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

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Abstract
Biological nicotinamide‐dependent oxidoreduction consists of reversible 2e‐oxidoreduction of substrates. A mechanism involving subsequent le‐steps is shown to be very unfavourable due to the high energy of the nicotinamide radical. 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. 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. 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 le‐oxidoreduction, essential for many flavoenzymes.