Engineering of the Conformational Dynamics of an Enzyme for Relieving the Product Inhibition

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Enzymes with a product inhibition are generally considered a limiting step of the metabolic pathway in producing valuable compounds. Most attempts to relieve the product inhibition have relied on mutations at the product binding site of enzymes. However, such an approach has resulted in a severe decrease in the catalytic activity, mainly owing to the shared binding site of product with substrate. Herein, we present the modulation of the conformational dynamics of chorismate-pyruvate lyase (CPL) for relieving the product inhibition without a decrease in the catalytic efficiency. CPL is a key enzyme in the biosynthesis of diverse aromatics but incurs a severe product inhibition owing to a strong product binding. On the basis of a structural analysis and molecular dynamics simulations, two key residues were identified for increasing the conformational dynamics of the flaps and thereby facilitating the product release. The designed mutants exhibited almost an 8-fold reduction in product inhibition and a 3-fold higher catalytic rate in comparison to the wild type. We demonstrate that mutation at two key residues leads to a significant increase in the conformational dynamics of the flaps, enhancing the product release through an opening of the flaps and thereby relieving the product inhibition.
Publisher
AMER CHEMICAL SOC
Issue Date
2016-12
Language
English
Article Type
Article
Keywords

CHORISMATE-PYRUVATE-LYASE; MOLECULAR-DYNAMICS; ESCHERICHIA-COLI; ALLOSTERIC REGULATION; FEEDBACK INHIBITION; CRYSTAL-STRUCTURE; LIGAND-BINDING; PROTEIN; TEMPERATURE; CATALYSIS

Citation

ACS CATALYSIS, v.6, no.12, pp.8440 - 8445

ISSN
2155-5435
DOI
10.1021/acscatal.6b02793
URI
http://hdl.handle.net/10203/216126
Appears in Collection
BS-Journal Papers(저널논문)
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