Fats are essential for our body. The core components of all fats are fatty acids. Their production is initiated by the enzyme ACC. Researchers at the University of Basel’s Biozentrum have now demonstrated how ACC assembles into distinct filaments. As the researchers report in “Nature,” the type of filament formed controls the activity of the enzyme and thus fatty acid production.
Fats are highly diverse molecules that serve as fuel and energy storage, and they constitute the building blocks for cell membranes, hormones and messengers. Despite the diversity of fats, all the fatty acids contained therein arise from the same precursor.
Only a single enzyme initiates its production: acetyl-CoA-carboxylase, ACC for short. ACC is therefore the linchpin of fatty acid synthesis and understanding the architecture of ACC is critical for treating many diseases.
While the enzyme and its function in metabolism have been known for nearly sixty years, scientists have understood very little about the structure of ACC. In fact, modern biochemistry textbooks continue to show old and blurry pictures of filaments formed by ACC, leaving the how and why of filament formation an enigma. Now, a team of researchers led by Prof. Timm Maier from the Biozentrum of the University of Basel has sharpened the picture.
“We have solved this long-standing puzzle in metabolism,” reports Maier. “Elucidating the detailed architectures of ACC filaments revealed their impact on enzymatic activity.”
Pacemaker of fatty acid synthesis
ACC is a key regulator of metabolism and the pacemaker enzyme of fatty acid production. Hence, the regulation of ACC activity is highly complex. Only about half of the ACC enzyme catalyzes chemical reactions while the other half is responsible for controlling ACC activity, acting as a sensor for the demand for ACC products and serving as on-off switch of the enzyme.
Shape of ACC determines its activity
ACC activity is not always the same. Depending on its shape, the activity is high or low. Metabolites signaling an excess of carbohydrates drive the enzyme into its active state. “Dozens of ACC enzymes are linked to form a single filament,” says Maier.
“In this filament, the enzymatic domains are stably arranged to functionally interact with each other. Only then can ACC efficiently catalyze chemical reactions and stimulate fatty acid production. When ACC is not integrated into a filament, the enzymatic domains are flexibly linked and do not collaborate productively.” ACC can also be switched off by filament formation.
Specific control factors force ACC to form inactive filaments, in which the enzymatic domains are strictly separated. This versatile mode of regulation by changing the overall shape of the enzyme is unique and was previously unknown.
ACC as a target structure for drug development
Due to its crucial role in metabolism, ACC is an important target for drug development. Inhibiting ACC activity has the potential to combat cancers or certain viral infections because rapidly proliferating tumor cells and membrane-enveloped viruses require a particularly large amount of fatty acids as membrane components. ACC may also serve as a target for controlling risk factors for developing cardiovascular disease and diabetes linked to aberrant lipid and carbohydrate metabolism, summarized as “metabolic syndrome.” This study opens new possibilities for the development of selective ACC inhibitors that interfere with the activation and filament formation of ACC and ultimately limit fatty acid biosynthesis.
Moritz Hunkeler, Anna Hagmann, Edward Stuttfeld, Mohamed Chami, Yakir Guri, Henning Stahlberg, Timm Maier
Structural basis for regulation of human acetyl-CoA carboxylase
Nature (2018), doi: 10.1038/s41586-018-0201-4
Prof. Dr. Timm Maier, University of Basel, Biozentrum, tel. +41 61 207 21 76, email: email@example.com
Dr. Katrin Bühler, University of Basel, Communications Biozentrum, tel. +41 61 207 09 74, email: firstname.lastname@example.org
Dr. Katrin Bühler | Universität Basel
Colorectal cancer risk factors decrypted
13.07.2018 | Max-Planck-Institut für Stoffwechselforschung
Algae Have Land Genes
13.07.2018 | Julius-Maximilians-Universität Würzburg
For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.
To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...
For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.
Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...
Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.
A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...
Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.
"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....
Ultra-short, high-intensity X-ray flashes open the door to the foundations of chemical reactions. Free-electron lasers generate these kinds of pulses, but there is a catch: the pulses vary in duration and energy. An international research team has now presented a solution: Using a ring of 16 detectors and a circularly polarized laser beam, they can determine both factors with attosecond accuracy.
Free-electron lasers (FELs) generate extremely short and intense X-ray flashes. Researchers can use these flashes to resolve structures with diameters on the...
13.07.2018 | Event News
12.07.2018 | Event News
03.07.2018 | Event News
13.07.2018 | Event News
13.07.2018 | Materials Sciences
13.07.2018 | Life Sciences