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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.<\/jats:p>","DOI":"10.1021\/acs.jnatprod.4c00394","type":"journal-article","created":{"date-parts":[[2025,3,10]],"date-time":"2025-03-10T08:00:51Z","timestamp":1741593651000},"page":"619-630","source":"Crossref","is-referenced-by-count":1,"title":["Efficient and\nSelective Biosynthesis of a Precursor-Directed\nFK506 Analogue: Paving the Way for Click Chemistry"],"prefix":"10.1021","volume":"88","author":[{"given":"Dus\u030can","family":"Goranovic\u030c","sequence":"first","affiliation":[{"name":"Acies Bio, d.o.o. , ,","place":["Ljubljana, Slovenia, 1000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Branko","family":"Jenko","sequence":"additional","affiliation":[{"name":"Acies Bio, d.o.o. , ,","place":["Ljubljana, Slovenia, 1000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Rams\u030cak","sequence":"additional","affiliation":[{"name":"University of Ljubljana , , ,","place":["Ljubljana, Slovenia, 1000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ajda","family":"Podgors\u030cek Berke","sequence":"additional","affiliation":[{"name":"Acies Bio, d.o.o. , ,","place":["Ljubljana, Slovenia, 1000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leon","family":"Bedrac\u030c","sequence":"additional","affiliation":[{"name":"Acies Bio, d.o.o. , ,","place":["Ljubljana, Slovenia, 1000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaka","family":"Horvat","sequence":"additional","affiliation":[{"name":"Acies Bio, d.o.o. , ,","place":["Ljubljana, Slovenia, 1000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7845-860X","authenticated-orcid":true,"given":"Martin","family":"S\u030cala","sequence":"additional","affiliation":[{"name":"National Institute of Chemistry , ,","place":["Ljubljana, Slovenia, 1000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damjan","family":"Makuc","sequence":"additional","affiliation":[{"name":"National Institute of Chemistry , ,","place":["Ljubljana, Slovenia, 1000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guilhermina M.","family":"Carriche","sequence":"additional","affiliation":[{"name":"University Medical Center of the Johannes Gutenberg-University , , ,","place":["Mainz, Germany, 55131"]},{"name":"Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture Between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI) , ,","place":["Hannover, Germany, 30625"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7297-9586","authenticated-orcid":true,"given":"Luana","family":"Silva","sequence":"additional","affiliation":[{"name":"University Medical Center of the Johannes Gutenberg-University , , ,","place":["Mainz, Germany, 55131"]},{"name":"Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture Between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI) , ,","place":["Hannover, Germany, 30625"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandra","family":"Lopez Krol","sequence":"additional","affiliation":[{"name":"University Medical Center of the Johannes Gutenberg-University , , ,","place":["Mainz, Germany, 55131"]},{"name":"Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture Between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI) , ,","place":["Hannover, Germany, 30625"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alen","family":"Ps\u030cenic\u030cnik","sequence":"additional","affiliation":[{"name":"University of Ljubljana , , ,","place":["Ljubljana, Slovenia, 1000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mari\u0301a Beatriz","family":"Dura\u0301n Alonso","sequence":"additional","affiliation":[{"name":"University of Valladolid , , ,","place":["Valladolid, Spain, 47005"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Avbelj","sequence":"additional","affiliation":[{"name":"University of Ljubljana , , ,","place":["Ljubljana, Slovenia, 1000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stojan","family":"Stavber","sequence":"additional","affiliation":[{"name":"Joz\u030cef Stefan Institute , , 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Proteins (CIPKeBiP) , Jamova 39 , ,","place":["Ljubljana, Slovenia, SI-1000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1377-9845","authenticated-orcid":true,"given":"Hrvoje","family":"Petkovic\u0301","sequence":"additional","affiliation":[{"name":"University of Ljubljana , , ,","place":["Ljubljana, Slovenia, 1000"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2025,3,10]]},"reference":[{"key":"2026090715154375000_cit1","doi-asserted-by":"publisher","first-page":"875","DOI":"10.1146\/annurev.mi.47.100193.004303","article-title":"Polyketide synthesis:\nProspects for Hybrid Antibiotics","volume":"47","author":"Katz","year":"1993","journal-title":"Annu. 