Carb2zyme: Unprecedented chemistry for carbon-carbon bond formation by an emerging class of metallo-enzymes – Carb2zyme

Carbon-carbon bond formation plays an important role in the chemical industry. However, only few methodologies are available for C–C bond formation at unreactive carbon atoms. These methods often require noble metals and stringent experimental conditions which are not compatible with green chemistry and sustainable development. It is hence of a major interest to develop novel methodologies allowing the selective formation of C-C bond. In a fascinating manner, methylation of unactivated C-H bonds in living organisms appears to be exclusively dependent on an emerging superfamily of metallo-enzymes, the so called “radical SAM enzymes”. These enzymes appear to use unprecedented mechanisms in order to catalyze the formation of C-C bonds.

Radical SAM enzymes are arguably the most diverse and versatile radical bio-catalysts, encompassing more than 300,000 members and catalyzing more than 70 different types of biochemical transformations. This includes virtually all types of chemical reactions, some of which not accessible by synthetic chemistry, as recently shown by the coordinator of the Carb2zyme project. In addition to catalyzing unique transformations, these enzymes are of tremendous biological importance. Indeed, they play a pivotal role for the biosynthesis of a myriad of natural products including major antibiotics (Carbapenem, thiopeptides, gentamycin etc.), anti-cancer agents and toxins. However, we still have a very limited knowledge of their mechanisms notably, we do not understand how these enzymes catalyze the formation of C-C bonds at unreactive carbon atoms.

The Carb2zyme project aims (I) to decipher the complex and unprecedented mechanism of novel radical SAM enzymes and (ii) to develop innovative catalysts for the synthesis of carbon-carbon bonds, a keystone for synthetic chemistry. We will focus on radical SAM enzymes that are dependent of vitamin B12 (cobalamin) (B12-dependent radical SAM enzymes) catalyzing methyl transfer at unreactive carbon atoms. Currently, very few B12-dependent radical SAM enzymes have been investigated and groundbreaking publications from partners of this project (Pierre et al. 2012 Nature Chem Biol; Benjdia et al. 2015 Nature Commun; Parent et al. JACS 2016) have shown they are able to catalyze C-C bond formation on a variety of sp2- and sp3-hybridized carbon atoms through ill-defined mechanisms.

The Carb2zyme consortium consists of four internationally renowned partners with complementary expertise in the fields of biochemistry, bioinorganic chemistry, synthetic chemistry and structural biology. By combining multidisciplinary approaches and cutting-edge technologies, we will make major advances in our knowledge of these unique and unprecedented enzymes at the mechanistic and structural levels. Not only the Carb2zyme project will have a major impact on biochemistry and structural biology but it will also lay the foundations of novel bio-inspired catalysts by developing novel artificial metallo-enzymes. The Carb2zyme project will have an outstanding scientific and societal impact from catalysis to the biosynthesis of natural products.