Catalytic innovation underlies independent recruitment of polyketide synthases in cocaine and hyoscyamine biosynthesis.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
25 08 2022
25 08 2022
Historique:
received:
22
12
2021
accepted:
16
08
2022
entrez:
25
8
2022
pubmed:
26
8
2022
medline:
30
8
2022
Statut:
epublish
Résumé
Tropane alkaloids such as hyoscyamine and cocaine are of importance in medicinal uses. Only recently has the hyoscyamine biosynthetic machinery become complete. However, the cocaine biosynthesis pathway remains only partially elucidated. Here we characterize polyketide synthases required for generating 3-oxo-glutaric acid from malonyl-CoA in cocaine biosynthetic route. Structural analysis shows that these two polyketide synthases adopt distinctly different active site architecture to catalyze the same reaction as pyrrolidine ketide synthase in hyoscyamine biosynthesis, revealing an unusual parallel/convergent evolution of biochemical function in homologous enzymes. Further phylogenetic analysis suggests lineage-specific acquisition of polyketide synthases required for tropane alkaloid biosynthesis in Erythroxylaceae and Solanaceae species, respectively. Overall, our work elucidates not only a key unknown step in cocaine biosynthesis pathway but also, more importantly, structural and biochemical basis for independent recruitment of polyketide synthases in tropane alkaloid biosynthesis, thus broadening the understanding of conservation and innovation of biosynthetic catalysts.
Identifiants
pubmed: 36008484
doi: 10.1038/s41467-022-32776-1
pii: 10.1038/s41467-022-32776-1
pmc: PMC9411544
doi:
Substances chimiques
Tropanes
0
Polyketide Synthases
79956-01-7
Cocaine
I5Y540LHVR
Hyoscyamine
PX44XO846X
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4994Informations de copyright
© 2022. The Author(s).
Références
Methods Enzymol. 2012;515:317-35
pubmed: 22999180
Trends Biochem Sci. 2002 Aug;27(8):419-26
pubmed: 12151227
J Biol Chem. 2019 Oct 18;294(42):15193-15205
pubmed: 31481469
Alkaloids Chem Biol. 2019;81:151-233
pubmed: 30685050
Nat Commun. 2018 Dec 11;9(1):5281
pubmed: 30538251
Chem Biol. 2007 Apr;14(4):359-69
pubmed: 17462571
Nature. 2012 May 30;485(7400):635-41
pubmed: 22660326
Proc Natl Acad Sci U S A. 1993 Oct 15;90(20):9591-5
pubmed: 8415746
Nat Prod Rep. 2001 Oct;18(5):494-502
pubmed: 11699882
Nat Struct Biol. 1999 Aug;6(8):775-84
pubmed: 10426957
J Agric Food Chem. 2019 Jan 30;67(4):1284-1291
pubmed: 30636415
Nat Prod Rep. 2021 Sep 23;38(9):1634-1658
pubmed: 33533391
EXCLI J. 2013 Sep 23;12:831-57
pubmed: 26648810
J Am Chem Soc. 2005 Feb 9;127(5):1362-3
pubmed: 15686354
Acta Crystallogr D Biol Crystallogr. 1997 May 1;53(Pt 3):240-55
pubmed: 15299926
Methods Enzymol. 1997;276:307-26
pubmed: 27754618
Nature. 2020 Sep;585(7826):614-619
pubmed: 32879484
Proc Natl Acad Sci U S A. 2012 Jun 26;109(26):10304-9
pubmed: 22665766
Proc Natl Acad Sci U S A. 2017 Jun 6;114(23):6133-6138
pubmed: 28536194
Hortic Res. 2020 May 2;7(1):75
pubmed: 32377365
Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2126-32
pubmed: 15572765
New Phytol. 2014 Mar;201(4):1141-9
pubmed: 23889087
Acta Crystallogr D Biol Crystallogr. 2002 Nov;58(Pt 11):1948-54
pubmed: 12393927
Proc Natl Acad Sci U S A. 2021 Jun 15;118(24):
pubmed: 34112718
New Phytol. 2020 Mar;225(5):1906-1914
pubmed: 31705812
Org Lett. 2020 Nov 6;22(21):8725-8729
pubmed: 33104367
Plant Physiol. 2015 Jan;167(1):89-101
pubmed: 25406120
J Nat Med. 2020 Sep;74(4):639-646
pubmed: 32500363
J Am Chem Soc. 2005 Sep 14;127(36):12709-16
pubmed: 16144421
Nat Prod Rep. 2010 Jun;27(6):809-38
pubmed: 20358127
Nat Commun. 2019 Sep 6;10(1):4036
pubmed: 31492848