Research Articles

Architecture of a Fungal Fatty Acid Synthase at 5 Å Resolution

Simon Jenni,^* Marc Leibundgut,^* Timm Maier, Nenad Ban

All steps of fatty acid synthesis in fungi are catalyzed by the fatty acid synthase, which forms a 2.6-megadalton ₆ß₆ complex. We have determined the molecular architecture of this multienzyme by fitting the structures of homologous enzymes that catalyze the individual steps of the reaction pathway into a 5 angstrom x-ray crystallographic electron density map. The huge assembly contains two separated reaction chambers, each equipped with three sets of active sites separated by distances up to 130 angstroms, across which acyl carrier protein shuttles substrates during the reaction cycle. Regions of the electron density arising from well-defined structural features outside the catalytic domains separate the two reaction chambers and serve as a matrix in which domains carrying the various active sites are embedded. The structure rationalizes the compartmentalization of fatty acid synthesis, and the spatial arrangement of the active sites has specific implications for our understanding of the reaction cycle mechanism and of the architecture of multienzymes in general.

Institute of Molecular Biology and Biophysics, Department of Biology, Swiss Federal Institute of Technology (ETH Zurich), 8093 Zurich, Switzerland.

^* These authors contributed equally to this work.

To whom correspondence should be addressed. E-mail: ban{at}mol.biol.ethz.ch

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The Crystal Structure of a Mammalian Fatty Acid Synthase.

T. Maier, M. Leibundgut, and N. Ban (2008)
Science 321, 1315-1322
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Inhibition of the fungal fatty acid synthase type I multienzyme complex.

P. Johansson, B. Wiltschi, P. Kumari, B. Kessler, C. Vonrhein, J. Vonck, D. Oesterhelt, and M. Grininger (2008)
PNAS 105, 12803-12808
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Crystal Structure of the Termination Module of a Nonribosomal Peptide Synthetase.

A. Tanovic, S. A. Samel, L.-O. Essen, and M. A. Marahiel (2008)
Science 321, 659-663
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Mass Spectrometry-Based Systems Approach for Identification of Inhibitors of Plasmodium falciparum Fatty Acid Synthase.

S. Sharma, S. K. Sharma, R. Modak, K. Karmodiya, N. Surolia, and A. Surolia (2007)
Antimicrob. Agents Chemother. 51, 2552-2558
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Structure of Fungal Fatty Acid Synthase and Implications for Iterative Substrate Shuttling.

S. Jenni, M. Leibundgut, D. Boehringer, C. Frick, B. Mikolasek, and N. Ban (2007)
Science 316, 254-261
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Structural Basis for Substrate Delivery by Acyl Carrier Protein in the Yeast Fatty Acid Synthase.

M. Leibundgut, S. Jenni, C. Frick, and N. Ban (2007)
Science 316, 288-290
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A singular enzymatic megacomplex from Bacillus subtilis.

P. D. Straight, M. A. Fischbach, C. T. Walsh, D. Z. Rudner, and R. Kolter (2007)
PNAS 104, 305-310
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Identification of a starter unit acyl-carrier protein transacylase domain in an iterative type I polyketide synthase.

J. M. Crawford, B. C. R. Dancy, E. A. Hill, D. W. Udwary, and C. A. Townsend (2006)
PNAS 103, 16728-16733
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Conformational switches modulate protein interactions in peptide antibiotic synthetases..

A. Koglin, M. R. Mofid, F. Lohr, B. Schafer, V. V. Rogov, M.-M. Blum, T. Mittag, M. A. Marahiel, F. Bernhard, and V. Dotsch (2006)
Science 312, 273-276
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Architecture of Mammalian Fatty Acid synthase at 4.5 a resolution..

T. Maier, S. Jenni, and N. Ban (2006)
Science 311, 1258-1262
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