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Effective modification of enzyme function by computational science

Effective alteration of enzyme function through computational science

Principle of MSPER: A noble method to increase the production rate of a target compound in enzyme reactions using computer-aided enzyme modification. Credit: Advanced Industrial Science and Technology

In bioproduction, enzyme reactions are used to produce compounds that serve as materials, such as drugs, foods, fibers and plastics. It is performed with aqueous solvents under normal temperature and pressure conditions, as compared to conventional chemical reactions with petroleum-derived organic solvents under high temperature and pressure conditions. For this reason, bioproduction is attracting attention as a next-generation technology that can reduce utility costs and environmental impacts, such as waste liquid treatment. Further improvement of enzyme function is important for the industrial use of enzymes.

Enzymes form specific complex structures for the enzymatic reaction with their substrate. Depending on the types of enzymes and the substrate, different complexes can be formed causing multiple product formations, and the formation of by-products reduces the production rate of the target compound. To address this problem, it is necessary to find and modify the amino acid sites involved in enzyme function among the hundreds to thousands of amino acids that make up the enzyme. The evolutionary molecular engineering method and various rational design methods have been devised as methods to achieve this. The evolutionary molecular engineering method repeatedly produces and performs verification tests of various modified enzymes, so enormous time, labor and costs are required to obtain the optimal modified enzyme. In contrast, rational design can save the labor for verification tests by predicting the amino sites that alter enzyme functions based on information such as the three-dimensional structures of enzymes and substrates. However, methods specialized in suppressing by-products had yet to be developed.

Researchers in AIST, in collaboration with KNC Laboratories Co., Ltd., have developed a computational method for predicting the amino acid sites that control enzyme reactions (Mutation Site Prediction method for Enhancing the Regioselectivity of substrate reaction sites, MSPER) the enzyme cytochrome P450 (P450) that is used in the production of perfume raw materials. The production rate of the target compound was increased up to 6.4 times as compared to the unmodified enzyme.

MSPER was developed that suppresses the production of byproducts by predicting and altering amino acid sites involved in the production of byproducts based on the structural information obtained from simulation analysis to reproduce multiple enzyme-substrate complexes generated in enzyme reactions. This method makes it possible to reduce the enzyme regions to be modified, resulting in labor savings by reducing the number of functional verification evaluation tests to 1/170 to 1/1000 that of conventional random mutation methods.


Directed evolution of a designer enzyme with an unnatural catalytic amino acid


More information:
Jinzen Ikebe et al, Enzyme modification using mutation site prediction method for improving the regioselectivity of substrate reaction sites, Scientific Reports (2021). DOI: 10.1038/s41598-021-98433-7

Provided by advanced industrial science and technology


Quote: Effective Modification of Enzyme Function by Computational Science (2022, Aug 3), retrieved Aug 3, 2022 from https://phys.org/news/2022-08- Effective-modification-enzyme-function-science.html

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