Press releases

FRANKFURT. The active agents of many drugs are natural products, so called because often only microorganisms are able to produce the complex structures. Similar to the production line in a factory, large enzyme complexes put these active agent molecules together. A team of Technical University of Munich (TUM) and Goethe University Frankfurt has now succeeded in investigating the basic mechanisms of one of these molecular factories. (Nature Chemistry, DOI: 10.1038/s41557-020-0491-7)

Many important drugs such as antibiotics or active agents against cancer are natural products which are built up by microorganisms for example bacteria or fungi. In the laboratory, these natural products can often be not produced at all or only with great effort. The starting point of a large number of such compounds are polyketides, which are carbon chains where every second atom has a double bound to an oxygen atom.

In the cell of a microorganism microbial cell such as the in the Photorhabdus luminescens bacterium, they are produced with the help of polyketide synthases (PKS). In order to build up the desired molecules step by step, in the first stage of PKS type II systems, four proteins work together in changing “teams".

In a second stage, they are then modified to the desired natural product by further enzymes. Examples of bacterial natural products which are produced that way are, inter alia, the clinically used Tetracyclin antibiotics or Doxorubicin, an anti-cancer drug.

Interdisciplinary cooperation

While the modified steps of the second stage are well researched studied for many active agents, there have up to now hardly been any insights into the general functioning of the first stage of these molecular factories where the highly reactive polyketide intermediate product is bound to the enzyme complex and protected so that it cannot react spontaneously.

This gap is now closed by the results of the cooperation between the working groups of Michael Groll, professor of biochemistry at the Technical University of Munich, and Helge Bode, professor of molecular biotechnology at Goethe University Frankfurt, which are published in the renowned scientific journal Nature Chemistry.

Findings inspire to new syntheses of active agents

“In the context of this work, we were for the first time able to analyze complexes of the different partner proteins of type II polyketide synthase type II with the help of X-ray structure analysis and now understand the complete catalytic cycle in detail," Michael Groll explains.

“Based on these findings, it will be possible in the future to intervene manipulatein the central biochemical processes in a targeted manner and thus change the basic structures instead of being restricted to the decorating enzymes," Helge Bode adds.

Although it is a long way to develop improved antibiotics and other drugs, both groups are optimistic that now also the structure and the mechanism of the missing parts of the molecular fabric factory can be explained. “We already have promising data of the further protein complexes," says Maximilian Schmalhofer, who was involved in the study as a doctoral candidate in Munich.

The work was supported with funds of the Deutsche Forschungsgemeinschaft (DFG) in the context of SPP 1617, SFB 1035 and the Center for Integrated Protein Science Munich (CIPSM) cluster of excellence and the LOEWE focus MegaSyn of the State of Hesse. X-ray structure data were measured at the Paul Scherrer Institute in Villigen (Switzerland). The Swedish National Infrastructure for Computing provided computing time for the theoretical modeling.


Publication: Alois Bräuer, Qiuqin Zhou, Gina L.C. Grammbitter, Maximilian Schmalhofer, Michael Rühl, Ville R.I. Kaila, Helge B. Bode und Michael Groll: Structural snapshots of the minimal PKS system responsible for octaketide biosynthesis, Nature Chemistry, DOI: 10.1038/s41557-020-0491-7, Link: https://www.nature.com/articles/s41557-020-0491-7

More information:
Goethe University Frankfurt
Prof. Dr. Helge B. Bode
Molecular Biotechnology
Faculty of Biological Sciences and
Buchmann Institute for Molecular Life Sciences (BMLS)
Phone +49 (0)69 798 29557
h.bode@bio.uni-frankfurt.de
https://www.goethe-university-frankfurt.de/45924717/Institute_for_Molecular_Bio_Science?locale=en

Technical University of Munich
Prof. Dr. Michael Groll
Professorship of Biochemistry
Lichtenbergstr. 4, 85748 Garching, Germany
Phone: +49 89 289 13360
michael.groll@tum.de
https://www.department.ch.tum.de/biochemie/

FRANKFURT. Acute lymphoblastic leukaemia (ALL) is the most common kind of cancer in children. T-ALL, a subtype that resembles T-lymphocytes, can be treated successfully with the drug nelarabine. The drug has not been successful, however, with B-ALL, a subtype resembling B-lymphocytes. Since the 1980s, oncologists have been puzzled as to the cause of this difference. Now, an international research team headed by Goethe University and the University of Kent has discovered the reason: B-ALL cells contain the enzyme SAMHD1, which deactivates the drug.

