Hostname: page-component-cd9895bd7-fscjk Total loading time: 0 Render date: 2024-12-27T14:37:25.034Z Has data issue: false hasContentIssue false
  • English
  • Français

Structure and function of eukaryotic fatty acid synthases

Published online by Cambridge University Press:  24 August 2010

Timm Maier ,
Marc Leibundgut ,
Daniel Boehringer  and
Nenad Ban
Timm Maier
Affiliation:
Institute of Molecular Biology and Biophysics, ETH Zurich, 8093 Zurich, Switzerland
Marc Leibundgut
Affiliation:
Institute of Molecular Biology and Biophysics, ETH Zurich, 8093 Zurich, Switzerland
Daniel Boehringer
Affiliation:
Institute of Molecular Biology and Biophysics, ETH Zurich, 8093 Zurich, Switzerland
Nenad Ban*
Affiliation:
Institute of Molecular Biology and Biophysics, ETH Zurich, 8093 Zurich, Switzerland
*
*Author for correspondence: Nenad Ban, Institute of Molecular Biology and Biophysics, ETH Zurich, 8093 Zurich, Switzerland. Tel.: +4144 6332785; Fax: +41 44 6331246; Email: ban@mol.biol.ethz.ch
Get access Rights & Permissions [Opens in a new window]

Abstract

In all organisms, fatty acid synthesis is achieved in variations of a common cyclic reaction pathway by stepwise, iterative elongation of precursors with two-carbon extender units. In bacteria, all individual reaction steps are carried out by monofunctional dissociated enzymes, whereas in eukaryotes the fatty acid synthases (FASs) have evolved into large multifunctional enzymes that integrate the whole process of fatty acid synthesis. During the last few years, important advances in understanding the structural and functional organization of eukaryotic FASs have been made through a combination of biochemical, electron microscopic and X-ray crystallographic approaches. They have revealed the strikingly different architectures of the two distinct types of eukaryotic FASs, the fungal and the animal enzyme system. Fungal FAS is a 2·6 MDa α6β6 heterododecamer with a barrel shape enclosing two large chambers, each containing three sets of active sites separated by a central wheel-like structure. It represents a highly specialized micro-compartment strictly optimized for the production of saturated fatty acids. In contrast, the animal FAS is a 540 kDa X-shaped homodimer with two lateral reaction clefts characterized by a modular domain architecture and large extent of conformational flexibility that appears to contribute to catalytic efficiency.

Type
Review Article
Information
Quarterly Reviews of Biophysics , Volume 43 , Issue 3 , August 2010 , pp. 373 - 422
Copyright
Copyright © Cambridge University Press 2010

