An Atypical Acyl-CoA Synthetase Enables Efficient Biosynthesis of Extender Units for Engineering a Polyketide Carbon Scaffold.
Angew Chem Int Ed Engl
; 61(43): e202208734, 2022 10 24.
Article
in En
| MEDLINE
| ID: mdl-36074522
Acyl-CoAs are key precursors of primary and secondary metabolism. Their efficient biosynthesis is often impeded by the limited substrate specificity and low in vivo activity of acyl-CoA synthetases (ACSs) due to regulatory acylation of the catalytically important lysine residue in motif A10 (Lys-A10). In this study, we identified an unusual ACS (UkaQ) from the UK-2A biosynthetic pathway that naturally lacks the Lys-A10 residue and exhibits extraordinarily broad substrate specificity. Protein engineering significantly improved its stability and catalytic activity, enabling it to synthesize a large variety of acyl-CoAs with highly robust activity. By combining it with permissive carboxylases, we produced a large array of polyketide extender units and obtained six novel halobenzyl-containing antimycin analogues through an engineered biosynthetic pathway. This study significantly expands the catalytic mode of ACSs and provides a potent tool for the biosynthesis of acyl-CoA-derived natural products.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Biological Products
/
Polyketides
Language:
En
Journal:
Angew Chem Int Ed Engl
Year:
2022
Document type:
Article
Affiliation country:
China
Country of publication:
Germany