Goethe-Universität — Press releases

Goethe University PR & Communication Department

Jan 15 2026

13:12

Research team at Goethe University Frankfurt classifies all human E3 ligases – New opportunities for targeted protein degradation therapies

The “broker” family helps tidy up the cell

Cells must continually adjust their protein composition, which includes protein synthesis as well as degradation. Most regulated protein degradation is executed by the ubiquitin–proteasome system (UPS), in which proteins are tagged with ubiquitin and routed to a protein-shredder called proteasome. The enzyme E3 ligase plays a key role here by acting as a “broker” that mediates the labeling of the proteins to be degraded. A research team at Goethe University Frankfurt has now made the first systematic catalog and relationship map of all human E3 ligases and identified 40 of them as potential key players in emerging drug classes such as PROTACs, which are used, for example, to treat cancer.

FRANKFURT. Maintaining cellular order is a major logistical challenge: Individual mammalian cells contain billions of protein molecules, which must be synthesized, deployed, and removed with precision. In the ubiquitin-proteasome system (UPS), proteins destined for degradation are tagged with chains of several ubiquitin proteins and then degraded by the proteasome. The crucial step is the target selection: E3 ligases are enzymes that act as molecular “broker” by binding specific target proteins and coordinating the transfer of ubiquitin from an E2 enzyme.

As an E3 ligase recognizes only a restricted set of target proteins, cells maintain a large and diverse E3 ligase repertoire. A research team at Goethe University Frankfurt, led by Dr. Ramachandra M. Bhaskara from the Institute of Biochemistry II, has now compiled all members of the “broker family” in a catalog and mapped for the first time how human E3 ligases relate to one another, and what that implies for function, substrate recognition, and drug discovery.

A data-driven map of the “E3 ligome”

To describe the broker family – the so-called “E3 ligome” – the researchers performed AI-supported computational comparisons of E3 ligase features and then validated key functional inferences in cell culture experiments. In this way, the Frankfurt researchers defined 13 major families, as well as subfamilies, which capture more similarities between E3 ligase family members than shared amino acid sequences and structural characteristics. Bhaskara explains: “Our data-driven machine-learning approach reveals family-specific functions. For example, members of one family are important for DNA repair programs and for preventing unplanned cell death, while those of another are involved in antiviral defense.”

Beyond their role in protein degradation, E3 ligases are also implicated in ubiquitin signaling, which is not used for protein degradation, broadening their relevance across cellular pathways and disease mechanisms.

Implications for next-generation therapeutics

The new E3 ligase map is particularly relevant for targeted protein degradation strategies used in novel types of active pharmaceutical substances such as PROTACs. PROTACs (Proteolysis Targeting Chimeras) are bifunctional molecules that bring an E3 ligase into proximity with a disease-relevant protein, triggering ubiquitin tagging and proteasomal destruction of the disease-relevant protein. Although the field has advanced rapidly, most existing PROTAC programs rely on only a small number of well-characterized E3 ligases.

By systematically analyzing the full E3 ligome, the team identified 40 additional E3 ligases that may be suitable for PROTAC development—and, importantly, the family relationships may help researchers repurpose or adapt ligands and design principles across related E3 ligases. This could widen the range of tissues, cellular contexts, and diseases that targeted degradation can reach.

Open resource for the research community

Because many groups worldwide are developing targeted degradation approaches, the Goethe University team has made the complete E3 ligome publicly available via a dedicated database, enabling other researchers to build on the classification and functional insights.

Publication: Arghya Dutta, Alberto Cristiani, Siddhanta V. Nikte, Jonathan Eisert, Yves Matthess, Borna Markusic, Cosmin Tudose, Chiara Becht, Varun Jayeshkumar Shah, Thorsten Mosler, Koraljka Husnjak, Ivan Dikic, Manuel Kaulich, Ramachandra M. Bhaskara: Multi-scale classification decodes the complexity of the human E3 ligome. Nature Communications (2025) https://doi.org/10.1038/s41467-025-67450-9

Picture download:
https://www.uni-frankfurt.de/181983680

Captions:
1.Sun of families: Researchers at Goethe University have elucidated the relationships among all 462 catalytic human E3 ligases; E3 ligases also support non-degradative functions. Image: Ramachandra M. Bhaskara, Goethe University Frankfurt