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

7. References

Abrahams, J. P. & Ban, N. (2003). X-ray crystallographic structure determination of large asymmetric macromolecular assemblies. Methods in Enzymology 374, 163–188.Google Scholar
Abrahams, J. P. & Leslie, A. G. (1996). Methods used in the structure determination of bovine mitochondrial F1 ATPase. Acta Crystallographica. Section D, Biological Crystallography 52, 30–42.CrossRefGoogle ScholarPubMed
Amy, C. M., Witkowski, A., Naggert, J., Williams, B., Randhawa, Z. & Smith, S. (1989). Molecular cloning and sequencing of cDNAs encoding the entire rat fatty acid synthase. Proceedings of the National Academy of Sciences of the United States of America 86, 3114–3118.Google Scholar
Arslanian, M. J. & Wakil, S. J. (1975). Fatty acid synthase from chicken liver. Methods in Enzymology 35, 59–65.Google Scholar
Asturias, F. J., Chadick, J. Z., Cheung, I. K., Stark, H., Witkowski, A., Joshi, A. K. & Smith, S. (2005). Structure and molecular organization of mammalian fatty acid synthase. Nature Structural and Molecular Biology 12, 225–232.Google Scholar
Brady, R. O. (1958). The enzymatic synthesis of fatty acids by aldol condensation. Proceedings of the National Academy of Sciences of the United States of America 44, 993–998.Google Scholar
Brady, R. O. (1960). Biosynthesis of fatty acids 2. Studies with enzymes obtained from brain. Journal of Biological Chemistry 235, 3099–3103.Google Scholar
Brady, R. O., Bradley, R. M. & Trams, E. G. (1960). Biosynthesis of fatty acids 1. Studies with enzymes obtained from liver. Journal of Biological Chemistry 235, 3093–3098.Google Scholar
Brady, R. O. & Gurin, S. (1952). Biosynthesis of fatty acids by cell-free or water-soluble enzyme systems. Journal of Biological Chemistry 199, 421–431.Google Scholar
Brignole, E. J., Smith, S. & Asturias, F. J. (2009). Conformational flexibility of metazoan fatty acid synthase enables catalysis. Nature Structural and Molecular Biology 16, 190–197.Google Scholar
Brindley, D. N., Matsumur, S. & Bloch, K. (1969). Mycobacterium phlei fatty acid synthetase – a bacterial multienzyme complex. Nature 224, 666–669.Google Scholar
Brink, J., Ludtke, S. J., Kong, Y., Wakil, S. J., Ma, J. & Chiu, W. (2004). Experimental verification of conformational variation of human fatty acid synthase as predicted by normal mode analysis. Structure 12, 185–191.Google Scholar
Brink, J., Ludtke, S. J., Yang, C. Y., Gu, Z. W., Wakil, S. J. & Chiu, W. (2002). Quaternary structure of human fatty acid synthase by electron cryomicroscopy. Proceedings of the National Academy of Sciences of the United States of America 99, 138–143.Google Scholar
Brown, D. W., Adams, T. H. & Keller, N. P. (1996). Aspergillus has distinct fatty acid synthases for primary and secondary metabolism. Proceedings of the National Academy of Sciences of the United States of America 93, 14873–14877.Google Scholar
Bunkoczi, G., Misquitta, S., Wu, X. Q., Lee, W. H., Rojkova, A., Kochan, G., Kavanagh, K. L., Oppermann, U. & Smith, S. (2009). Structural basis for different specificities of acyltransferases associated with the human cytosolic and mitochondrial fatty acid synthases. Chemistry and Biology 16, 667–675.Google Scholar
Bunkoczi, G., Pasta, S., Joshi, A., Wu, X., Kavanagh, K. L., Smith, S. & Oppermann, U. (2007). Mechanism and substrate recognition of human holo ACP synthase. Chemistry and Biology 14, 1243–1253.Google Scholar
Chakravarty, B., Gu, Z., Chirala, S. S., Wakil, S. J. & Quiocho, F. A. (2004). Human fatty acid synthase: structure and substrate selectivity of the thioesterase domain. Proceedings of the National Academy of Sciences of the United States of America 101, 15567–15572.Google Scholar
Chinte, U., Shah, B., Chen, Y. S., Pinkerton, A. A., Schall, C. A. & Hanson, B. L. (2007). Cryogenic (<20 K) helium cooling mitigates radiation damage to protein crystals. Acta Crystallographica. Section D Biological Crystallography 63, 486–492.Google Scholar
