Nitrogen–Nitrogen Bond Formation Reactions Involved in Natural Product Biosynthesis

Abstract

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.

Synthetic and biosynthetic routes to nitrogen–nitrogen bonds

“…CNQ-766, they found all carbons of both A80915C 313 and azamerone 286 originated from acetate, except the methyl group of C-8, which is instead methionine-derived. The results also revealed that both the naphthoquinone unit of 313 and the phthalazinone unit of 286 display two distinct 13 C-labeling patterns, consistent with the outcome from feeding studies for napyradiomycins biosynthesis in actinomycete Chainia rubra. 248 These data together suggest that phthalazinone unit of azamerone would be derived from symmetrical pentaketide 1,3,6,8tetrahydroxynaphthalene (THN, 311) and two isoprenoid moieties originated from the mevalonate pathway (Fig.…”

Molecular basis of enzymatic nitrogen-nitrogen formation by a family of zinc-binding cupin enzymes

“…The biosynthetic strategies for constructing N-N bonds in natural products have received great attention over the past decade 13 , 14 , 24 , 25 . Despite that there is an increasing number of dedicated enzymes from different protein families that were discovered to be responsible for the formation of N-N linkages in various natural products, little is known about their catalytic mechanism 26 .…”

“…Although hundreds of these molecules have also been isolated from nature (Fig. 1a ), the biosynthetic enzymes that are responsible for constructing those unusual N-N bonds, including hydrazine, diazo, and N -nitroso moieties, are only starting to be uncovered very recently 2 – 14 . Among them, the piperazate synthase KtzT is a heme-dependent enzyme that catalyzes N-N cyclization of l - N 5 -OH-ornithine to give the hydrazine-bearing piperazate, which is a nonproteinogenic amino acid building block for many non-ribosomal peptides 2 .…”

Fullerene Derivatives for Drug Delivery against COVID-19: A Molecular Dynamics Investigation of Dendro[60]fullerene as Nanocarrier of Molnupiravir

“…Although the N–N bond has a relatively small dissociation energy of 240 kJ/mol, this value is only 20% smaller than that corresponding to the C–N bond, which is the next weakest link existing in the proposed system [ 53 ]. In addition, it is worth mentioning at this point that over the last few years, plenty of reactions capable of forming the nitrogen−nitrogen bond in natural product biosynthesis have been revealed, overcoming the technical difficulties due to the inherent nucleophilic nature of nitrogen elements [ 54 ]. Moreover, some nitrogen–nitrogen-bond-containing bioactive products have already been used in clinical practice, evidencing their promising long-life capabilities [ 54 ].…”