Enigma of fatty acid metabolism solved—enzyme shape controls activity

June 14, 2018, University of Basel
ACC filaments regulate enzyme activity and thus control fatty acid production. Credit: University of Basel, Biozentrum

The core components of all body 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 arise from the same precursor. A single initiates its production: acetyl-CoA-carboxylase (ACC). ACC is therefore the linchpin of fatty acid synthesis and understanding its architecture is critical for treating many diseases.

While the enzyme and its function in metabolism have been known for nearly 60 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 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."

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.

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 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 biosynthesis.

Explore further: Architecture of cellular control center mTORC2 elucidated

More information: Moritz Hunkeler et al, Structural basis for regulation of human acetyl-CoA carboxylase, Nature (2018). DOI: 10.1038/s41586-018-0201-4

Related Stories

Architecture of cellular control center mTORC2 elucidated

February 20, 2018

The protein complex mTORC2 controls cellular lipid and carbohydrate metabolism. Researchers from the Biozentrum of the University of Basel and the ETH Zurich have now succeeded in deciphering the 3-D structure of this important ...

Dicer enzyme cuts down on fats

May 24, 2018

The enzyme Dicer cleaves long precursors into short RNA molecules called microRNAs. A new study reveals how Dicer enhances energy metabolism and reduces levels of fat storage in macrophages, thus slowing the progression of ...

Removing the brakes on plant oil production

April 9, 2018

Scientists studying plant biochemistry at the U.S. Department of Energy's Brookhaven National Laboratory have discovered new details about biomolecules that put the brakes on oil production. The findings suggest that disabling ...

Blood fatty acids reveal your child's diet

March 23, 2017

Eating lots of sugary candy may strain the liver, alter the body's fatty acid metabolism and increase the risk of cardiometabolic diseases already in childhood. Children's blood fatty acid composition reflects their diet ...

Recommended for you

Nanodiamonds as photocatalysts

October 19, 2018

Climate change is in full swing and will continue unabated as long as CO2 emissions continue. One possible solution is to return CO2 to the energy cycle: CO2 could be processed with water into methanol, a fuel that can be ...

Producing defectless metal crystals of unprecedented size

October 19, 2018

A research group at the Center for Multidimensional Carbon Materials, within the Institute for Basic Science (IBS), has published an article in Science describing a new method to convert inexpensive polycrystalline metal ...

Shining light on the separation of rare earth metals

October 18, 2018

Inside smartphones and computer displays are metals known as the rare earths. Mining and purifying these metals involves waste- and energy-intense processes. Better processes are needed. Previous work has shown that specific ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.