological and medicinal chemistry perspectives. It can be quickly involved in proteins and cause protein misfolding, disrupting the normal function of the protein. L-AZC can be biodegraded as the only carbon and nitrogen source by bacteria, and the hydrolysis on the ring opening of L-AZC has an effective practical detoxification function. We identified an L-AZC hydrolase from Novosphingobium sp. MBES04 (NsA2CH), which belongs to the haloacid dehalogenase-like superfamily and participates in cyclic amino acid metabolism. This enzyme has high substrate and stereospecificity for the hydrolysis of L-AZC. We determined the high-resolution crystal structures of NsA2CH in the form of apo- and covalent complexes with the reaction intermediate. Detailed biochemical, structural, and computational studies provide the molecular mechanism of the substrate and stereoselectivity of NsA2CH. Further bioinformatics analysis revealed 328 NsA2CH homologues (sequence identity more than 60%) widely distributed in bacteria. Our work provides the first structural insight into A2CH covalently complexed with the reaction intermediate. The results will enable the engineering of L-AZC to the building block of aminoglycoside antibiotics.
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