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

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

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.

• Language: English
• Keywords: biosynthesis, carbohydrates, chemical structure, metabolism, peptides, proteins
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: BF - Biotechnical Faculty; FKKT - Faculty of Chemistry and Chemical Technology
• Publication status: Published
• Publication version: Version of Record
• Year: 2025
• Number of pages: Str. 619-630
• Numbering: Vol. 88, iss. 3
• PID: 20.500.12556/RUL-168117
• UDC: 604.4:615.332
• ISSN on article: 0163-3864
• DOI: 10.1021/acs.jnatprod.4c00394
• COBISS.SI-ID: 228597507
• Publication date in RUL: 28.03.2025

Record is a part of a journal

• Title: Journal of natural products
• Shortened title: J. nat. prod.
• Publisher: American Chemical Society, American Society of Pharmacognosy
• ISSN: 0163-3864
• COBISS.SI-ID: 1069327

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: sekundarni metaboliti, biosinteza, FK506