In the current issue of “Communications Biology", Professor Jindrich Cinatl from the Institute for Medical Virology at Goethe University and Professor Martin Michaelis from the School of Biosciences at the University of Kent report on their investigations with nelarabine on different cell lines. “Nelarabine is the precursor of the drug, a prodrug, that does not become effective until it is combined with three phosphate groups in the leukaemia cell," explains Professor Cinatl. “In studies of various ALL cell lines and leukaemia cells from ALL patients, we have been able to demonstrate that the enzyme SAMHD1 splits the phosphate groups off so that the medicine loses its effect." Because B-ALL cells contain more SAMHD1 than T-ALL cells, nelarabine is less effective with B-ALL.

These results could improve the treatment of ALL in the future. In rare cases, B-ALL cells contain very little SAMHD1 so that treatment with nelarabine would be possible. On the contrary, there are also rare cases of T-ALL exhibiting a lot of SAMHD1. In such cases, the otherwise effective nelarabine would not be the right medication. Professor Michaelis observes: “SAMHD1 is thus a biomarker that allows us to better adapt treatment with nelarabine to the individual situation of ALL patients."

Tamara Rothenburger, whose doctoral dissertation was funded by the association “Hilfe für krebskranke Kinder Frankfurt e.V“, is satisfied when she looks back at her research. “I hope that many children with leukaemia will benefit from the results." The research was also supported by the Frankfurt Stiftung für krebskranke Kinder. Additional members of the research group are Ludwig-Maximilians-Universität Munich, and University College London.

Publication: Tamara Rothenburger, Katie-May McLaughlin, Tobias Herold, Constanze Schneider, Thomas Oellerich, Florian Rothweiler, Andrew Feber, Tim R. Fenton, Mark N. Wass, Oliver T. Keppler, Martin Michaelis, Jindrich Cinatl. SAMHD1 is a key regulator of the lineage-specific response of acute lymphoblastic leukaemias to nelarabine, in: Communications Biology, DOI 10.1038/s42003-020-1052-8, https://www.nature.com/commsbio/

Further information:
Prof. Dr. rer. nat. Jindrich Cinatl
Institute for Medical Virology
University Hospital Frankfurt
Tel.: +49 69 6301-6409
E-mail: cinatl@em.uni-frankfurt.de

FRANKFURT. Because the tsetse fly can transmit sleeping sickness, it is commonly combatted with insecticides or caught in traps. Bioscientists at Goethe University have now developed a method for producing the attractants for the traps in a biotechnological procedure. The Frankfurt scientists hope that in the future, the attractants can then be produced locally in rural areas of Africa at low cost (Scientific Reports, DOI: 10.1038/s41598-020-66997-5).

The tsetse fly occurs in large regions of sub-Saharan Africa. The flies feed on human and animal blood, transmitting trypanosoma in the process – small, single-cell organisms that use the flies as intermediate host and cause a dangerous inflammation of the lymph and nervous system in both animals and humans. There is no vaccination for this sleeping sickness; untreated, it usually ends in death. In agriculture, particularly cattle breeding, sleeping sickness – or trypanosomiasis – causes enormous damages in the form of sick and dead animals.

In addition to the use of insecticides, the insects are also caught in traps. The attractants used include substances that also occur in cattle urine and which attract tsetse flies. These substances (3-ethylphenol and 3-propylphenol, or 3-EP and 3-PP for short) are synthesized out of oil derivatives or also extracts from cashew nut shells through chemical processes. However, both processes are complex and neither practical nor affordable for rural communities in Africa.

In the LOEWE collaborative research project MegaSyn, molecular biologists at Goethe University have now succeeded in producing 3-EP and 3-PP in genetically modified brewer’s yeast (Saccharomyces cerevisiae). They used a yeast strain into which they had previously introduced a new metabolic pathway, and changed its sugar metabolism. This enabled the yeasts to produce similarly high concentrations of 3-EP and 3-PP as those which occur in cow urine.

