Mixing and Matching of Hybrid Megasynthases is a Hub for the Evolution of Metabolic Diversity in Cyanobacteria

Angewandte Chemie International Edition · 2025-04-17 · 5 citations

Modular megasynthases, such as polyketide synthases (PKSs) and nonribosomal peptide synthetases (NRPSs), are molecular assembly lines that biosynthesize many pharmaceutically and ecologically important natural products. Understanding how these compounds evolve could inspire the artificial evolution of compound diversity by metabolic engineering. Over the past two decades, a number of seminal studies have significantly contributed to our understanding of natural product evolution. However, the evolution of NRPS and PKS assembly lines remains poorly understood, especially for NRPS/PKS hybrids. Here, we provide substantial evidence for a remarkable cluster-mixing event involving three cyanobacterial biosynthetic gene clusters (BGCs), resulting in the emergence of novel peptide-polyketide hybrids that were named minutumamides. By combining retro-evolutionary analysis with structure-guided genome mining, we could discover a potential evolutionary ancestor that links nostopeptolide and minutumamide biosynthesis. In addition, we were able to trace nostopeptolide-related module and domain blocks in various other biosynthetic pathways, indicating a surprisingly vivid mixing and matching of biosynthesis genes in the evolution of NRPS and cis-acyltransferase PKS/NRPS pathways, which was previously regarded as a unique feature of trans-acyltransferase (trans-AT) PKS. These remarkable insights into the evolutionary plasticity of NRPS-PKS assembly lines provide valuable guidance for pathway engineers looking for productive combinations that yield "nonnatural" hybrid natural products.

Rekombination hybrider Megasynthasen als Schlüssel für die Evolution metabolischer Diversität in Cyanobakterien

Angewandte Chemie · 2025-04-17

Zusammenfassung Modulare Megasynthasen, wie Polyketidsynthasen (PKS) und nicht‐ribosomale Peptidsynthetasen (NRPS) biosynthetisieren viele pharmazeutisch und ökologisch wichtige Naturstoffe. Das Verständnis davon, wie sich diese Verbindungen entwickeln, könnte die künstliche Diversifizierung durch metabolisches Engineering inspirieren. In den letzten zwei Jahrzehnten hat eine Reihe bahnbrechender Studien wesentlich zu unserem Verständnis der Evolution von Naturstoffen beigetragen. Die Evolution von NRPS‐ und PKS‐Systemen ist jedoch nach wie vor nur unzureichend verstanden, insbesondere für NRPS/PKS‐Hybride. In dieser Studie liefern wir substanzielle Hinweise auf ein bemerkenswertes Cluster‐Mixing‐Ereignis, an dem drei cyanobakterielle Biosynthese‐Gencluster beteiligt waren. Dieses Ereignis führte zur Entstehung neuartiger Peptid‐Polyketid‐Hybride, die Minutumamide genannt wurden. Durch die Kombination von retro‐evolutionären Analysen mit strukturgeleitetem Genom‐Mining konnten wir einen möglichen evolutionären Vorfahren entdecken, der die Biosynthese von Nostopeptoliden und Minutumamiden verbindet. Darüber hinaus konnten wir Modul‐ und Domänenblöcke mit Homologie zu Nostopeptolid‐Synthasen in verschiedenen anderen Biosynthesewegen aufspüren. Diese Ergebnisse weisen auf eine überraschend lebhafte Vermischung und Anpassung von Biosynthesegenen in der Evolution von NRPS‐ und cis ‐Acyltransferase‐PKS/NRPS‐Wegen hin, was bisher als einzigartiges Merkmal von trans ‐Acyltransferase‐PKS angesehen wurde. Diese bemerkenswerten Einblicke in die evolutionäre Plastizität der NRPS‐PKS‐Baupläne bieten wertvolle Anhaltspunkte für metabolisches Engineering auf der Suche nach produktiven Kombinationen, die „nicht‐natürliche” hybride Naturstoffe hervorbringen.

