{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T11:46:58Z","timestamp":1792583218667,"version":"4.5.0"},"reference-count":42,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T00:00:00Z","timestamp":1792540800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T00:00:00Z","timestamp":1792540800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100010665","name":"H2020 Marie Sk\u0142odowska-Curie Actions","doi-asserted-by":"publisher","award":["945478"],"award-info":[{"award-number":["945478"]}],"id":[{"id":"10.13039\/100010665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005357","name":"Agent\u00fara na Podporu V\u00fdskumu a V\u00fdvoja","doi-asserted-by":"publisher","award":["APVV\u201023\u20100178"],"award-info":[{"award-number":["APVV\u201023\u20100178"]}],"id":[{"id":"10.13039\/501100005357","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003193","name":"Ministerstvo \u0161kolstva, vedy, v\u00fdskumu a \u0161portu Slovenskej republiky","doi-asserted-by":"publisher","award":["VEGA 1\/0619\/24"],"award-info":[{"award-number":["VEGA 1\/0619\/24"]}],"id":[{"id":"10.13039\/501100003193","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FEBS Journal"],"abstract":"<jats:p>\n                    Cystathionine\u2010\u03b2\u2010synthase (CBS) is the key regulatory enzyme of the transsulfuration pathway and plays a crucial role in eliminating homocysteine. Homocysteine, a by\u2010product of methylation reactions, is a known risk factor for cardiovascular, neurodegenerative and metabolic disorders, all of which are among the leading causes of death worldwide. CBS represents a promising therapeutic target due to its allosterically inducible capacity to redirect homocysteine into sulfur metabolism, yielding the protective antioxidants cysteine, hydrogen sulfide and glutathione. Although the therapeutic benefit of CBS activation was established more than a decade ago, there are as yet no drug\u2010like small\u2010molecule allosteric activators of CBS. Therefore, we establish a framework for the development of CBS activators. Starting from\n                    <jats:italic>S<\/jats:italic>\n                    \u2010adenosyl\u2010\n                    <jats:sc>l<\/jats:sc>\n                    \u2010methionine (SAM), the endogenous allosteric activator of CBS as a template, we rationally designed 15 analogues and synthesized them using biocatalysis. We characterized their action on isolated recombinant human CBS and cell lysate and their metabolic breakdown in DNA methylation. Besides SAM, three analogues enhanced the catalytic activity of CBS and stabilized CBS during thermal denaturation, suggesting binding. Thermodynamic parameters were quantified using isothermal titration calorimetry (ITC). All active compounds participated in the methylation of lambda DNA. We confirmed\n                    <jats:italic>S<\/jats:italic>\n                    \u2010adenosyl\u2010\n                    <jats:sc>l<\/jats:sc>\n                    \u2010ethionine, an established CBS activator, and seleno\u2010adenosyl\u2010\n                    <jats:sc>l<\/jats:sc>\n                    \u2010methionine, recently reported by us. Additionally, we introduce a novel CBS activator,\n                    <jats:italic>S<\/jats:italic>\n                    \u20102\u2010amino\u2010adenosyl\u2010\n                    <jats:sc>l<\/jats:sc>\n                    \u2010methionine. Taken together, CBS allosteric activation required compounds that do not deviate far from the structure of SAM. Nevertheless, we discovered a new allosteric activator of CBS and propose that our work represents a structural framework for further development of small\u2010molecule activators of CBS.\n                  <\/jats:p>","DOI":"10.1111\/febs.70774","type":"journal-article","created":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T11:32:11Z","timestamp":1792582331000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Biocatalytic synthesis of\n                    <i>S<\/i>\n                    \u2010adenosyl\u2010\n                    <scp>l<\/scp>\n                    \u2010methionine analogues for allosteric activation of cystathionine\u2010\u03b2\u2010synthase"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0900-0130","authenticated-orcid":false,"given":"Dalibor","family":"Nakl\u00e1dal","sequence":"first","affiliation":[{"name":"Comenius University Science Park  Bratislava Slovakia"},{"name":"Department of Physical Chemistry of Drugs, Faculty of Pharmacy Comenius University Bratislava  Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u017daneta","family":"Zajacov\u00e1","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy Comenius University Bratislava  Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rick","family":"Oerlemans","sequence":"additional","affiliation":[{"name":"Department of Chemical and Pharmaceutical Biology University of Groningen  The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jana","family":"Havlikova","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Analysis and Nuclear Pharmacy, Faculty of Pharmacy Comenius University Bratislava  Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel","family":"Zork\u00f3cy","sequence":"additional","affiliation":[{"name":"Comenius University Science Park  Bratislava Slovakia"},{"name":"Department of Molecular Biology, Faculty of Natural Sciences Comenius University Bratislava  Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luk\u00e1\u0161","family":"Kerti","sequence":"additional","affiliation":[{"name":"Department of Physical Chemistry of Drugs, Faculty of Pharmacy Comenius University Bratislava  Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katar\u00edna","family":"Sujov\u00e1","sequence":"additional","affiliation":[{"name":"Department of Physical Chemistry of Drugs, Faculty of Pharmacy Comenius University Bratislava  Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian","family":"Lengyel","sequence":"additional","affiliation":[{"name":"Department of Chemical Theory of Drugs, Faculty of Pharmacy Comenius University Bratislava  Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zo\u00eb","family":"van der Gun","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy and Pharmacology University of Groningen, University Medical Center Groningen  The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Yoseif","sequence":"additional","affiliation":[{"name":"Sulfateq BV Groningen  The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrianus Cornelis","family":"van der Graaf","sequence":"additional","affiliation":[{"name":"Sulfateq BV Groningen  The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guido","family":"Krenning","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy and Pharmacology University of Groningen, University Medical Center Groningen  The Netherlands"},{"name":"Sulfateq BV Groningen  The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00e1n","family":"Kyselovi\u010d","sequence":"additional","affiliation":[{"name":"V. Department of Internal Medicine, Faculty of Medicine Comenius University Bratislava  Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladim\u00edr","family":"Frecer","sequence":"additional","affiliation":[{"name":"Department of Physical Chemistry of Drugs, Faculty of Pharmacy Comenius University Bratislava  Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9859-5177","authenticated-orcid":false,"given":"Matthew R.","family":"Groves","sequence":"additional","affiliation":[{"name":"Department of Chemical and Pharmaceutical Biology University of Groningen  The Netherlands"},{"name":"Genomics for Health in Africa (GHA) Africa\u2010Europe Cluster of Research Excellence (CoRE)  Groningen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zdenko","family":"Levarski","sequence":"additional","affiliation":[{"name":"Comenius University Science Park  Bratislava 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