Novel enzymes for the synthesis of chiral drugs Bacterial enzymes provide rapid and selective reaction catalysts for the synthesis of chiral drugs. A joint effort from European researchers detected and validated new biocatalytic enzymes. Climate Change and Environment © Thinkstock A chiral drug consists of a mixture of two compounds of the same chemical structure but different stereo-symmetry, that is they are mirror images of each other - enantiomers. This leads to significant differences in their biological activity. The chiral separation of enantiomers is difficult, therefore specific enzymes are used as biocatalysts for the synthesis of the bioactive isomer. Chiral drugs and the selective technology of biocatalytic synthesis of chiral intermediates represent a field of emerging interest. In the quest for novel pathways in chiral synthesis new enzymes are being searched for. The currently available genomic data is a unique recourse of enzymes for biocatalysis. However a fast, rational and effective way to extract the best candidates is not yet available. The EU-funded ‘Post-genomic data mining of enzymes for the synthesis of chiral pharmaceutical intermediates’ (Datagenom) project focused on the discovery of novel enzymes for the synthesis of chiral drugs. Specifically, the available eubacteria genome databases were examined for three classes of enzymes, namely alcohol dehydrogenases, cytochrome P450 monooxygenases and amino acid modifying enzymes. DATAGENOM researchers covered a wide variety of expertise, such as bioinformatic genome analysis, cloning, expression, enzyme production, screening and protein engineering, and production of chiral biomolecules. Initially, an innovative data mining of putative enzymes from the previously mentioned classes in the available eubacteria genomes, provided a list of the best candidates. Subsequently, these candidates were further tested and optimised by improved ‘wet chemistry’ protocols. Several enzymes with biocatalytic activities were detected and tested resulting in improved procedures and the development of new ones. In particular, a new biosynthesis of (S)-Dapoxetine (for treatment of premature ejaculation in men) was developed with a good yield. Established oxidase biotransformations were optimised, leading to the production of new synthetic amino acids. In addition, the productivity and the effectiveness of many procedures were significantly increased, while their robustness, in many cases, led to their full commercial manufacturing. DATAGENOM has provided a faster, effective and robust approach to detect, validate, apply and optimise bacterial enzymes for the synthesis of chiral drugs and bioactive compounds.
