Discovery and characterization of a nickel enzyme family that catalyses intermolecular hydride shuttling

2026/06/17 by Zoë Semersky, Conor G. Raymond, John M. Rossi +3 · 1 voice
Biochemistry, Genetics and Molecular Biology · Energy · #Aldose Reductase and Taurine #Enzyme Catalysis and Immobilization #Metalloenzymes and iron-sulfur proteins

paper · pdf · doi:10.1038/s41557-026-02184-9

openalex publication_date 2026/06/17 · openalex created_date 2026/06/18 · openalex updated_date 2026/08/04

Abstract

Nickel-dependent enzymes catalyse incredible transformations. However, few have been discovered so far, limiting our understanding of the role of nickel in nature. Here we develop a bioinformatic pipeline to discover a family of nickel pincer mononucleotide (NPMN)-dependent enzymes with structures that are completely distinct from previously reported NPMN-dependent enzymes. We characterize one family member, NPMN-dependent hydride transferase (NphT), and find that it catalyses intermolecular hydride transfer, which we elucidate through its promiscuous disproportionation of sugars. We solve a 1.3-Å resolution crystal structure of NphT bound to NPMN and interrogate its mechanism through mutagenesis. We discover that NphT is one of many unexplored nickel enzymes within the large aldo-keto reductase superfamily, which catalyses reactions on a wide range of molecules, including secondary metabolites, sugars and drugs. This work reveals a unique enzymatic scaffold that can harness nickel, expands the known NPMN-catalysed transformations to intermolecular hydride transfer and establishes a pipeline for the discovery of distinct families of nickel-dependent enzymes.

Citations

• A Metabolic Bypass of the Triosephosphate Isomerase Reaction
• Ribonucleotide Reductases: Structure, Chemistry, and Metabolism Suggest New Therapeutic Targets
• Using nature’s blueprint to expand catalysis with Earth-abundant metals
• Fast and accurate protein structure search with Foldseek
• Accurate structure prediction of biomolecular interactions with AlphaFold 3
• Structure of the ATP-driven methyl-coenzyme M reductase activation complex
• UCSF Chimera—A visualization system for exploratory research and analysis

Discussions

• Discovering nickel enzymes within the aldo-keto reductase superfamily #chemistry #enzymes #nickel doi.org/10.1038/s415... [bsky, 1 points, 0 comments]

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