2. PROTACs and E3 ligases: PROTACs link a target protein (protein of interest, POI) with an E3 ligase, which mediates the ubiquitin labeling (yellow) of the POI via an E2 enzyme. The POI is then degraded in the proteasome shredder (blue). Image: Institute of Biochemistry II, Goethe University Frankfurt

Contact:
Dr. Ramachandra M. Bhaskara
Team Leader Computational Cell Biology
Institute of Biochemistry II
Goethe University Frankfurt, Germany
Tel. +49 (0)69 7984-2526
Bhaskara@med.uni-frankfurt.de
https://biochem2.com/people/bhaskara-ramachandra-m

Jan 12 2026

11:53

Protein Engineering Enables Sustainable Production of Industrially Important Fatty Acids

From Palm Oil to Designer Enzymes: Frankfurt Researchers Reprogram Yeast Cells

Fatty acids derived from palm oil and coconut oil are found in countless everyday products, but their extraction drives deforestation. Researchers at Goethe University Frankfurt (Germany) have now reprogrammed the enzyme fatty acid synthase to produce custom fatty acids of any chain length. With just two targeted modifications, the enzyme can be redirected from producing the usual 16-carbon fatty acids to generating shorter chains. In collaboration with a partner laboratory in China, the engineered fatty acid synthase was implemented in yeast strains to enable sustainable bioreactor-based production of industrially relevant fatty acids.

FRANKFURT. Whether laundry detergents, mascara, or Christmas chocolate – many everyday products contain fatty acids from palm oil or coconut oil. However, the extraction of these raw materials is associated with massive environmental issues: rainforests are cleared, habitats for endangered species are destroyed, and traditional farmers lose their livelihoods. The team led by Prof. Martin Grininger at Goethe University in Frankfurt, Germany, has now developed a biotechnological approach that could enable a more environmentally friendly production method.

A Molecular Assembly Line with Precise Control
At the heart of this research is an enzyme called fatty acid synthase (FAS) – a type of molecular assembly line that builds fatty acids in all living organisms. “FAS is one of the most important enzymes in a cell's metabolism and has been fine-tuned by evolution over millions of years," explains Grininger.

The enzyme typically produces palmitic acid, a 16-carbon fatty acid that serves as a building block for cell membranes and energy storage. Industry, however, primarily requires shorter variants with 6 to 14 carbon atoms, which today are sourced from plant oils produced on large-scale oil palm plantations linked to deforestation and biodiversity loss. The decisive advantage of the new, FAS-based method: “Fundamentally, our advantage lies in the very precise control of chain length. We can theoretically make any chain length, and we're demonstrating this with the example of C12 fatty acid, which otherwise can only be obtained from palm kernels or coconut," says Grininger.

Understanding Through Modification
Grininger and his team have significantly contributed to understanding the molecular foundations of FAS over the past 20 years. They discovered that chain length is regulated by the interplay between two subunits: ketosynthase repeatedly elongates the chain by two carbon atoms while thioesterase cleaves off the finished chain as a fatty acid. “We then asked ourselves whether we could go beyond analysis and build FAS with new chain length regulation," says Grininger. “True understanding begins when you can change or customize a phenomenon."

Two Targeted Interventions Lead to Success
Grininger's doctoral student Damian Ludig took up this idea. “We asked what would happen if we specifically intervened in the interaction between these two subunits," Ludig explains. “Could we then control the chain length of the fatty acids that are produced?"

Ludig employed protein engineering methods where individual amino acids can be exchanged or entire protein regions modified. “Two changes to FAS through protein engineering ultimately led us to our goal," says Ludig. “In the ketosynthase subunit, I first exchanged one amino acid which resulted in chains being extended only with low efficiency beyond a certain length. Additionally, I replaced the thioesterase subunit with a similar protein from bacteria that shows activity in cleaving short chains." Depending on further adjustments, Ludig was able to produce short- and medium-length fatty acids.

