Nicotinamide‐Dependent One‐Electron and Two‐Electron (Flavin) Oxidoreduction : Thermodynamics, Kinetics, and Mechanism

1. Biological nicotinamide-dependent oxidoreduction consists of reversible 2e- oxidoreduction of substrates. A mechanism involving subsequent 1e- steps is shown to be very unfavourable due to the high energy of the nicotinamide radical. 2. Free energy relationships provide a convenient tool, allowing one to differentiate between hydride transfer and hydrogen atom transfer. It is concluded that biological nicotinamide-dependent, as well as flavin-nicotinamide oxidoreduction, proceed via hydride transfer but not via hydrogen atom transfer. 3. In flavin-nicotinamide oxidoreduction, flavin-nicotinamide charge transfer complexes are very likely the catalytic intermediates, preceding transfer of hydride ion. The energy of the long-wavelength charge transfer transition of zwitterionic oxidized-nicotinamide/reduced-flavin complexes is strongly dependent on polarity. It is maximal in a highly polar environment. 4. 5-Deazaflavins show the high thermodynamic radical instability of nicotinamides. They have to be considered as nicotinamide analog 2e- oxidoreductants rather than flavin analogs, therefore, lacking the ability to catalyze reversible 1e- oxidoreduction, essential for many flavoenzymes.