20.500.12556/RUL-168117 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. biosynthesis carbohydrates chemical structure metabolism peptides proteins sekundarni metaboliti biosinteza FK506 true false true Angleški jezik Slovenski jezik Članek v reviji 2025-03-28 14:55:18 2025-03-28 14:55:20 2025-03-29 04:14:37 0000-00-00 00:00:00 2025 0 0 Str. 619-630 iss. 3 Vol. 88 2025 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 604.4:615.332 0163-3864 10.1021/acs.jnatprod.4c00394 228597507 goranovic-et-al-2025-efficient-and-selective-biosynthesis-of-a-precursor-directed-fk506-analogue-paving-the-way-for.pdf goranovic-et-al-2025-efficient-and-selective-biosynthesis-of-a-precursor-directed-fk506-analogue-paving-the-way-for.pdf 1 E8065F025BA3418B16D391A6929A10FD eb6b089f3c01b28924a4a2194bb10a01f6be6ecefb96d9e6c16cefbee5b9da63 94dbb666-0bdb-11f0-b232-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=201149 https://pubs.acs.org/doi/10.1021/acs.jnatprod.4c00394 0 8dab037f-0bdb-11f0-b232-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=201148 Biotehniška fakulteta Fakulteta za kemijo in kemijsko tehnologijo 0 0 0