{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T18:56:33Z","timestamp":1791226593452,"version":"4.1.0"},"reference-count":66,"publisher":"Wiley","issue":"41","license":[{"start":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T00:00:00Z","timestamp":1785974400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T00:00:00Z","timestamp":1785974400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Angew Chem Int Ed"],"published-print":{"date-parts":[[2026,10,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Fabry disease (FD), one of the most prevalent lysosomal storage disorders in Europe, is caused by mutations in the\n                    <jats:italic>GLA<\/jats:italic>\n                    gene leading to deficient \u03b1\u2010galactosidase A activity with lysosomal accumulation of globotriaosylceramide (Gb3). Enzyme replacement therapy (ERT) and pharmacological chaperone therapy (PCT) are used in the clinic to treat FD but are limited in efficacy, underscoring the need for alternative therapeutic strategies. Inhibiting \u03b1\u20101,4\u2010galactosyltransferase (A4GALT), the glycosyltransferase responsible for Gb3 biosynthesis, represents an attractive strategy. Here, we reveal the molecular mechanism of human A4GALT at atomic detail using QM\/MM simulations. We reveal a conformational rearrangement involving a 3\n                    <jats:sub>10<\/jats:sub>\n                    \u2010helix that stabilizes the donor substrate and promotes a front\u2010face S\n                    <jats:sub>N<\/jats:sub>\n                    i\u2010like catalytic mechanism, in which a short\u2010lived oxocarbenium\u2010ion intermediate forms. The simulations informed the synthesis of a panel of glycosylceramide substrate analogues. Among these, AdaGalCer (Ada = adamantyl) proved able to reduce Gb3 production in fibroblasts while simultaneously being converted by A4GALT into the galactosylated product AdaGb2. These results provide a clear path towards inhibiting A4GALT, paving the way for potential new and effective FD therapeutics.\n                  <\/jats:p>","DOI":"10.1002\/anie.9633257","type":"journal-article","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T11:39:04Z","timestamp":1786016344000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Unraveling A4GALT Mechanism and Its Modulation With Adamantyl\u2010Galactosylceramide Analogues: Advancing Fabry Disease Therapeutic Strategies"],"prefix":"10.1002","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9291-5026","authenticated-orcid":false,"given":"Nicky","family":"de Koster","sequence":"first","affiliation":[{"name":"Department of Medical Biochemistry and Department of Bio\u2010organic Synthesis Leiden Institute of Chemistry (LIC) Leiden University  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7841-141X","authenticated-orcid":false,"given":"\u00d2scar","family":"Vidal\u2010Giron\u00e8s","sequence":"additional","affiliation":[{"name":"Departament De Qu\u00edmica Inorg\u00e0nica i Org\u00e0nica (Secci\u00f3 de Qu\u00edmica Org\u00e0nica) and Institut de Qu\u00edmica Te\u00f2rica i Computacional (IQTCUB) Universitat de Barcelona Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rowan","family":"de Graaf","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry and Department of Bio\u2010organic Synthesis Leiden Institute of Chemistry (LIC) Leiden University  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken","family":"Kok","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry and Department of Bio\u2010organic Synthesis Leiden Institute of Chemistry (LIC) Leiden University  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsey T.","family":"Lelieveld","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry and Department of Bio\u2010organic Synthesis Leiden Institute of Chemistry (LIC) Leiden University  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jackelien","family":"Hoogervorst","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry and Department of Bio\u2010organic Synthesis Leiden Institute of Chemistry (LIC) Leiden University  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5765-9645","authenticated-orcid":false,"given":"Maria J.","family":"Ferraz","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry and Department of Bio\u2010organic Synthesis Leiden Institute of Chemistry (LIC) Leiden University  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1349-3049","authenticated-orcid":false,"given":"Jos\u00e9 Pablo","family":"Rivas\u2010Fern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Departament De Qu\u00edmica Inorg\u00e0nica i Org\u00e0nica (Secci\u00f3 de Qu\u00edmica Org\u00e0nica) and Institut de Qu\u00edmica Te\u00f2rica i Computacional (IQTCUB) Universitat de Barcelona Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7237-2303","authenticated-orcid":false,"given":"Rob F.","family":"Lammers","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry and Department of Bio\u2010organic Synthesis Leiden Institute of Chemistry (LIC) Leiden University  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6976-7005","authenticated-orcid":false,"given":"Herman S.","family":"Overkleeft","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry and Department of Bio\u2010organic Synthesis Leiden Institute of Chemistry (LIC) Leiden University  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8168-2565","authenticated-orcid":false,"given":"Johannes M. 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