Phosphorylation of peptides by a kinase domain in cyanobactin pathways

Raquel Castelo-Branco, Xiaodan Ouyang, João P. A. Reis, Sara Freitas, Diana Sousa, David P. Fewer () and Pedro N. Leão ()
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Raquel Castelo-Branco: s/n, Interdisciplinary Centre of Marine and Environmental Research (CIIMAR/CIMAR), Avenida General Norton de Matos
Xiaodan Ouyang: University of Helsinki, Department of Microbiology
João P. A. Reis: s/n, Interdisciplinary Centre of Marine and Environmental Research (CIIMAR/CIMAR), Avenida General Norton de Matos
Sara Freitas: s/n, Interdisciplinary Centre of Marine and Environmental Research (CIIMAR/CIMAR), Avenida General Norton de Matos
Diana Sousa: s/n, Interdisciplinary Centre of Marine and Environmental Research (CIIMAR/CIMAR), Avenida General Norton de Matos
David P. Fewer: University of Helsinki, Department of Microbiology
Pedro N. Leão: s/n, Interdisciplinary Centre of Marine and Environmental Research (CIIMAR/CIMAR), Avenida General Norton de Matos

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Phosphorylation is an important protein post-translational modification and a valuable tool in medicinal chemistry for improving the pharmacological properties of small molecules, but rare in natural product biosynthesis. Here we report phosphorylation in cyanobactins, a family of ribosomally synthesized and post-translationally modified peptides. We identify an unusual kinase domain embedded in the C-terminal macrocyclase encoded in cyanobactin biosynthetic gene clusters and link it to the production of phosphorylated dolichospermamides and aphanizomenamides. Heterologous expression, domain deletion and site directed mutagenesis confirm the role of the kinase domain, while transplantation of this domain into the sphaerocyclamide pathway leads to the production of phosphorylated sphaerocyclamides. The kinase domain acts on both linear and cyclic substrates with preference for Tyr residues. Collectively, these findings expand the diversity of post-translational modifications in cyanobactins and establish a versatile strategy for the engineering and combinatorial biosynthesis of phosphorylated peptides.

Date: 2025
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DOI: 10.1038/s41467-025-65184-2

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