Reconstructing enzymes for novel nitrogen-nitrogen bond forming chemistry

Description du projet

Catalyse enzymatique personnalisée des liaisons azote-azote

Les activités biologiques de nombreux produits naturels et pharmaceutiques sont souvent basées sur les liaisons azote-azote (N-N). La formation des liaisons N-N étant difficile à réaliser par voie chimique conventionnelle, la voie de biosynthèse a suscité un grand intérêt et a conduit à l’identification de plusieurs enzymes capables de catalyser la formation de ces liaisons. Financé par le Conseil européen de la recherche, le projet ReCNNSTRCT entend développer une boîte à outils enzymatique pour la formation de liaisons N-N qui s’appuie sur des enzymes naturelles ou reconçues. Les chercheurs délimiteront également la structure de ces enzymes et leurs mécanismes catalytiques, ouvrant ainsi la voie à des réactions de liaison N-N polyvalentes pouvant être exploitées dans des applications cliniques et de recherche.

Objectif

Nitrogen-nitrogen (N-N) bonds have fascinating structural and functional properties, are ubiquitously found in diverse pharmaceuticals and fine chemicals, and represent important key structural motifs in diverse natural products, endowing them with potent biological activities. However, traditional chemical procedures to synthesize N-N bond-containing compounds are often difficult to realize, costly and environmentally unfriendly. In addition, the formation of intermolecular N-N linkages is particularly difficult and remains a mostly unaddressed problem in chemistry.
ReCNNSTRCT will address this challenge by decoding novel reaction chemistries from the underexploited family of N-N bond-forming enzymes (NNZYMES), while tackling reactions that are difficult to realize by traditional chemical approaches and currently not feasible by enzyme catalysis. As such, ReCNNSTRCT aims to break new ground in chemical synthesis: it will develop an enzymatic toolbox for versatile N-N bond-forming reaction chemistries by exploring naturally promiscuous and redesigned NNZYMES for diverse intra- and intermolecular, as well as non-natural N-N-bond formations. To achieve this, ReCNNSTRCT will combine methodologies from enzyme catalysis and evolution, genome mining and the latest achievements in bioinformatics. In this way, ReCNNSTRCT will not only establish the chemistry performed by the enzymes, it will also elucidate enzyme structures, catalytic mechanisms, and design biocatalytic cascades to showcase the potential of tailored NNZYMES.
ReCNNSTRCT will thus revolutionize our synthetic strategies and aims to substantially contribute to a ‘greener’ chemical industry by creating versatile catalytic platforms for N-N bond formation, leading to streamlined routes to high-value chemicals. Beyond this groundbreaking direct impact in the field of enzyme catalysis, ReCNNSTRCT will boost the clinical and research environment by providing new biocatalysts for future drug discovery efforts