The rational construction of new enzymes: design and synthesis of a dehydrogenase which accepts an unnatural substrate.
Advances in organic chemistry now make it possible for computer-controlled instruments to synthesize new and unnatural genes. When these genes are inserted into bacterial plasmids they can code for the over-production of new, synthetic enzyme proteins. One use for these new enzymes is as catalysts for the production of only a single one of the possible optical isomers of unnatural chemicals--a technology required for the synthesis of purer and safer drugs. The article describes attempts to use this new technology to design a new enzyme which recognizes a -CH2 -COO- side chain instead of the -CH3 side chain recognized by the naturally evolved enzyme. One of the new designs is shown to enable the construction of a new enzyme which is at least as catalytically active as the natural enzyme, and in which the substrate specificity has been shifted 10(7)-fold in favour of the new target molecule. Thus, given a firm understanding of the structural properties of a natural enzyme, which determine its efficiency as a catalyst, it can be manipulated to accept a new substrate and it is reasonably hopeful that useful products will be cheaply available from the redesign of natural proteins.
Clarke
A R
AR
Holbrook
J J
JJ
D001698:Biomedical Engineering; D010088:Oxidoreductases / Q000138:chemical synthesis*; D013379:Substrate Specificity
D010088:Oxidoreductases