‘Designer Enzymes’: A Major Breakthrough in Chemistry

by Hannah Punitha on  March 22, 2008 at 5:26 PM Research News
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‘Designer Enzymes’: A Major Breakthrough in Chemistry
Chemists at the University of California - Los Angeles (UCLA) have reported the successful development of 'designer enzymes,' a major breakthrough in computational chemistry and protein engineering.

The UCLA chemistry team, led by professor Kendall Houk and a Washington group headed by biochemist David Baker, reports that it combined chemistry, mathematics and physics to effectively create designer enzymes for a chemical reaction known as the Kemp elimination, a non-natural chemical transformation in which hydrogen is pulled off a carbon atom.

Houk said that the enzymes could prove useful for defence against biological warfare, by deactivating pathogenic biological agents, and for developing more efficient medications.

'The design of new enzymes for reactions not normally catalyzed in nature is finally feasible. The goal of our research is to use computational methods to design the arrangement of groups inside a protein to cause any desired reaction to occur,' Nature quoted Houk, as saying.

Research co-author Jason DeChancie, an advanced UCLA chemistry graduate student working with Houk's group, said: 'Enzymes are such potent catalysts; we want to harness that catalytic ability. We want to design enzymes for reactions that naturally occurring enzymes don't do. There are limits on the reactions that natural enzymes carry out, compared with what we can dream up that enzymes can potentially do.'

In a previous paper, published in the journal Science on March 7, the chemists reported another successful chemical reaction that uses designer enzymes to catalyze a retro-aldol reaction, which involves breaking a carbon-carbon bond. The aldol reaction is a key process in living organisms associated with the processing and synthesis of carbohydrates.

This reaction is also widely used in the large-scale production of commodity chemicals and in the pharmaceutical industry, Houk said.

'Previous reports of designed enzymes have not been very successful, and some have been withdrawn. That is hardly surprising, considering the challenge of designing in days or weeks what nature has perfected over billions of years of evolution. The rate enhancements by our designer enzymes are modest and hardly competitive, so far, with those observed for their natural counterparts,' Houk said.

The implementation of the aldol reaction in the active site of an enzyme has been an important challenge. The reaction involves at least six chemical transformations, requiring UCLA scientists to compute all six chemical steps with their corresponding transition states. The structures were then combined in such a way to allow all six steps to occur.

Houk's team of 30 computational chemists used quantum mechanical calculations to discover chemical reactions with supercomputers.

Using algorithms and supercomputers, the UCLA chemists designed the active site for the enzymes, the area of the enzymes in which the chemical reactions take place, and give a blueprint for the active site to their University of Washington colleagues.

Baker and his group then used their computer programs to design a sequence of amino acids that fold to produce an active site like the one designed by Houk's group. Baker's group then produced the enzymes.

Enzymes are the ultimate 'green' catalysts by performing under ambient conditions in water, Houk said.

The study is published in the journal Nature.

Source: ANI

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