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Publication Abstract from PubMed

The LarA family consists of diverse racemases/epimerases that interconvert the diastereomers of a variety of alpha-hydroxyacids by using a nickel-pincer nucleotide (NPN) cofactor. The hidden redox reaction catalyzed by the NPN cofactor makes LarA enzymes attractive engineering targets for applications. However, how a LarA enzyme binds its natural substrate and recognizes different alpha-hydroxyacids has not been elucidated. Here, we report three high-resolution structures of the enzyme-substrate complexes of a broad-spectrum LarA enzyme from Isosphaera pallida (LarA (Ip) ). The substrate binding mode reveals an optimal orientation and distance between the hydride donor and acceptor, strongly supporting the proposed proton-coupled hydride transfer mechanism. The experimentally solved structures, together with the structural models of other LarA enzymes, allow us to identify the residues/structural elements critically involved in the interactions with different alpha-hydroxyacid substrates. Collectively, this work provides a critical structural basis for catalysis and substrate recognition of the diverse enzymes in the LarA family, thus building a foundation for enzyme engineering.

Structural Basis for Catalysis and Substrate Specificity of a LarA Racemase with a Broad Substrate Spectrum.,Gatreddi S, Urdiain-Arraiza J, Desguin B, Hausinger RP, Hu J bioRxiv [Preprint]. 2024 Nov 28:2024.11.28.625916. doi: , 10.1101/2024.11.28.625916. PMID:39651260^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.