Doctoral student Julia Hitschler from the Institute for Molecular Biosciences at Goethe University explains: “Our yeasts could ideally grow in Africa in nutrient solutions on the basis of plant waste products, food rests or fodder rests. This would make production of the attractant almost cost-free. We are currently looking for partners to help us test our yeasts locally and provide them to the local population.”

The potential for the new yeasts go beyond the tsetse attractants, add Professor Eckhard Boles, who heads the project. In the future, other substances that have been previously won through oil or coal could be produced through the new yeasts: “Our yeasts could be developed to produce other alkylphenols besides 3-EP and 3-PP. These alkylphenols could be used for the production of lubricant additives or surface-active substances in cleaning agents.”

Publication: Julia Hitschler, Martin Grininger, Eckhard Boles: Substrate promiscuity of polyketide synthase enables production of tsetse fly attractants 3-ethylphenol and 3-propylphenol by engineering precursor supply in yeast. Scientific Reports, https://doi.org/10.1038/s41598-020-66997-5

Further information:
Prof. Dr. Eckhard Boles
Institute for Molecular Biosciences
Goethe University Frankfurt
Tel: +49 69 798 29513
e.boles@bio.uni-frankfurt.de
http://www.bio.uni-frankfurt.de/boles

FRANKFURT. Can class differences come about endogenously, i.e. independent of birth and education? Professor Claudius Gros from the Institute for Theoretical Physics at Goethe University pursued this issue in a game theoretical study. He was able to show that the basic human need to compare oneself with others may be the root cause of the formation of social classes.

It's generally recognized that differences in background and education cement class differences. It is less clear when and under what circumstances individual psychological forces can drive an initially homogenous social group apart and ultimately divide it. Claudius Gros, professor for theoretical physics at Goethe University, investigated this question in a mathematical precise way using game theory methods. “In the study, societies of agents – acting individuals – are simulated within game theory, which means that everybody optimises her/his success according to predetermined rules. I wanted to find out whether social differences can emerge on their own if no one starts off with advantages – that is, when all actors have the same skills and opportunity," the physicist explains.

The study is based on the assumption that there are things in every society that are coveted but limited – such as jobs, social contacts and positions of power. An inequality is created if the top position is already occupied and someone must therefore accept the second-best job – but not, however, a societal division. With the help of mathematical calculations Gros was able to demonstrate that envy, which arises from the need to compare oneself with others, alters individual behaviour and consequently the agents' strategies in characteristic ways. As a result of this changed behaviour, two strictly separate social classes arise.

Game theory provides the mathematical tools necessary for the modelling of decision situations with several participants, as in Gros' study. In general, constellations in which the decision strategies of the individual actors mutually influence each other are particularly revealing. The success of the individual depends then not only on his or her own actions, but on others' actions as well, which is typical of both economic and social contexts. Game theory is consequently firmly anchored in the economy. The stability condition of game theory, the “Nash equilibrium", is a concept developed by John Forbes Nash in his dissertation in 1950, using the example of poker players. It states that in equilibrium no player has anything to gain by changing their strategy if the other players do not change theirs either. An individual only tries out new behaviour patterns if there is a potential gain. Since this causal chain also applies to evolutionary processes, the evolutionary and behavioural sciences regularly fall back on game theoretical models, for example when researching animal behaviours such as the migratory flight routes of birds, or their competition for nesting sites.

Even in an envy-induced class society there is no incentive for an individual to change his or her strategy, according to Gros. It is therefore Nash stable. In the divided envy society there is a marked difference in income between the upper and lower class which is the same for all members of each social class. Typical for the members of the lower class is, according to Gros, that they spend their time on a series of different activities, something game theory terms a “mixed strategy". Members of the upper class, however, concentrate on a single task, i.e., they pursue a “pure strategy". It is also striking that the upper class can choose between various options while the lower class only has access to a single mixed strategy. “The upper class is therefore individualistic, while agents in the lower class are lost in the crowd, so to speak," the physicist sums up.

