Control of Unsaturation in De Novo Fatty Acid Biosynthesis by FabA.
Biochemistry
; 61(7): 608-615, 2022 04 05.
Article
in En
| MEDLINE
| ID: mdl-35255690
ABSTRACT
Carrier protein-dependent biosynthesis provides a thiotemplated format for the production of natural products. Within these pathways, many reactions display exquisite substrate selectivity, a regulatory framework proposed to be controlled by protein-protein interactions (PPIs). In Escherichia coli, unsaturated fatty acids are generated within the de novo fatty acid synthase by a chain length-specific interaction between the acyl carrier protein AcpP and the isomerizing dehydratase FabA. To evaluate PPI-based control of reactivity, interactions of FabA with AcpP bearing multiple sequestered substrates were analyzed through NMR titration and guided high-resolution docking. Through a combination of quantitative binding constants, residue-specific perturbation analysis, and high-resolution docking, a model for substrate control via PPIs has been developed. The in silico results illuminate the mechanism of FabA substrate selectivity and provide a structural rationale with atomic detail. Helix III positioning in AcpP communicates sequestered chain length identity recognized by FabA, demonstrating a powerful strategy to regulate activity by allosteric control. These studies broadly illuminate carrier protein-dependent pathways and offer an important consideration for future inhibitor design and pathway engineering.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Acyl Carrier Protein
/
Fatty Acid Synthase, Type II
/
Fatty Acids
/
Hydro-Lyases
Language:
En
Journal:
Biochemistry
Year:
2022
Document type:
Article
Affiliation country:
Estados Unidos