Flavins as Covalent Catalysts: New Mechanisms Emerge

• Published in: Trends in biochemical sciences (Amsterdam. Regular ed.) 2017-06, Vol.42 (6), p.457-469
• Main Authors: Piano, Valentina, Palfey, Bruce A., Mattevi, Andrea
• Format: Article
• Language: English
• Subjects: Biocatalysis; Flavins - chemistry; Flavins - metabolism; Oxidation-Reduction; Oxidoreductases - chemistry; Oxidoreductases - metabolism
• ISSN: 0968-0004; 1362-4326
• DOI: 10.1016/j.tibs.2017.02.005

With approximately 1% of proteins being flavoproteins, flavins are at the heart of a plethora of redox reactions in all areas of biology. Thanks to a series of fascinating recent discoveries, in addition to redox chemistry, covalent catalysis is now being recognized more frequently as a common strategy in flavoenzymes, with unprecedented mechanisms becoming apparent. Thus, noncanonical covalent reactions by flavins are emerging as a new pervasive concept in basic enzymology and biochemistry. These diverse enzymes are engaged in most biological processes, positioning the knowledge being gained from these new mechanisms to be translated into drugs that function through covalent mechanisms. New and unexpected flavoenzyme reactions are being uncovered that involve unprecedented chemistries and mechanisms, extending biochemistry beyond their classic paradigm as redox factors. A common property of new flavoenzyme chemistry is the formation of covalent flavin–substrate complexes to form highly reactive intermediates. Specific flavin-modifying enzymes are found to generate flavin derivatives endowed with radically different and mostly unexplored functional properties. The insight gained from this new branch of ‘covalent flavoenzymology’ is being translated into drug candidates.