Chirala, S. S., Huang, W. Y., Jayakumar, A., Sakai, K. & Wakil, S. J. (1997). Animal fatty acid synthase: functional mapping and cloning and expression of the domain I constituent activities. Proceedings of the National Academy of Sciences of the United States of America 94, 5588–5593.Google Scholar
Chirala, S. S., Jayakumar, A., Gu, Z. W. & Wakil, S. J. (2001). Human fatty acid synthase: role of interdomain in the formation of catalytically active synthase dimer. Proceedings of the National Academy of Sciences of the United States of America 98, 3104–3108.Google Scholar
Chirala, S. S. & Wakil, S. J. (2004). Structure and function of animal fatty acid synthase. Lipids 39, 1045–1053.Google Scholar
Chopra, S., Singh, S. K., Sati, S. P., Ranganathan, A. & Sharma, A. (2002). Expression, purification, crystallization and preliminary X-ray analysis of the acyl carrier protein synthase (acpS) from Mycobacterium tuberculosis. Acta Crystallographica. Section D, Biological Crystallography 58, 179–181.Google Scholar
Cowtan, K. (1994). Joint CCP4 and ESF-EACBM Newsletter on protein. Crystallography 31, 34–38.Google Scholar
Cowtan, K. (2002). Generic representation and evaluation of properties as a function of position in reciprocal space. Journal of Applied Crystallography 35, 655–663.Google Scholar
Crawford, J. M., Vagstad, A. L., Ehrlich, K. C., Udwary, D. W. & Townsend, C. A. (2008). Acyl-carrier protein-phosphopantetheinyltransferase partnerships in fungal fatty acid synthases. Chembiochem 9, 1559–1563.Google Scholar
Dauter, Z. (1999). Data-collection strategies. Acta Crystallographica. Section D, Biological Crystallography 55, 1703–1717.Google Scholar
Dauter, Z. (2005). Use of polynuclear metal clusters in protein crystallography. Comptes Rendus Chimie 8, 1808–1814.Google Scholar
Dils, R. & Carey, E. M. (1975). Fatty acid synthase from rabbit mammary gland. Methods in Enzymology 35, 74–83.Google Scholar
Dym, O., Albeck, S., Peleg, Y., Schwarz, A., Shakked, Z., Burstein, Y. & Zimhony, O. (2009). Structure-function analysis of the acyl carrier protein synthase (AcpS) from Mycobacterium tuberculosis. Journal of Molecular Biology 393, 937–950.Google Scholar
Edwards, D. J., Marquez, B. L., Nogle, L. M., McPhail, K., Goeger, D. E., Roberts, M. A. & Gerwick, W. H. (2004). Structure and biosynthesis of the jamaicamides, new mixed polyketide-peptide neurotoxins from the marine cyanobacterium Lyngbya majuscula. Chemistry and Biology 11, 817–833.Google Scholar
Engeser, H., Hubner, K., Straub, J. & Lynen, F. (1979). Identity of malonyl and palmitoyl transferase of fatty acid synthetase from yeast. 2. A comparison of active-site peptides. European Journal of Biochemistry 101, 413–422.Google Scholar
Fichtlscherer, F., Wellein, C., Mittag, M. & Schweizer, E. (2000). A novel function of yeast fatty acid synthase. Subunit alpha is capable of self-pantetheinylation. European Journal of Biochemistry 267, 2666–2671.Google Scholar
Fujii, I., Yoshida, N., Shimomaki, S., Oikawa, H. & Ebizuka, Y. (2005). An iterative type I polyketide synthase PKSN catalyzes synthesis of the decaketide alternapyrone with regio-specific octa-methylation. Chemistry and Biology 12, 1301–1309.Google Scholar
Green, D. E. & Oda, T. (1961). On unit of mitochondrial structure and function. Journal of Biochemistry 49, 742–757.Google Scholar
Ha, J. Y., Min, J. Y., Lee, S. K., Kim, H. S., Kim Do, J., Kim, K. H., Lee, H. H., Kim, H. K., Yoon, H. J. & Suh, S. W. (2006). Crystal structure of 2-nitropropane dioxygenase complexed with FMN and substrate. Identification of the catalytic base. Journal of Biological Chemistry 281, 18660–18667.Google Scholar
Hackenjos, W. A. & Schramm, H. J. (1987). Electron microscopical structure analysis of yeast fatty-acid synthase at low resolution. Biological Chemistry Hoppe-Seyler 368, 19–36.Google Scholar
Hoppe, W., Gassmann, J., Hunsmann, N., Schramm, H. J. & Sturm, M. (1974). Three-dimensional reconstruction of individual negatively stained yeast fatty-acid synthetase molecules from tilt series in the electron microscope. Hoppe Seylers Zeitschrift für Physiologische Chemie 355, 1483–1487.Google Scholar