Abdominal radiographic features of anticoagulant rodenticide toxicity in 14 dogs and 2 cats

Open Veterinary Journal · 2024-01-01 · 2 citations

Background: Anticoagulant rodenticide toxicity is commonly encountered in veterinary practice that can result in internal bleeding. We have observed dogs with retroperitoneal hemorrhage secondary to anticoagulant rodenticide toxicity. However, abdominal radiographic changes in dogs with rodenticide toxicity have not been studied and retroperitoneal hemorrhage secondary to rodenticide toxicity has rarely been reported. Aim: The objective is to describe abdominal radiographic features of anticoagulant rodenticide toxicity and concurrent thoracic radiographic changes in dogs and cats. Methods: Dogs and cats diagnosed with rodenticide toxicity and with available abdominal radiographs were included in this retrospective analysis. Board-certified radiologists reviewed the abdominal and thoracic radiographs. Evaluation of abdominal radiographic changes included assessment of peritoneal or retroperitoneal effusion, subcutaneous hemorrhage, and internal hemorrhage of abdominal organs. Results: Fourteen dogs and two cats with confirmed rodenticide toxicity were included in the study. In dogs, retroperitoneal effusion (28.6%) was the most commonly observed abdominal radiographic change, followed by peritoneal effusion (14.3%). Thoracic radiographic changes in dogs included pleural effusion (63.6%) and mediastinal widening (63.6%) as the most common findings, followed by pulmonary hemorrhage (36.4%) and tracheal narrowing (36.4%). Subcutaneous hemorrhage or edema (9.1%) was also noted. No abdominal radiographic changes consistent with hemorrhage secondary to rodenticide toxicity were noted in the two cats. Conclusion: Based on our findings, it is suggested that rodenticide toxicity may result in retroperitoneal effusion even in the absence of thoracic disease. Therefore, abdominal radiographs may be valuable when suspecting hemorrhage due to coagulopathy. However, abdominal radiographic changes associated with rodenticide toxicity are considered rare in cats.

Dehydrogenative Coupling of Alkylamines with Primary Alcohols Forming α-Amino Ketones

Journal of the American Chemical Society · 2024-06-17 · 14 citations

Acceptorless dehydrogenative coupling reactions between C-H bonds offer straightforward and atom-economical methods connecting readily available materials while liberating gaseous hydrogen as the sole byproduct. Despite the growing interest in such transformations, their realization still poses a significant challenge. Here we report a photoinduced dehydrogenative coupling reaction of alkylamines with primary alcohols. C-H bonds adjacent to nitrogen and oxygen are site-selectively cleaved, and a C-C bond is created between the carbon atoms in a cross-selective manner to produce α-amino ketones. Diverse polar functionalities such as esters, amides, and carboxylic acids survived, demonstrating the broad applicability of the present method.

CCDC 2285511: Experimental Crystal Structure Determination

The Cambridge Structural Database · 2023-08-18

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

CCDC 2219398: Experimental Crystal Structure Determination

The Cambridge Structural Database · 2023-07-07

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Ligand‐Controlled Regiodivergence in Nickel‐Catalyzed Vinylcyclopropane Rearrangement

Angewandte Chemie · 2023-06-13 · 1 citations

Abstract A ligand‐controlled regiodivergence in Ni‐catalyzed rearrangement of vinylcyclopropanes to 1,4‐ or 1,5‐disubstituted cyclopentenes is reported. The 1,4‐ or 1,5‐disubstituted cyclopentene is selectively obtained depending on the choice of ligands. Detailed kinetic studies and density functional theory calculations on the catalytic cycle revealed that the product selectivity is determined at the reductive elimination step from the six‐membered η 1 ‐allyl intermediate.

CCDC 2241071: Experimental Crystal Structure Determination

The Cambridge Structural Database · 2023-08-18

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

CCDC 2219396: Experimental Crystal Structure Determination

The Cambridge Structural Database · 2023-07-07

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Ligand‐Controlled Regiodivergence in Nickel‐Catalyzed Vinylcyclopropane Rearrangement

Angewandte Chemie International Edition · 2023-06-13 · 18 citations

Abstract A ligand‐controlled regiodivergence in Ni‐catalyzed rearrangement of vinylcyclopropanes to 1,4‐ or 1,5‐disubstituted cyclopentenes is reported. The 1,4‐ or 1,5‐disubstituted cyclopentene is selectively obtained depending on the choice of ligands. Detailed kinetic studies and density functional theory calculations on the catalytic cycle revealed that the product selectivity is determined at the reductive elimination step from the six‐membered η 1 ‐allyl intermediate.