Mammalian fatty acid synthase is one of the most complex molecular synthetic machines in human cells. It is also a promising target for the development of anti-cancer and anti-obesity drugs and the treatment of metabolic disorders. Now researchers at ETH Zurich have determined the atomic structure of a mammalian fatty acid synthase. Their results have just been published in Science magazine.
Synthesis of fatty acids is a central cellular process that has been studied for many decades. Fatty acids are used in the cell as energy storage compounds, messenger molecules and building blocks for the cellular envelope. Until now, individual steps of this process have been investigated using isolated bacterial enzymes. However, in higher organisms – except plants – fatty acid synthesis is catalyzed by large multifunctional proteins where many individual enzymes are brought together to form a “molecular assembly line”.
The atomic structure is the result of many years of research
As described in this week’s issue of “Science” magazine, researchers at ETH Zurich, supported by the National Centre of Excellence in Research (NCCR) in Structural Biology at the Swiss National Science Foundation, determined the high-resolution structure of a mammalian fatty acid synthase using data collected at the Swiss Light Source (SLS) of the Paul Scherrer Institute (PSI) in Switzerland.
These results crown the efforts begun in 2001 to determine the detailed structures of fatty acid synthases in higher organisms by a relatively small group of scientists at ETH Zurich. The group, consisting of Timm Maier, Marc Leibundgut and Simon Jenni in the laboratory of Prof. Nenad Ban, published their first papers describing architectures of fungal and mammalian fatty acid synthases two years ago. That was followed last year by two papers on the atomic structures of fungal fatty acid synthases and the mechanism of substrate shuttling and delivery in these multi-enzymes.
Now this latest publication describes the atomic structure of the mammalian fatty acid synthase. These results reveal the details of all catalytic active sites responsible for iterative fatty acid synthesis and show how the flexibility of this large multi-enzyme is used for transferring substrates from one enzymatic active site to the next. The structure can be considered a milestone for future research in the field.
Fatty acid synthases as drug targets?
In addition to the fundamental scientific interest in the function of this multi-enzyme that plays a central role in primary metabolism, mammalian fatty acid synthase is also considered a promising drug target. Although most fat accumulated in animals and humans is delivered to cells by ingestion and not by de novo synthesis, compounds that inhibit the function of the mammalian fatty acid synthase induce weight reduction in animals, showing potential for the treatment of obesity and obesity-related diseases, such as diabetes and coronary disorders. Furthermore, due to the increased requirement for fatty acid synthesis in cancer cells, inhibitors of this enzyme have anti-tumor activity, making fatty acid synthase an attractive drug target for anti-cancer therapy.
Multi-enzymes: the ultimate organic chemists
Mammalian fatty acid synthase belongs to a large family of multi-enzymes, some of which are responsible for the synthesis of complex natural products with antibiotic, anti-cancer, anti-fungal and immunosuppressive properties that are of outstanding medical relevance. The structure of mammalian fatty acid synthase reveals how different catalytic domains are excised or inserted in various members of this family to yield multi-enzymes capable of synthesizing a large variety of chemical products. The structure will facilitate the design of molecular assembly lines for the production of improved compounds. In particular, the engineering of novel multi-enzymes for the production of modified antibiotics is important in the fight against resistant strains of bacteria.Literature reference:
Roman Klingler | alfa
Mass spectrometry sheds new light on thallium poisoning cold case
14.12.2018 | University of Maryland
Protein involved in nematode stress response identified
14.12.2018 | University of Illinois College of Agricultural, Consumer and Environmental Sciences
The more objects we make "smart," from watches to entire buildings, the greater the need for these devices to store and retrieve massive amounts of data quickly without consuming too much power.
Millions of new memory cells could be part of a computer chip and provide that speed and energy savings, thanks to the discovery of a previously unobserved...
What if, instead of turning up the thermostat, you could warm up with high-tech, flexible patches sewn into your clothes - while significantly reducing your...
A widely used diabetes medication combined with an antihypertensive drug specifically inhibits tumor growth – this was discovered by researchers from the University of Basel’s Biozentrum two years ago. In a follow-up study, recently published in “Cell Reports”, the scientists report that this drug cocktail induces cancer cell death by switching off their energy supply.
The widely used anti-diabetes drug metformin not only reduces blood sugar but also has an anti-cancer effect. However, the metformin dose commonly used in the...
A research team from the University of Zurich has developed a new drone that can retract its propeller arms in flight and make itself small to fit through narrow gaps and holes. This is particularly useful when searching for victims of natural disasters.
Inspecting a damaged building after an earthquake or during a fire is exactly the kind of job that human rescuers would like drones to do for them. A flying...
Over the last decade, there has been much excitement about the discovery, recognised by the Nobel Prize in Physics only two years ago, that there are two types...
12.12.2018 | Event News
10.12.2018 | Event News
06.12.2018 | Event News
14.12.2018 | Power and Electrical Engineering
14.12.2018 | Physics and Astronomy
14.12.2018 | Physics and Astronomy