Construction
of nitrogen–nitrogen bonds involves sophisticated
biosynthetic mechanisms to overcome the difficulties inherent to the
nucleophilic nitrogen atom of amine. Over the past decade, a multitude
of reactions responsible for nitrogen–nitrogen bond formation
in natural product biosynthesis have been uncovered. On the basis
of the intrinsic properties of these reactions, this Review classifies
these reactions into three categories: comproportionation, rearrangement,
and radical recombination reactions. To expound the metallobiochemistry
underlying nitrogen–nitrogen bond formation reactions, we discuss
the enzymatic mechanisms in comparison to well characterized canonical
heme-dependent enzymes, mononuclear nonheme iron-dependent enzymes,
and nonheme di-iron enzymes. We also illuminate the intermediary properties
of nitrogen oxide species NO2
–, NO+, and N2O3 in nitrogen–nitrogen
bond formation reactions with clues derived from inorganic nitrogen
metabolism driven by anammox bacteria and nitrifying bacteria. These
multidimentional discussions will provide further insights into the
mechanistic proposals of nitrogen–nitrogen bond formation in
natural product biosynthesis.