20.500.12556/DiRROS-21968 Efficient and selective biosynthesis of a precursor-directed FK506 analogue paving the way for click chemistry The medically important immunosuppressant FK506 is a structurally complex macrolactone biosynthesized by a combined polyketide synthase and a nonribosomal peptide synthetase enzyme complex. Its acyltransferase domain 4 (AT4) selects an unusual extender unit, resulting in an allyl moiety on carbon 21 of the macrolactone backbone. Based on the AT4 domain, chemobiosynthetic processes have been developed that enable the introduction of diverse moieties at the carbon 21 position. However, the novel moieties that were introduced into the polyketide backbone are chemically inert. Reported here is a novel and efficient chemobiosynthetic approach that ensures high titer of an FK506 analogue containing a propargyl moiety. The novel FK506 analogue displays lower immunosuppression activity than FK506 with significantly reduced cytotoxicity. More importantly, the propargyl moiety contains a terminal alkyl group, which makes click chemistry reactions possible; this approach may potentially be translated to other medically important drugs of polyketide origin. sekundarni metaboliti biosinteza FK506 true false true ACS Publications ZDA Angleški jezik Slovenski jezik © 2025 The Authors. Neznano 2025-04-15 11:52:29 2025-04-15 11:52:29 2025-10-24 03:50:16 0000-00-00 00:00:00 2025 0 0 Soavtorji: Branko Jenko, Barbara Ramšak, Ajda Podgoršek Berke, Leon Bedrač, Jaka Horvat, Martin Šala, Damjan Makuc, Guilhermina M. Carriche, Luana Silva, Aleksandra Lopez Krol, Alen Pšeničnik, María Beatriz Durán Alonso, Martina Avbelj, Stojan Stavber, Janez Plavec, Tim Sparwasser, Rolf Müller, Gregor Kosec, Štefan Fujs, Hrvoje Petković; str. 619-630 issue 3 Vol. 88 2025 0000-00-00 Zaloznikova Objavljeno NiDoloceno 2024-04-05 2025-02-05 2025-03-10 604.4:615.332 0163-3864 10.1021/acs.jnatprod.4c00394 228597507 RAZ_Goranovic_Dusan_2025.pdf RAZ_Goranovic_Dusan_2025.pdf 1 38677463FC15C2DE8D1F6500AF981EE8 87e06030815b6dee901cd61775e89e44e6287fd0656ac6123908499a9a064db1 0a2bb16d-19e1-11f0-963a-001a4af901a5 https://dirros.openscience.si/Dokument.php?lang=slv&id=31693 Institut Jožef Stefan Kemijski inštitut 0 0 0