In Claudius Gros' model, whether an agent lands in the upper or lower class is ultimately a matter of coincidence. It is decided by the dynamics of competition, and not by origin. For his study, Gros developed a new game theoretical model, the “shopping trouble model" and worked out a precise analytical solution.  From it, he derives that an envy-induced class society possesses characteristics that are deemed universal in the theory of complex systems. The result is that the class society is beyond political control to a certain degree. Political decision-makers lose a portion of their options for control when society spontaneously splits into social classes. In addition, Gros' model demonstrates that envy has a stronger effect when the competition for limited resources is stronger. “This game theoretical insight could be of central significance. Even an 'ideal society' cannot be stably maintained in the long term – which ultimately makes the striving for a communistic society seem unrealistic," the scientist remarks.

Publication: Claudius Gros, „Self induced class stratification in competitive societies of agents: Nash stability in the presence of envy“, Royal Society Open Science , Vol 7, 200411 (2020).

Link: https://royalsocietypublishing.org/doi/10.1098/rsos.200411

Further information: Professor Claudius Gros, Institute for Theoretical Physics, Riedberg Campus, E-Mail gros07@itp.uni-frankfurt.de

FRANKFURT. Light exerts a certain amount of pressure onto a body: sun sails could thus power space probes in the future. However, when light particles (photons) hit an individual molecule and knock out an electron, the molecule flies toward the light source. Atomic physicists at Goethe University have now observed this for the first time, confirming a 90 year-old theory.

As early as the 16th century, the great scholar Johannes Kepler postulated that sunlight exerted a certain pressure, as the tail of the comets he observed consistently pointed away from the sun. In 2010 the Japanese space probe Ikaros used a sun sail for the first time in order to use the power of sunlight to gain a little speed.

Physically and intuitively, the pressure of light or radiation can be explained by the particle characteristic of light: light particles (photons) strike the atoms of a body and transfer a portion of their own momentum (mass times speed) onto that body, which thus becomes faster.

However, when in the 20th century physicists studied this momentum transfer in the laboratory during experiments on photons of certain wavelengths which knocked individual electrons out of atoms, they were met by a surprising phenomenon: the momentum of the ejected electron was greater than that of the photon that struck it. This is actually impossible – since Isaac Newton it has been known that within a system, for every force there must exist an equal but opposite force: the recoil, so to speak. For this reason, the Munich scientist Arnold Sommerfeld concluded in 1930 that the additional momentum of the ejected electron must come from the atom it left. This atom must fly in the opposite direction; in other words, toward the light source. However, this was impossible to measure with the instruments available at that time.

Ninety years later the physicists in the team of doctoral student Sven Grundmann and Professor Reinhard Dörner from the Institute for Nuclear Physics have succeeded for the first time in measuring this effect using the COLTRIMS reaction microscope developed at Goethe University Frankfurt. To do so, they used X-rays at the accelerators DESY in Hamburg and ESRF in French Grenoble, in order to knock electrons out of helium and nitrogen molecules. They selected conditions that would require only one photon per electron. In the COLTRIMS reaction microscope, they were able to determine the momentum of the ejected electrons and the charged helium and nitrogen atoms – which are called ions – with unprecedented precision.

Professor Reinhard Dörner explains: “We were not only able to measure the ion’s momentum, but also see where it came from – namely, from the recoil of the ejected electron. If photons in these collision experiments have low energy, the photon momentum can be neglected for theoretical modelling. With high photon energies, however, this leads to imprecision. In our experiments, we have now succeeded in determining the energy threshold for when the photon momentum may no longer be neglected. Our experimental breakthrough allows us to now pose many more questions, such as what changes when the energy is distributed between two or more photons.”

Publication: Sven Grundmann, Max Kircher, Isabel Vela-Perez, Giammarco Nalin, Daniel Trabert, Nils Anders, Niklas Melzer, Jonas Rist, Andreas Pier, Nico Strenger, Juliane Siebert, Philipp V. Demekhin, Lothar Ph. H. Schmidt, Florian Trinter, Markus S. Schöffler, Till Jahnke, and Reinhard Dörner: Observation of Photoion Backward Emission in Photoionization of He and N2. Phys. Rev. Lett. 124, 233201 https://doi.org/10.1103/PhysRevLett.124.233201

Further information:

Prof. Dr. Reinhard Dörner
Institute for Nuclear Physics
Tel. +49 69 798-47003
doerner@atom.uni-frankfurt.de
https://www.atom.uni-frankfurt.de/