Objectif Enzymes are now established as highly selective biocatalysts in organic synthesis with the range of catalysts and reactions rapidly increasing through access to large protein databases and high-throughput molecular biology tools for biocatalyst engineering. The diversity of biocatalytic reactions is now at a stage where they can be linked in (chemo)-enzymatic reaction cascades, where two or more chemical and/or enzymatic reactions can be catalysed simultaneously generating de novo biosynthetic pathways for chemical synthesis not found in Nature. These reaction cascades have demonstrated important prior art, however they have been mostly limited to few steps and lack the complexity provided by the natural pharmacopeia. ProgrES aims to achieve a step-change by introducing unprecedented structural complexity into de novo pathways and by moving away from manual to automated, high-throughput cascade design and implementation. The proposal is to use a transdisciplinary approach that addresses three important bottlenecks: i. Identification of enzymatic reactions that allow early functionalisation and late stage diversification of the cascade toolkit to increase structural complexity, building on C-H activation mediated by monooxygenases, which are well established in our research group. ii. As diversity of targets increases, high resolution structural analysis of pathway intermediates and products becomes a bottleneck, which is addressed by high-throughput label free mass spectrometry based analytical tools that will match the demands on timescale and numbers. iii. In parallel, we will establish bioinformatics tools adapted from both chemical synthesis and biosynthesis, to allow programmable enzymatic synthesis for cascade design. As proof-of-concept and test bed for the ProgrES platform we aim to generate a library of diverse synthetic imino sugars. This proposal will lead to a major breakthrough in creating a diverse range of scaffolds of therapeutic interest. Champ scientifique natural sciencescomputer and information sciencesdatabasesnatural scienceschemical sciencescatalysisbiocatalysisnatural scienceschemical sciencesanalytical chemistrymass spectrometrynatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymesnatural sciencesbiological sciencesmolecular biology Mots‑clés Biocatalysts organic synthesis reaction cascades de novo biosynthetic pathways analytical tools programmable enzymatic synthesis imino sugars Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Thème(s) ERC-2017-ADG - ERC Advanced Grant Appel à propositions ERC-2017-ADG Voir d’autres projets de cet appel Régime de financement ERC-ADG - Advanced Grant Institution d’accueil THE UNIVERSITY OF MANCHESTER Contribution nette de l'UE € 2 399 830,00 Adresse OXFORD ROAD M13 9PL Manchester Royaume-Uni Voir sur la carte Région North West (England) Greater Manchester Manchester Type d’activité Higher or Secondary Education Establishments Liens Contacter l’organisation Opens in new window Site web Opens in new window Participation aux programmes de R&I de l'UE Opens in new window Réseau de collaboration HORIZON Opens in new window Coût total € 2 399 831,00 Bénéficiaires (1) Trier par ordre alphabétique Trier par contribution nette de l'UE Tout développer Tout réduire THE UNIVERSITY OF MANCHESTER Royaume-Uni Contribution nette de l'UE € 2 399 830,00 Adresse OXFORD ROAD M13 9PL Manchester Voir sur la carte Région North West (England) Greater Manchester Manchester Type d’activité Higher or Secondary Education Establishments Liens Contacter l’organisation Opens in new window Site web Opens in new window Participation aux programmes de R&I de l'UE Opens in new window Réseau de collaboration HORIZON Opens in new window Coût total € 2 399 831,00
