Structural Basis for the Catalysis and Substrate Specificity of a LarA Racemase with a Broad Substrate Spectrum

Gatreddi, Santhosh;Urdiain-Arraiza, Julian;Desguin, Benoît;Hausinger, Robert P.;Hu, Jian
(2025) ACS Catalysis — p. 2857-2866 (2025)

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Abstract
The LarA family consists of diverse racemases/epimerases that interconvert the diastereomers of α-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 various applications. However, how a LarA enzyme binds its natural substrate and recognizes different α-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 (LarAIp). The substrate binding mode reveals a near-optimal orientation and distance between the hydride donor and acceptor, consistent with an updated proton-coupled hydride transfer mechanism. The experimentally solved structures, together with the structural models of other LarA enzymes, lead to the identification of the residues/structural elements that are critically involved in the interactions with different α-hydroxyacids. Collectively, this work provides a structural basis for the catalysis and substrate specificity of the LarA enzymes.
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Gatreddi, S., Urdiain-Arraiza, J., Desguin, B., Hausinger, R. P., & Hu, J. (2025). Structural Basis for the Catalysis and Substrate Specificity of a LarA Racemase with a Broad Substrate Spectrum. ACS Catalysis, 2857-2866. https://doi.org/10.1021/acscatal.4c07804 (Original work published 2025)