Work

Structural and Mechanistic Insights into Bacterial Hydrazine Biosynthesis

Year: 2025

Type: article

Abstract: ABSTRACT Nitrogen-nitrogen (N-N) bond-containing motifs are prevalent in both clinical drugs and natural products. Bacterial hydrazine synthetases catalyze N-N bond formation by coupling an amino acid and a hydroxylamine via a distinctive O -aminoacyl-hydroxylamine intermediate. Despite its wide occurrence, the structural and mechanistic basis of this process has remained elusive. Here, we report the first crystal structures of the O -aminoacyl-hydroxylamine synthetase component of a bacterial hydrazine synthetase, captured in binary and ternary complexes with substrates and catalytic intermediates. These structures reveal the molecular determinants of substrate recognition and, together with biochemical and computational analyses, establish a detailed mechanistic framework for the hydrazine synthetase family. Leveraging these insights, we expanded hydrazine biosynthesis through the targeted discovery of novel hydrazine synthetases and implemented a chemoenzymatic synthesis strategy. This work provides fundamental insights into hydrazine synthetases and lays the groundwork for their rational engineering as versatile biocatalysts.

Source: Journal of the American Chemical Society

DOI: 10.1021/jacs.5c15949