Chemoenzymatic synthesis of fluorinated polyketides.
Journal
Nature chemistry
ISSN: 1755-4349
Titre abrégé: Nat Chem
Pays: England
ID NLM: 101499734
Informations de publication
Date de publication:
09 2022
09 2022
Historique:
received:
30
07
2021
accepted:
10
06
2022
pubmed:
26
7
2022
medline:
31
8
2022
entrez:
25
7
2022
Statut:
ppublish
Résumé
Modification of polyketides with fluorine offers a promising approach to develop new pharmaceuticals. While synthetic chemical methods for site-selective incorporation of fluorine in complex molecules have improved in recent years, approaches for the biosynthetic incorporation of fluorine in natural compounds are still rare. Here, we report a strategy to introduce fluorine into complex polyketides during biosynthesis. We exchanged the native acyltransferase domain of a polyketide synthase, which acts as the gatekeeper for the selection of extender units, with an evolutionarily related but substrate tolerant domain from metazoan type I fatty acid synthase. The resulting polyketide-synthase/fatty-acid-synthase hybrid can utilize fluoromalonyl coenzyme A and fluoromethylmalonyl coenzyme A for polyketide chain extension, introducing fluorine or fluoro-methyl units in polyketide scaffolds. We demonstrate the feasibility of our approach in the chemoenzymatic synthesis of fluorinated 12- and 14-membered macrolactones and fluorinated derivatives of the macrolide antibiotics YC-17 and methymycin.
Identifiants
pubmed: 35879443
doi: 10.1038/s41557-022-00996-z
pii: 10.1038/s41557-022-00996-z
pmc: PMC9832397
mid: NIHMS1857404
doi:
Substances chimiques
Polyketides
0
Fluorine
284SYP0193
Polyketide Synthases
79956-01-7
Acyltransferases
EC 2.3.-
Coenzyme A
SAA04E81UX
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1000-1006Subventions
Organisme : NIGMS NIH HHS
ID : R35 GM118101
Pays : United States
Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Nature Limited.
Références
J Am Chem Soc. 2019 Feb 6;141(5):1961-1969
pubmed: 30676722
Science. 2013 Sep 6;341(6150):1089-94
pubmed: 24009388
ACS Chem Biol. 2018 Mar 16;13(3):723-732
pubmed: 29328619
Nat Prod Rep. 2001 Aug;18(4):380-416
pubmed: 11548049
Bioorg Med Chem. 2016 Dec 15;24(24):6420-6428
pubmed: 27595539
Drug Des Devel Ther. 2017 Dec 13;11:3559-3566
pubmed: 29263651
Nucleic Acids Res. 2017 Sep 19;45(16):9573-9582
pubmed: 28934499
Proc Natl Acad Sci U S A. 2006 Jul 25;103(30):11124-9
pubmed: 16844787
Nat Chem Biol. 2015 Sep;11(9):660-70
pubmed: 26284673
Science. 2007 Sep 28;317(5846):1881-6
pubmed: 17901324
J Am Chem Soc. 2017 Sep 27;139(38):13450-13455
pubmed: 28836772
ACS Synth Biol. 2017 Jan 20;6(1):139-147
pubmed: 27548700
Nat Prod Rep. 2018 Oct 17;35(10):1070-1081
pubmed: 29938731
Biochemistry. 2014 Jun 17;53(23):3796-806
pubmed: 24871074
Nat Chem. 2016 Mar;8(3):276-80
pubmed: 26892561
J Med Chem. 2008 Aug 14;51(15):4359-69
pubmed: 18570365
Crit Rev Biotechnol. 2017 Nov;37(7):880-897
pubmed: 28049355
J Am Chem Soc. 2015 Mar 25;137(11):3735-8
pubmed: 25730816
Nature. 2014 Jun 26;510(7506):512-7
pubmed: 24965652
J Nat Prod. 2012 Mar 23;75(3):311-35
pubmed: 22316239
J Biotechnol. 2013 Oct 20;168(2):142-8
pubmed: 23770075
JACS Au. 2021 Oct 18;1(12):2162-2171
pubmed: 34977887
Nat Commun. 2021 Apr 13;12(1):2193
pubmed: 33850151
Angew Chem Int Ed Engl. 2006 Aug 4;45(31):5072-129
pubmed: 16881035
J Am Chem Soc. 2017 Jun 14;139(23):7913-7920
pubmed: 28525276
Angew Chem Int Ed Engl. 2009;48(26):4688-716
pubmed: 19514004
Science. 2008 Sep 5;321(5894):1315-22
pubmed: 18772430
Bioorg Med Chem Lett. 2007 Jun 1;17(11):3034-7
pubmed: 17428661
Angew Chem Int Ed Engl. 2017 Oct 23;56(44):13637-13640
pubmed: 28861937
Appl Environ Microbiol. 2008 Apr;74(7):1972-9
pubmed: 18245260
Angew Chem Int Ed Engl. 2015 Nov 2;54(45):13457-61
pubmed: 26383129
J Am Chem Soc. 2013 Jul 31;135(30):11232-8
pubmed: 23866020
Nature. 2006 Apr 20;440(7087):1078-82
pubmed: 16495946
Molecules. 2019 Feb 23;24(4):
pubmed: 30813407
Drugs. 2016 Dec;76(18):1737-1757
pubmed: 27909995
ACS Chem Biol. 2016 Sep 16;11(9):2642-54
pubmed: 27420774
J Biol Chem. 2008 Jan 4;283(1):518-528
pubmed: 17971456
Angew Chem Int Ed Engl. 2015 Feb 16;54(8):2370-3
pubmed: 25564997
Angew Chem Int Ed Engl. 2020 Aug 3;59(32):13575-13580
pubmed: 32357274