Fatty Acid Synthesis

Introduction

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 and as messenger molecules. Previously, individual steps of this process have been studied on isolated bacterial enzymes. However, in higher organisms, fatty acid synthesis is catalyzed by large multifunctional proteins where many individual enzymes are brought together to form a “molecular assembly line”. Our recent work focused on studying the architecture of two representative classes of fatty acid synthases in higher organisms. The fungal and mammalian systems reveal two different architectural solutions that allow these giant multi-enzymes to hand over the products of one enzymatic active site to the next.
As a culmination of many years of research in our group we have determined the high resolution structure of the fungal FAS particle, a huge 2.6 MDa molecular assembly. The atomic structure reveals that the flexible acyl carrier domain (ACP) is double anchored at opposite sides of the reaction chamber with implications on its range of motion (Jenni et al. 2007). Furthermore, we have been able to visualize this flexible domain stalled at the synthetic stage of the reaction cycle (Leibundgut et al. 2007). These results allow us to propose a plausible mechanistic model for substrate channeling, which involves circular precession of the ACP domain coupled with substrate delivery by a switchblade-like motion of the prosthetic group.
Mammalian fatty acid synthase (FAS) is a remarkably complex enzyme that carries seven functional domains on a single polypeptide chain of approximately 2500 amino acids and forms a 540,000 Da α_2 dimer. The essential FAS has a central role in the primary metabolism of mammalian cells and is considered a promising drug target for the treatment of obesity and obesity-related diseases as well as cancer.

Following our initial interpretation of the mammalian FAS at medium resolution, which revealed the spatial arrangement of the active sites that form two semicircular reaction chambers, we recently determined an atomic structure of this molecule (Maier et al, 2008). The structure simultaneously provides high-resolution information on five catalytic and two non-enzymatic domains, none of which were visualized before even in isolation, and reveals the topology of its linkers and inserted functional domains. Remarkably, one of the additional domains, a pseudo-methylase, reveals that mammalian FAS very likely originated from ancestral bacterial polyketide synthases, enzymes that produce a vast variety of structurally diverse natural compounds. Consequently, mammalian FAS can be considered as a specialized iterative polyketide synthase, which retained all the structural features that allow efficient insertions and excisions of various enzymatic domains in related polyketide synthases.

Research Articles Fungal FAS

• Leibundgut M, Jenni S, Frick C, Ban N. (2007)
  Structural Basis for Substrate Delivery by Acyl Carrier Protein in the Yeast Fatty Acid Synthase.
  Science 316(5822):288-290 Pubmed
• Jenni S, Leibundgut M, Boehringer D, Frick C, Mikolásek B, Ban N. (2007)
  Structure of Fungal Fatty Acid Synthase and Implications for Iterative Substrate Shuttling.
  Science 316:(5822):254-261. Pubmed
• Jenni S, Leibundgut M, Maier T and Ban N. (2006)
  Architecture of a fungal fatty acid synthase at 5 Å resolution.
  Science 311(5765):1263-7 Pubmed Comment Comment

Research Articles Mammalian FAS

• Maier T, Leibundgut M, and Ban N (2008)
  The Crystal Structure of a Mammalian Fatty Acid Synthase.
  Science 321(5894):1315-22 Pubmed Comment
• Maier T, Jenni S, and Ban N. (2006)
  Architecture of mammalian fatty acid synthase at 4.5 Å resolution.
  Science 311(5765):1258-62 Pubmed Comment Comment

Reviews and Comments

• Leibundgut M, Maier T, Jenni S, Ban N. (2008)
  The multienzyme architecture of eukaryotic fatty acid synthases.
  Curr Opin Struct Biol. 18(6):714-25 Pubmed
  Science 316(5822):288-290 Pubmed
• Editors comment (2007)
  This week in Science
  Science 316(5822) read comment
• Science & Technology Concentrates (2007)
  Sharper image of fatty acid synthase
  Chemical and Engineering News. 85(16): 40. read comment
• Chemistry World News (2007)
  Fatty acid factory revealed
  Chemistry World. 12.04.2007 read comment
• Cronan J.E. (2006)
  Remarkable structural variation within fatty acid megasynthases.
  Nat Chem Biol. 2(5): 232-4. PubMed
  
• Arnaud C.H. (2006)
  Supersize Enzymes Come Into Focus
  Chemical and Engineering News. 84(11): 34-35. read comment
  
• Townsend CA, Crawford JM, Bililign T. (2006)
  New images evoke FAScinating questions.
  Chem Biol. 13(4): 349-51. Pubmed
• Smith S. (2006)
  Structural biology. Architectural options for a fatty acid synthase.
  Science. 311(5765): 1251-2. Pubmed

Movies

Overall architecture of the heterododecameric 2.6MDa fungal fatty acid synthase (FAS) complex

The movie shows the overall architecture of the heterododecameric 2.6MDa fungal fatty acid synthase (FAS) complex. The alpha chains (red and blue) form the hexameric central wheel of the barrel-shaped particle and the central and peripheral anchors for the double-tethered acyl carrier protein (ACP) domains (indicated schematically in cyan). The ACPs shuttle the covalently linked fatty acid reaction intermediates between the different catalytic sites. Two beta chain trimers (yellow, magenta and green) are located on both sides of the central wheel and form the domes of both reaction chambers. For downloading a high-resolution version of this movie in avi format (~ 270 MBytes), you can click the following link. © Marc Leibundgut