{
  "abstract": "Biological reducing power is carried by nicotinamide adenine dinucleotide (phosphate) (NAD(P)/H), which supports cellular functions and cannot be specifically directed to engineered metabolic pathways. Nicotinamide mononucleotide (NMN(H)) has emerged as an orthogonal redox cofactor to address this. Herein, to create NMN(H)-specific enzymes that no longer interact with cellular NAD(P)/H pools, we perturb the ancient, conserved GxGxxG motif in Rossmann fold enzymes that enables persistent NAD(P)/H recognition. We build variants NRC-01 and NRC-02 on phosphite dehydrogenase (PTDH), which eliminate electron leaking to NAD(P)H-dependent side reactions while driving NMNH-dependent biotransformation with ~240-fold higher productivity than existing catalysts. Testing the design principle on 12 other vastly diverse enzymes yields additional NMN(H)-orthogonal enzymes catalyzing valuable biomanufacturing reactions, and reveals a potential rule predicting the translatability of this method. Rosetta modeling, structural alignment, and experimental results reveal that Rossmann fold reprogramming, paired with engineered structural reinforcement, may offer a general route to orthogonal redox biocatalysts.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Chemical and Biomolecular Engineering, University of California, Irvine, Irvine, CA, USA.",
    "Genome Center, University of California, Davis, Davis, CA, USA.",
    "Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA.",
    "Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA, USA.",
    "Department of Chemistry, University of California, Davis, Davis, CA, USA.",
    "Department of Biochemistry and Molecular Medicine, University of California, Davis, Davis, CA, USA.",
    "Department of Chemical and Biomolecular Engineering, University of California, Irvine, Irvine, CA, USA. han.li@uci.edu.",
    "Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA. han.li@uci.edu.",
    "Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA, USA. han.li@uci.edu.",
    "UCI Center for Synthetic Biology (CSB), University of California, Irvine, Irvine, CA, USA. han.li@uci.edu."
  ],
  "article_type": "research support, non u.s. gov't",
  "arxiv": null,
  "author_total": 15,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Yu Ping"
    },
    {
      "affs": [
        0
      ],
      "name": "Jin Young Kim"
    },
    {
      "affs": [
        0
      ],
      "name": "Minh-Anh L Dinh",
      "orcid": "0009-0003-3914-2882"
    },
    {
      "affs": [
        1
      ],
      "name": "Emma Luu",
      "orcid": "0000-0002-0388-9330"
    },
    {
      "affs": [
        0
      ],
      "name": "Suphanida Worakaensai"
    },
    {
      "affs": [
        0
      ],
      "name": "Shiding Zhang",
      "orcid": "0009-0003-3497-820X"
    },
    {
      "affs": [
        0
      ],
      "name": "William B Black",
      "orcid": "0009-0007-2851-9997"
    },
    {
      "affs": [
        2
      ],
      "name": "Emma Monge"
    },
    {
      "affs": [
        0
      ],
      "name": "Hans Jefferson C Ng"
    },
    {
      "affs": [
        0
      ],
      "name": "Sean Perea"
    },
    {
      "affs": [
        0
      ],
      "name": "Yulai Zhang"
    },
    {
      "affs": [
        1
      ],
      "name": "Youtian Cui"
    },
    {
      "affs": [
        3
      ],
      "name": "Edward King"
    },
    {
      "affs": [
        1,
        4,
        5
      ],
      "name": "Justin B Siegel"
    },
    {
      "affs": [
        6,
        7,
        8,
        9
      ],
      "name": "Han Li",
      "orcid": "0000-0002-6113-6433"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/1dcr2kpyqfddx.bib",
  "cited_by": 0,
  "doi": "10.1038/s41467-026-77633-7",
  "fulltext_url": "https://europepmc.org/articles/PMC13661529",
  "id": "1dcr2kpyqfddx",
  "issns": [
    "2041-1723"
  ],
  "landing_url": "https://europepmc.org/article/MED/42869905",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|Enzyme Catalysis and Immobilization"
    ]
  ],
  "openalex": "W7212354265",
  "pdf_url": "https://europepmc.org/articles/PMC13661529?pdf=render",
  "pmcid": "PMC13661529",
  "pmid": "42869905",
  "published": "2026-09-12",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/1dcr2kpyqfddx.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:18Z",
      "native_id": "MED:42869905",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42869905"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Enzyme Catalysis and Immobilization",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Reprogramming the Rossmann fold signature motif creates orthogonal redox biocatalysts.",
  "title_text": "Reprogramming the Rossmann fold signature motif creates orthogonal redox biocatalysts.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:19:18Z",
  "url": "https://research.draconitic.com/paper/1dcr2kpyqfddx",
  "venue": "Nature communications",
  "versions": []
}