Hoppe, W., Schramm, H. J., Sturm, M., Hunsmann, N. & Gassmann, J. (1976). 3-dimensional electron-microscopy of individual biological objects 3. Experimental results on yeast fatty-acid synthetase. Zeitschrift Fur Naturforschung Section a-a Journal of Physical Sciences 31, 1380–1390.Google Scholar
Huang, W. Y., Chirala, S. S. & Wakil, S. J. (1994). Amino-terminal blocking group and sequence of the animal fatty acid synthase. Archives of Biochemistry and Biophysics 314, 45–49.Google Scholar
Jayakumar, A., Huang, W. Y., Raetz, B., Chirala, S. S. & Wakil, S. J. (1996). Cloning and expression of the multifunctional human fatty acid synthase and its subdomains in Escherichia coli. Proceedings of the National Academy of Sciences of the United States of America 93, 14509–14514.Google Scholar
Jenik, R. A. & Porter, J. W. (1981). Fatty acid synthase from red blood cells. Methods in Enzymology 71, 97–103.Google Scholar
Jenni, S. & Ban, N. (2009). Imperfect pseudo-merohedral twinning in crystals of fungal fatty acid synthase. Acta Crystallographica. Section D, Biological Crystallography 65, 101–111.Google Scholar
Jenni, S., Leibundgut, M., Boehringer, D., Frick, C., Mikolasek, B. & Ban, N. (2007). Structure of fungal fatty acid synthase and implications for iterative substrate shuttling. Science 316, 254–261.Google Scholar
Jenni, S., Leibundgut, M., Maier, T. & Ban, N. (2006). Architecture of a fungal fatty acid synthase at 5 A resolution. Science 311, 1263–1267.Google Scholar
Johansson, P., Mulinacci, B., Koestler, C., Vollrath, R., Oesterhelt, D. & Grininger, M. (2009). Multimeric options for the auto-activation of the Saccharomyces cerevisiae FAS type I megasynthase. Structure 17, 1063–1074.Google Scholar
Johansson, P., Wiltschi, B., Kumari, P., Kessler, B., Vonrhein, C., Vonck, J., Oesterhelt, D. & Grininger, M. (2008). Inhibition of the fungal fatty acid synthase type I multienzyme complex. Proceedings of the National Academy of Sciences of the United States of America 105, 12803–12808.CrossRefGoogle ScholarPubMed
Joshi, A. K., Rangan, V. S., Witkowski, A. & Smith, S. (2003). Engineering of an active animal fatty acid synthase dimer with only one competent subunit. Chemistry and Biology 10, 169–173.Google Scholar
Joshi, A. K. & Smith, S. (1993a). Construction of a cDNA encoding the multifunctional animal fatty acid synthase and expression in Spodoptera frugiperda cells using baculoviral vectors. Biochemical Journal 296, 143–149.Google Scholar
Joshi, A. K. & Smith, S. (1993b). Construction, expression, and characterization of a mutated animal fatty acid synthase deficient in the dehydrase function. Journal of Biological Chemistry 268, 22508–22513.Google Scholar
Joshi, A. K., Witkowski, A., Berman, H. A., Zhang, L. & Smith, S. (2005). Effect of modification of the length and flexibility of the acyl carrier protein-thioesterase interdomain linker on functionality of the animal fatty acid synthase. Biochemistry 44, 4100–4107.Google Scholar
Kawaguchi, A., Tomoda, H., Okuda, S. & Omura, S. (1981). Fatty acid synthase from Cephalosporium caerulens. Methods in Enzymology 71, 117–120.Google Scholar
Kim, I. C., Neudahl, G. & Deal, W. C. Jr (1981). Fatty acid synthase from pig liver. Methods in Enzymology 71, 79–85.Google Scholar
Kimber, M. S., Martin, F., Lu, Y., Houston, S., Vedadi, M., Dharamsi, A., Fiebig, K. M., Schmid, M. & Rock, C. O. (2004). The structure of (3R)-hydroxyacyl-acyl carrier protein dehydratase (FabZ) from Pseudomonas aeruginosa. Journal of Biological Chemistry 279, 52593–52602.Google Scholar
Kitamoto, T., Nishigai, M., Sasaki, T. & Ikai, A. (1988). Structure of fatty acid synthetase from the Harderian gland of guinea pig. Proteolytic dissection and electron microscopic studies. Journal of Molecular Biology 203, 183–195.Google Scholar
Klein, H. P. & Lipmann, F. (1953a). The relationship of coenzyme A to lipide synthesis. I. Experiments with yeast. Journal of Biological Chemistry 203, 95–99.Google Scholar
