Substrate Length Controls Atropopeptide Complexity and Triggers Excision-Driven Scaffold Hop to Diketopiperazine Alkaloids.
7 affiliations
- 1Institute for Molecular Bio Science, Goethe University Frankfurt, Max-von-Laue Strasse 9, 60438Frankfurt am Main, Germany.
- 2Buchmann Institute for Molecular Life Science; Institute of Organic Chemistry and Chemical Biology, Goethe University Frankfurt, Max-von-Laue Strasse 9, 60438Frankfurt am Main, Germany.
- 3Institute of Microbiology, ETH Zurich, 8093Zurich, Switzerland.
- 4Department of Chemistry, Vanderbilt University, Stevenson Center 7330, Nashville, Tennessee37240, United States.
- 5Department of Biological Sciences, Vanderbilt University, VU Station B, Box 35-1634, Nashville, Tennessee37235, United States.
- 6Department of Bioresources, Fraunhofer Institute for Molecular Biology and Applied Ecology, Ohlebergsweg 12, 35392Giessen, Germany.
- 7Senckenberg Research Institute and Natural History Museum, Senckenberganlage 25, 60325Frankfurt, Germany.
Abstract
Atropopeptides are a family of ribosomally synthesized and posttranslationally modified peptides (RiPPs) that share conserved cross-link-forming amino acids in their core peptides, yet adopt architectures ranging from simple monocyclic to complex polycyclic structures with intriguing three-dimensional shapes. These complex architectures arise from multiple C-C and C-N cross-links that are installed by a single cytochrome P450 enzyme, but the factors governing these divergent cross-linking patterns and resulting structural complexities have remained elusive. Recent studies on RiPP biosynthesis have revealed a form of substrate-controlled catalysis, in which the precursor sequence, rather than the modifying enzyme, dictates the reaction course. Here, we describe a distinct form of substrate-controlled catalysis in atropopeptide biosynthesis, demonstrating that core peptide length, rather than sequence, determines the cross-linking pattern installed by an atropopeptide-forming cytochrome P450. We further uncover an unusual proteolytic excision of an internal amino acid in mature atropopeptides, generating peptides that spontaneously convert into pyrroloindoline-containing diketopiperazines (DKPs) and thereby effecting a nonenzymatic scaffold-hop from atropopeptides to DKP-derived alkaloids, for which we provide mechanistic insight. Both the atropopeptide and the corresponding DKP exhibit antiviral activity, and their structural diversity can be further expanded through precursor engineering. Our work reveals substrate length as a key determinant of atropopeptide complexity, provides insights into the catalysis of a multicross-link-forming P450, and establishes an unprecedented route connecting atropopeptides to pyrroloindoline DKP alkaloids.
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BibTeX
@article{tan2026substrate,
title = {{Substrate Length Controls Atropopeptide Complexity and Triggers Excision-Driven Scaffold Hop to Diketopiperazine Alkaloids.}},
author = {Bin Tan and Ziheng Cui and Yuya Kakumu and Sandra J Panczyk and Mai Ikeda and Dongyu Liu and Christine M Pestalozzi and Julia A Vorholt and Allison S Walker and Kornelia Hardes and Martin Grininger and Eric J N Helfrich},
journal = {Journal of the American Chemical Society},
year = {2026},
month = oct,
doi = {10.1021/jacs.6c12504},
url = {https://europepmc.org/article/MED/42954517},
note = {CC BY},
}
RIS
TY - JOUR
TI - Substrate Length Controls Atropopeptide Complexity and Triggers Excision-Driven Scaffold Hop to Diketopiperazine Alkaloids.
AU - Bin Tan
AU - Ziheng Cui
AU - Yuya Kakumu
AU - Sandra J Panczyk
AU - Mai Ikeda
AU - Dongyu Liu
AU - Christine M Pestalozzi
AU - Julia A Vorholt
AU - Allison S Walker
AU - Kornelia Hardes
AU - Martin Grininger
AU - Eric J N Helfrich
PY - 2026
DA - 2026/10/01
JO - Journal of the American Chemical Society
DO - 10.1021/jacs.6c12504
UR - https://europepmc.org/article/MED/42954517
AB - Atropopeptides are a family of ribosomally synthesized and posttranslationally modified peptides (RiPPs) that share conserved cross-link-forming amino acids in their core peptides, yet adopt architectures ranging from simple monocyclic to complex polycyclic structures with intriguing three-dimensional shapes. These complex architectures arise from multiple C-C and C-N cross-links that are installed by a single cytochrome P450 enzyme, but the factors governing these divergent cross-linking patterns and resulting structural complexities have remained elusive. Recent studies on RiPP biosynthesis have revealed a form of substrate-controlled catalysis, in which the precursor sequence, rather than the modifying enzyme, dictates the reaction course. Here, we describe a distinct form of substrate-controlled catalysis in atropopeptide biosynthesis, demonstrating that core peptide length, rather than sequence, determines the cross-linking pattern installed by an atropopeptide-forming cytochrome P450. We further uncover an unusual proteolytic excision of an internal amino acid in mature atropopeptides, generating peptides that spontaneously convert into pyrroloindoline-containing diketopiperazines (DKPs) and thereby effecting a nonenzymatic scaffold-hop from atropopeptides to DKP-derived alkaloids, for which we provide mechanistic insight. Both the atropopeptide and the corresponding DKP exhibit antiviral activity, and their structural diversity can be further expanded through precursor engineering. Our work reveals substrate length as a key determinant of atropopeptide complexity, provides insights into the catalysis of a multicross-link-forming P450, and establishes an unprecedented route connecting atropopeptides to pyrroloindoline DKP alkaloids.
SN - 0002-7863
SN - 1520-5126
ER -