Enzymes are biocatalysts that enable all living cells to carry out reactions under the mild conditions found in cells. Without enzymes, many reactions in living organisms would either not take place at all or only very slowly. Enzymes therefore fulfil a variety of tasks in organisms in all domains of life to the extent that life would not be possible without them. Acetyl-CoA synthetase is an enzyme that occurs in mammals, plants and bacteria. It is involved in the production of the central metabolic molecule acetyl-coenzyme A. This molecule is essential for a wide range of biosyntheses for the production of proteins, carbohydrates and fats.
All organisms can adapt their metabolism to the available nutrients. If there is a rich abundance of nutrients, organisms are able to initiate biosynthetic processes in order to produce proteins, carbohydrates and fats as components and for energy reserves (anabolism). However, if the supply of nutrients becomes scarce, these nutrients can be broken down to produce energy (catabolism). Central to these two metabolic processes is the molecule acetyl-coenzyme A. One way in which the cells of plants, animals and bacteria produce this molecule is a reaction catalysed by the enzyme acetyl-CoA synthetase. This enzyme must be very strictly regulated so that it is not permanently active and acetyl-coenzyme A only forms when it is appropriate for the metabolic state of the cells.
It had been established that acetyl-CoA synthetase from both bacteria and mammals is regulated by a modification. Similar to a light switch, the enzyme can be very specifically switched off by certain reactions and then switched on again. This process has been known for some time in organisms such as plants or mammals. Until now, however, it was not clear how this regulation works mechanistically. In the recently published study, new artificial intelligence (AI) approaches were used to elucidate the regulatory mechanism of the enzyme in detail, down to almost atomic resolution. AlphaFold2 uses AI to perform high quality protein structure predictions. AlphaFold2 was successfully installed at the University of Greifswald's Computer Centre, enabling the elucidation of a completely unknown regulatory mechanism of the enzyme.
“With this study, we were able to elucidate a completely unknown regulatory mechanism of this fundamental enzyme. The results will also be relevant for higher organisms as the regulatory mechanism is strongly conserved in evolutionary terms,” explains Chuan Qin, doctoral candidate and lead author of the study. Prof. Michael Lammers, head of the Synthetic and Structural Biochemistry research group, adds: “It is amazing that even in an organism as well studied as Bacillus subtilis, there is still so much to discover that is also relevant for organisms in other domains of life. This work was only possible thanks to the excellent collaboration between the groups at the Institute of Biochemistry and the University of Greifswald's Computer Centre.”
Further information
Participating groups:
- Prof. Michael Lammers, Institute of Biochemistry
- Prof. Mihaela Delcea, Institute of Biochemistry
- Prof. Uwe Bornscheuer, Institute of Biochemistry
- Dr. Stefan Kemnitz, University Computer Centre
Paper: C. Qin, L. G. Graf, K. Striska, M. Janetzky, N. Geist, R. Specht, S. Schulze, G. J. Palm, B. Girbardt, B. Dörre, L. Berndt, S. Kemnitz, M. Doerr, U. T. Bornscheuer, M. Delcea, M. Lammers, Nature Communications 2024,15, 6002. doi: 0.1038/s41467-024-49952-0
Research Group Synthetic & Structural Biochemistry [de]
Contact at the University of Greifswald
Prof. Dr. Michael Lammers
Institute of Biochemistry
Felix-Hausdorff-Straße 4, 17489 Greifswald
Tel.: +49 3834 420 4356
michael.lammersuni-greifswaldde