From Frankfurt to Dalian
Collaboration with Prof. Yongjin Zhou's research group at Dalian Institute of Chemical Physics, Chinese Academy of Sciences, ultimately achieved breakthrough results. Supported by the German Research Foundation (DFG) and the National Natural Science Foundation of China (NSFC), Zhou and his lab succeeded in developing yeast strains that produce fatty acids containing only 12 carbon atoms instead of 16. Various designer FAS from Grininger's lab were integrated into these yeasts for optimization.
Both laboratories have already filed patents for their technologies. “On the Chinese side, Unilever was involved in this project. Our development has thus far taken place without industrial participation. However, we are striving for a collaboration with an industry partner in order to bring the technology into application," says Grininger.

Thinking Ahead: From Fatty Acids to Pharmaceuticals
In a second project, Felix Lehmann from Grininger's lab took the research even further by investigating how universally applicable FAS are for tailored biosyntheses: “This question is also driven by necessity – to continually develop chemical processes towards more sustainable green chemistry," explains Grininger.

The specific question was: Can FAS be redirected to make not only fatty acids, but also entirely different compounds, such as styrylpyrones? These molecules are precursors to substances derived from kava plants that attract medical interest due to their potential anxiolytic properties. Here, too, Lehmann achieved success with relatively few modifications: “First we cut away part of FAS that we didn't need for our target products; then we altered ketosynthase so that cinnamic acid could be used as starting material," he explains. The team even integrated another protein into the FAS structure so it became part of multi-enzyme complex.

“In this project we systematically examined how entire biosynthetic pathways can be constructed with FAS from readily available building blocks," Grininger explains. While the results do not yet have immediate practical applications, they provide important guidance for the future design of novel synthases.

At the Intersection of Chemistry and Biology
“Our lab has made significant strides towards biocatalysis and biotechnological applications over recent years, driven by the contributions of many projects and collaborations. We will continue down this path", Grininger summarizes. “Within the Cluster of Excellence SCALE, we will also use this enzyme to generate tailored biomembranes, whose analysis will help deepen our understanding of key organelles such as the endoplasmic reticulum and mitochondria."

Whether technology can indeed alleviate palm oil issues now depends on successful scaling up alongside industry partners. The scientific foundation has certainly been laid and the lab still has many ideas to explore.

Publications:
Damian L. Ludig, Xiaoxin Zhai, Alexander Rittner, Christian Gusenda, Maximilian Heinz, Svenja Berlage, Ning Gao, Adrian J. Jervis, Yongjin J. Zhou & Martin Grininger. Engineering metazoan fatty acid synthase to control chain length applied in yeast. Nature Chemical Biology (2026) https://doi.org/10.1038/s41589-025-02105-w

Felix Lehmann, Nadja Joachim, Carolin Parthun, Martin Grininger. Design of a Multienzyme Derived from Mouse Fatty Acid Synthase for the Compartmentalized Production of 2-Pyrone Polyketides. Angewandte Chemie International Edition (2025). https://doi.org/10.1002/anie.202511726

Picture download:
https://www.uni-frankfurt.de/181986496

Caption:
File “Palmoil_Shutterstock": Palm oil plantations often stretch for kilometers and pose a problem for humans and animals alike (Image: Shutterstock).
File “Biosynthesis_LehmannGrininger_EN": Schematic representation of biosynthesis in a cell (top) and in the laboratory (bottom). The designer enzyme shortens the chain length of the fatty acid (Image: Felix Lehmann & Martin Grininger/Goethe University).

Further Information:
Prof. Dr. Martin Grininger
Institute for Organic Chemistry and Chemical Biology
Buchmann Institute for Molecular Life Sciences
Goethe University Frankfurt
Max-von-Laue-Str. 15
60438 Frankfurt am Main, Germany
+49 (0)69 798 42705
grininger@chemie.uni-frankfurt.de
https://www.greeninger-chemistry.com/

Editor: Dr. Phyllis Mania, Science Editor, PR & Communications Office, Theodor-W.-Adorno-Platz 1, 60323 Frankfurt, Tel: +49 (0) 69 798-13001, mania@physik.uni-frankfurt.de

Press releases – 2026

Goethe University PR & Communication Department

The “broker” family helps tidy up the cell

From Palm Oil to Designer Enzymes: Frankfurt Researchers Reprogram Yeast Cells