{
  "abstract": "Posttranslational lysine acetylation and methylation are generally considered mutually exclusive modifications of the ε-amino group. The recent discovery of N-acetyl-N-methyl lysine (KAcMe) on histone H4 showed that both marks can coexist on the same lysine side chain, raising the question of whether this dual modification is enzymatically reversible. Here, we synthesized model peptides containing N-acyl lysine or N-acyl-N-methyl lysine residues and tested their processing by Zn2+-dependent HDACs and NAD+-dependent sirtuins. While the corresponding unmethylated substrates were deacylated by the expected enzymes, KAcMe-containing peptides were not detectably deacetylated by either enzyme family. N-methylation also blocked HDAC8/11-mediated demyristoylation and SIRT5-mediated desuccinylation, whereas SIRT2 and SIRT6 retained weak demyristoylase activity toward N-myristoyl-N-methyl lysine. X-ray crystal structures of sirtuin-peptide complexes, supported by inhibition studies and molecular docking, reveal that N-methylation disrupts productive substrate positioning and misaligns the scissile amide bond for catalysis. These findings suggest that KAcMe is resistant to canonical lysine deacetylases and may represent a persistent chromatin-associated modification.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Str. 3, Halle/Saale06120, Germany.",
    "Department of Enzymology, Charles Tanford Protein Center, Institute of Biochemistry and Biotechnology, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Str. 3a, Halle/Saale06120, Germany.",
    "Institute of Pharmaceutical Sciences, University of Freiburg, Albertstr. 25, Freiburg79104, Germany.",
    "Department of Biochemistry, University of Bayreuth, Universitaetsstr. 30, Bayreuth95447, Germany.",
    "Institute of Biochemistry, University of Freiburg, Albertstr. 21, Freiburg79104, Germany.",
    "Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV, Prumyslova 595, Vestec252 50, Czech Republic."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 13,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Sebastian Hilscher",
      "orcid": "0009-0003-0611-7365"
    },
    {
      "affs": [
        1
      ],
      "name": "Paul Horst Böttcher"
    },
    {
      "affs": [
        2
      ],
      "name": "Florian Friedrich",
      "orcid": "0000-0001-5420-6184"
    },
    {
      "affs": [
        3
      ],
      "name": "Martin Pannek"
    },
    {
      "affs": [
        0
      ],
      "name": "Fady Baselious"
    },
    {
      "affs": [
        1
      ],
      "name": "Marat Meleshin"
    },
    {
      "affs": [
        4
      ],
      "name": "Oliver Einsle"
    },
    {
      "affs": [
        5
      ],
      "name": "Cyril Barinka",
      "orcid": "0000-0003-2751-3060"
    },
    {
      "affs": [
        3
      ],
      "name": "Clemens Steegborn",
      "orcid": "0000-0002-0913-1467"
    },
    {
      "affs": [
        0
      ],
      "name": "Wolfgang Sippl",
      "orcid": "0000-0002-5985-9261"
    },
    {
      "affs": [
        2
      ],
      "name": "Manfred Jung",
      "orcid": "0000-0002-6361-7716"
    },
    {
      "affs": [
        1
      ],
      "name": "Mike Schutkowski",
      "orcid": "0000-0003-0919-7076"
    },
    {
      "affs": [
        1
      ],
      "name": "Cordelia Schiene-Fischer",
      "orcid": "0009-0006-5807-9315"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/92hf6272d2cbg.bib",
  "cited_by": 0,
  "doi": "10.1021/acs.biochem.6c00508",
  "fulltext_url": "https://europepmc.org/articles/PMC13648224",
  "id": "92hf6272d2cbg",
  "issns": [
    "0006-2960",
    "1520-4995"
  ],
  "landing_url": "https://europepmc.org/article/MED/42917127",
  "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|Histone Deacetylase Inhibitors Research"
    ]
  ],
  "openalex": "W7211972992",
  "pdf_url": "https://europepmc.org/articles/PMC13648224?pdf=render",
  "pmcid": "PMC13648224",
  "pmid": "42917127",
  "published": "2026-10-01",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/92hf6272d2cbg.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:20:36Z",
      "native_id": "MED:42917127",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42917127"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Histone Deacetylase Inhibitors Research",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Structural and Enzymatic Basis for Impaired Deacylation of N-Acyl-N-Methyl Lysine Residues.",
  "title_text": "Structural and Enzymatic Basis for Impaired Deacylation of N-Acyl-N-Methyl Lysine Residues.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:20:36Z",
  "url": "https://research.draconitic.com/paper/92hf6272d2cbg",
  "venue": "Biochemistry",
  "versions": []
}