Designer enzymes for protein engineering

Designer enzymes for protein engineering

December 11, 2014
in Category: health
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Designer enzymes for protein engineering
Enzymes are efficient catalysts with high specificity and selectivity that are biodegradable and non-toxic and have enormous potential in sustainable industrial-scale production of many drugs. Limitations are the lack of stable natural enzymes and issues with scalability and cost.
The EU-funded ‘Enzyme design of medical interest‘ (MEDENZYMEDESIGN) project worked on designing three enzymes for application in biotechnology, biomedicine and industrial processes. Researchers used a previously developed inside-out methodology combining computational protein design with directed evolution (DE) to design novel enzymes.
Novel quantum mechanical/molecular mechanical (QM/MM)-molecular dynamics (MD) and density-functional theory strategies were applied to optimise enzyme designs through simulations.Researchers developed a transaminase enzyme to produce the type 2 anti-diabetes drug called sitagliptin using the inside-out protocol. However, there were several problems with the computational designs and the protocol proved unsuccessful.

Following this, researchers worked on designing new enzyme variants to produce a cholesterol-lowering active ingredient called lovastatin acid. These enzymes produced through DE were computationally evaluated using the Anton supercomputer and MD simulations. Analysis revealed that enzymes produced by DE were more effective than computationally designed ones due to a better pre-organisation of the enzyme’s polar environment.

MEDENZYMEDESIGN scientists worked on redesigning natural NADP-dependent enzymes to produce glucose-6-phosphate dehydrogenase activity and to reduce drug-induced oxidative stress for G6PD deficient patients. MD simulations were performed to understand differences in catalytic activity and reaction kinetics of enzymes and their variants.

Project activities have laid the foundation for future research endeavours to improve computational protocols for biocatalyst design. This should facilitate the commercial application of biocatalysts for sustainable industrial-scale production of important chemicals. Targets include diabetes, Alzheimer’s, Parkinson’s and Huntington’s diseases.

Provided by Cordis

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