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.
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 recently described in the journal Science, 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
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
ETH Zuerich. September 2008.