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Current Medicinal Chemistry\n- Anti-Inflammatory & Anti-Allergy Agents"},{"key":"2026090715154375000_cit6","doi-asserted-by":"publisher","first-page":"827","DOI":"10.2165\/00003495-200565060-00011","article-title":"Tacrolimus Ointment: A Review of Its Use in Atopic Dermatitis and\nIts Clinical Potential in Other Inflammatory Skin Conditions","volume":"65","author":"Simpson","year":"2005","journal-title":"Drugs"},{"key":"2026090715154375000_cit7","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1039\/B707678A","article-title":"Mutasynthesis,\nChemobiosynthesis, and Back to Semi-Synthesis: Combining Synthetic\nChemistry and Biosynthetic Engineering for Diversifying Natural Products","volume":"25","author":"Kennedy","year":"2008","journal-title":"Nat. Prod. Rep."},{"key":"2026090715154375000_cit8","doi-asserted-by":"publisher","first-page":"368","DOI":"10.1038\/sj.jim.7000206","article-title":"Genetic\nApproaches for Controlling Ratios of Related Polyketide Products in\nFermentation Processes","volume":"27","author":"Cropp","year":"2001","journal-title":"J. Ind. Microbiol. Biotechnol."},{"key":"2026090715154375000_cit9","doi-asserted-by":"publisher","first-page":"4757","DOI":"10.1002\/anie.200462784","article-title":"Mutasynthesis of\nRapamycin Analogues through the Manipulation of a Gene Governing Starter\nUnit Biosynthesis","volume":"44","author":"Gregory","year":"2005","journal-title":"Angew. Chem., Int. Ed. Engl."},{"key":"2026090715154375000_cit10","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1021\/acs.jnatprod.0c00767","article-title":"Biosynthesis\nof Nonimmunosuppressive\nProlylFK506 Analogues with Neurite Outgrowth and Synaptogenic Activity","volume":"84","author":"Jung","year":"2021","journal-title":"J. Nat. Prod."},{"key":"2026090715154375000_cit11","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1021\/sb3001062","article-title":"Designed Biosynthesis of 36-Methyl-FK506\nby Polyketide\nPrecursor Pathway Engineering","volume":"2","author":"Lechner","year":"2013","journal-title":"ACS Synth. Biol."},{"key":"2026090715154375000_cit12","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1007\/s00253-013-5362-3","article-title":"Trends in\nthe Biosynthesis and Production\nof the Immunosuppressant Tacrolimus (FK506)","volume":"98","author":"Barreiro","year":"2014","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"2026090715154375000_cit13","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1007\/s10295-003-0062-0","article-title":"Domain and Module\nSwaps in Modular Polyketide Synthases","volume":"30","author":"Del Vecchio","year":"2003","journal-title":"J. Ind.\nMicrobiol. Biotechnol."},{"key":"2026090715154375000_cit14","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1039\/C1NP00082A","article-title":"Beyond Ethylmalonyl-CoA: The Functional\nRole of Crotonyl-CoA\nCarboxylase\/Reductase Homologs in Expanding Polyketide Diversity","volume":"29","author":"Wilson","year":"2012","journal-title":"Nat. Prod. Rep."},{"key":"2026090715154375000_cit15","doi-asserted-by":"publisher","first-page":"976","DOI":"10.1021\/ja108399b","article-title":"Biosynthesis of the Allylmalonyl-CoA Extender Unit\nfor the FK506 Polyketide Synthase Proceeds through a Dedicated Polyketide\nSynthase and Facilitates the Mutasynthesis of Analogues","volume":"133","author":"Mo","year":"2011","journal-title":"J. Am. Chem. Soc."},{"key":"2026090715154375000_cit16","doi-asserted-by":"publisher","first-page":"14292","DOI":"10.1074\/jbc.M109.059600","article-title":"Origin of\nthe Allyl Group in FK506 Biosynthesis","volume":"285","author":"Goranovic\u030c","year":"2010","journal-title":"J. Biol.\nChem."},{"key":"2026090715154375000_cit17","doi-asserted-by":"publisher","first-page":"13609","DOI":"10.1038\/ncomms13609","article-title":"A Crotonyl-CoA\nReductase-Carboxylase\nIndependent Pathway for Assembly of Unusual Alkylmalonyl-CoA Polyketide\nSynthase Extender Units","volume":"7","author":"Ray","year":"2016","journal-title":"Nat. Commun."},{"key":"2026090715154375000_cit18","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.ymben.2011.11.003","article-title":"Novel Chemobiosynthetic\nApproach for Exclusive Production of FK506","volume":"14","author":"Kosec","year":"2012","journal-title":"Metab. Eng."},{"key":"2026090715154375000_cit19","doi-asserted-by":"publisher","first-page":"757","DOI":"10.1016\/S1074-5521(97)90314-8","article-title":"Molecular Recognition of Diketide Substrates by a \u03b2-Ketoacyl-Acyl\nCarrier Protein Synthase Domain within a Bimodular Polyketide Synthase","volume":"4","author":"Chuck","year":"1997","journal-title":"Chem. Biol."