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Azaserine is a bacterial metabolite containing a biologically unusual and synthetically enabling α‐diazoester functional group. Herein, we report the discovery of the azaserine (aza) biosynthetic gene cluster fromGlycomyces harbinensis. Discovery of related gene clusters reveals previously unappreciated azaserine producers, and heterologous expression of theazagene cluster confirms its role in azaserine assembly. Notably, this gene cluster encodes homologues of hydrazonoacetic acid (HYAA)‐producing enzymes, implicating HYAA in α‐diazoester biosynthesis. Isotope feeding and biochemical experiments support this hypothesis. These discoveries indicate that a 2‐electron oxidation of a hydrazonoacetyl intermediate is required for α‐diazoester formation, constituting a distinct logic for diazo biosynthesis. Uncovering this biological route for α‐diazoester synthesis now enables the production of a highly versatile carbene precursor in cells, facilitating approaches for engineering complete carbene‐mediated biosynthetic transformations in vivo.

Azaserine is a bacterial metabolite containing a biologically unusual and synthetically enabling α‐diazoester functional group. Herein, we report the discovery of the azaserine (aza) biosynthetic gene cluster fromGlycomyces harbinensis. Discovery of related gene clusters reveals previously unappreciated azaserine producers, and heterologous expression of theazagene cluster confirms its role in azaserine assembly. Notably, this gene cluster encodes homologues of hydrazonoacetic acid (HYAA)‐producing enzymes, implicating HYAA in α‐diazoester biosynthesis. Isotope feeding and biochemical experiments support this hypothesis. These discoveries indicate that a 2‐electron oxidation of a hydrazonoacetyl intermediate is required for α‐diazoester formation, constituting a distinct logic for diazo biosynthesis. Uncovering this biological route for α‐diazoester synthesis now enables the production of a highly versatile carbene precursor in cells, facilitating approaches for engineering complete carbene‐mediated biosynthetic transformations in vivo.