Efficient and selective biosynthesis of a precursor-directed FK506 analogue : paving the way for click chemistry

Goranovič, Dušan (avtor), Jenko, Branko (avtor), Ramšak, Barbara (avtor), Podgoršek Berke, Ajda (avtor), Bedrač, Leon (avtor), Horvat, Jaka (avtor), Šala, Martin (avtor), Makuc, Damjan (avtor), Carriche, Guilhermina M. (avtor), Silva, Luana (avtor), Lopez Krol, Aleksandra (avtor), Pšeničnik, Alen (avtor), Durán Alonso, María Beatriz (avtor), Avbelj, Martina (avtor), Stavber, Stojan (avtor), Plavec, Janez (avtor), Sparwasser, Tim (avtor), Müller, Rolf (avtor), Kosec, Gregor (avtor), Fujs, Štefan (avtor), Petković, Hrvoje (avtor)

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.

• Jezik: Angleški jezik
• Ključne besede: biosynthesis, carbohydrates, chemical structure, metabolism, peptides, proteins
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: BF - Biotehniška fakulteta ; FKKT - Fakulteta za kemijo in kemijsko tehnologijo
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2025
• Št. strani: Str. 619-630
• Številčenje: Vol. 88, iss. 3
• PID: 20.500.12556/RUL-168117
• UDK: 604.4:615.332
• ISSN pri članku: 0163-3864
• DOI: 10.1021/acs.jnatprod.4c00394
• COBISS.SI-ID: 228597507
• Datum objave v RUL: 28.03.2025

Gradivo je del revije

• Naslov: Journal of natural products
• Skrajšan naslov: J. nat. prod.
• Založnik: American Chemical Society, American Society of Pharmacognosy
• ISSN: 0163-3864
• COBISS.SI-ID: 1069327

Licence

• Licenca: CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by/4.0/deed.sl
• Opis: To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: sekundarni metaboliti, biosinteza, FK506