},{"key":"2026090715154375000_cit20","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1002\/bit.10086","article-title":"Precursor-Directed\nProduction of Erythromycin Analogs by Saccharopolyspora Erythraea","volume":"76","author":"Frykman","year":"2001","journal-title":"Biotechnol. Bioeng."},{"key":"2026090715154375000_cit21","doi-asserted-by":"publisher","first-page":"1455","DOI":"10.1021\/acs.bioconjchem.1c00247","article-title":"An Overview of Recent Advances in\nBiomedical Applications of Click Chemistry","volume":"32","author":"Kaur","year":"2021","journal-title":"Bioconjugate Chem."},{"key":"2026090715154375000_cit22","doi-asserted-by":"publisher","first-page":"4905","DOI":"10.1021\/cr200409f","article-title":"Click Chemistry\nfor Drug Development\nand Diverse Chemical\u2013Biology Applications","volume":"113","author":"Thirumurugan","year":"2013","journal-title":"Chem. Rev."},{"key":"2026090715154375000_cit23","doi-asserted-by":"publisher","first-page":"779","DOI":"10.1080\/17460441.2019.1614910","article-title":"Recent Applications\nof Click Chemistry in Drug Discovery","volume":"14","author":"Jiang","year":"2019","journal-title":"Expert\nOpin. Drug Discovery"},{"key":"2026090715154375000_cit24","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1016\/j.drudis.2015.08.004","article-title":"Discovery\nof Bioactive\nMolecules from CuAAC Click-Chemistry-Based Combinatorial Libraries","volume":"21","author":"Wang","year":"2016","journal-title":"Drug Discovery Today"},{"key":"2026090715154375000_cit25","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1002\/9780470559277.ch110148","article-title":"Copper-Catalyzed\nAzide\u2013Alkyne\nClick Chemistry for Bioconjugation","volume":"3","author":"Presolski","year":"2011","journal-title":"Curr. Protoc.\nChem. Biol."},{"key":"2026090715154375000_cit26","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1038\/ja.2016.137","article-title":"Nature Nurtures the Design of New\nSemi-Synthetic Macrolide Antibiotics","volume":"70","author":"Fernandes","year":"2017","journal-title":"J. Antibiot."},{"key":"2026090715154375000_cit27","unstructured":"Kosec, G.; Goranovic\u030c, D.; Horvat, J.; Fujs, S\u030c.; Jenko, B.; Petkovic\u0301, H.\n          Novel Polyketide\nCompounds\nand Methods of Making Same. EP2658855 A2, 2013."},{"key":"2026090715154375000_cit28","doi-asserted-by":"publisher","first-page":"2139","DOI":"10.1007\/s00253-012-4364-x","article-title":"Taxonomy and Chemically Semi-Defined\nMedia for the\nAnalysis of the Tacrolimus Producer \u201cStreptomyces Tsukubaensis","volume":"97","author":"Marti\u0301nez-Castro","year":"2013","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"2026090715154375000_cit29","doi-asserted-by":"publisher","first-page":"2527","DOI":"10.1111\/febs.13296","article-title":"An Acyltransferase\nDomain of FK506 Polyketide Synthase Recognizing Both an Acyl Carrier\nProtein and Coenzyme A as Acyl Donors to Transfer Allylmalonyl and\nEthylmalonyl Units","volume":"282","author":"Jiang","year":"2015","journal-title":"FEBS J."},{"key":"2026090715154375000_cit30","doi-asserted-by":"publisher","first-page":"2078","DOI":"10.1021\/acs.jnatprod.9b00144","article-title":"Biosynthesis of\nNonimmunosuppressive FK506 Analogues with Antifungal Activity","volume":"82","author":"Beom","year":"2019","journal-title":"J. Nat. Prod."},{"key":"2026090715154375000_cit31","volume-title":"Practical Streptomyces\nGenetics","author":"Kieser","year":"2000"},{"key":"2026090715154375000_cit32","volume-title":"IBM SPSS Statistics\nfor Windows [Internet]","author":"IBM Corp.","year":"2017"},{"key":"2026090715154375000_cit33","doi-asserted-by":"publisher","first-page":"107438","DOI":"10.1016\/j.phrs.2024.107438","article-title":"Revisiting the nature and pharmacodynamics of tacrolimus\nmetabolites","volume":"209","author":"Mevizou","year":"2024","journal-title":"Pharmacol. Res."}],"container-title":["Journal of Natural Products"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.jnatprod.4c00394","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jnprdf\/article-pdf\/88\/3\/619\/68432240\/acs.jnatprod.4c00394.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jnprdf\/article-pdf\/88\/3\/619\/68432240\/acs.jnatprod.4c00394.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T19:38:01Z","timestamp":1788809881000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jnprdf\/article\/88\/3\/619\/3756290\/Efficient-and-Selective-Biosynthesis-of-a"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,10]]},"references-count":33,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2025,3,10]]},"published-print":{"date-parts":[[2025,3,28]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.jnatprod.4c00394","relation":{},"ISSN":["0163-3864","1520-6025"],"issn-type":[{"value":"0163-3864","type":"print"},{"value":"1520-6025","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,10]]}}}