Klein, H. P. & Lipmann, F. (1953b). The relationship of coenzyme A to lipide synthesis. II. Experiments with rat liver. Journal of Biological Chemistry 203, 101–108.Google Scholar
Knowles, J. R. (1989). The mechanism of biotin-dependent enzymes. Annual Review of Biochemistry 58, 195–221.Google Scholar
Koglin, A., Mofid, M. R., Lohr, F., Schafer, B., Rogov, V. V., Blum, M. M., Mittag, T., Marahiel, M. A., Bernhard, F. & Dotsch, V. (2006). Conformational switches modulate protein interactions in peptide antibiotic synthetases. Science 312, 273–276.Google Scholar
Kolattukudy, P. E., Poulose, A. J. & Buckner, J. S. (1981). Fatty acid synthase from the uropygial gland of goose. Methods in Enzymology 71, 103–109.Google Scholar
Kolodziej, S. J., Penczek, P. A. & Stoops, J. K. (1997). Utility of Butvar support film and methylamine tungstate stain in three-dimensional electron microscopy: agreement between stain and frozen-hydrated reconstructions. Journal of Structural Biology 120, 158–167.Google Scholar
Koski, K. M., Haapalainen, A. M., Hiltunen, J. K. & Glumoff, T. (2005). Crystal structure of 2-enoyl-CoA hydratase 2 from human peroxisomal multifunctional enzyme type 2. Journal of Molecular Biology 345, 1157–1169.Google Scholar
Koski, M. K., Haapalainen, A. M., Hiltunen, J. K. & Glumoff, T. (2004). A two-domain structure of one subunit explains unique features of eukaryotic hydratase 2. Journal of Biological Chemistry 279, 24666–24672.Google Scholar
Kresze, G. B., Oesterhelt, D., Lynen, F., Castorph, H. & Schweizer, E. (1976). Localization of the central and peripheral SH-groups on the same polypeptide chain of yeast fatty acid synthetase. Biochemical and Biophysical Research Communications 69, 893–899.Google Scholar
Kumar, S. & Dodds, P. F. (1981). Fatty acid synthase from lactating bovine mammary gland. Methods in Enzymology 71, 86–97.Google Scholar
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, 288–290.Google Scholar
Leschziner, A. E. & Nogales, E. (2007). Visualizing flexibility at molecular resolution: analysis of heterogeneity in single-particle electron microscopy reconstructions. Annual Review of Biophysics and Biomolecular Structure 36, 43–62.Google Scholar
Lin, C. Y. & Smith, S. (1978). Properties of the thioesterase component obtained by limited trypsinization of the fatty acid synthetase multienzyme complex. Journal of Biological Chemistry 253, 1954–1962.Google Scholar
Linn, T. C. (1981). Purification and crystallization of rat liver fatty acid synthetase. Archives of Biochemistry and Biophysics 209, 613–619.Google Scholar
Lomakin, I. B., Xiong, Y. & Steitz, T. A. (2007). The crystal structure of yeast fatty acid synthase, a cellular machine with eight active sites working together. Cell 129, 319–332.CrossRefGoogle ScholarPubMed
Lynen, F. (1953). Functional group of coenzyme A and its metabolic relations, especially in the fatty acid cycle. Federation Proceedings 12, 683–691.Google Scholar
Lynen, F. (1961). Biosynthesis of saturated fatty acids. Federation Proceedings 20, 941–951.Google Scholar
Lynen, F. (1964). The pathway from ‘activated acetic acid’ to the terpenes and fatty acids. In Nobel Lectures, Physiology or Medicine 1963–1970. Amsterdam: Elsevier.Google Scholar
Lynen, F. (1967). Role of biotin-dependent carboxylations in biosynthetic reactions – 3rd Jubilee Lecture. Biochemical Journal 102, 381–400.Google Scholar
Lynen, F. (1980). On the structure of fatty acid synthetase of yeast. European Journal of Biochemistry 112, 431–442.Google Scholar
Mahler, H. R. (1953). Role of coenzyme A in fatty acid metabolism. Federation Proceedings 12, 694–702.Google Scholar
Maier, T., Jenni, S. & Ban, N. (2006). Architecture of mammalian fatty acid synthase at 4·5 Å resolution. Science 311, 1258–1262.Google Scholar
Maier, T., Leibundgut, M. & Ban, N. (2008). The crystal structure of a mammalian fatty acid synthase. Science 321, 1315–1322.Google Scholar
Majerus, P. W., Alberts, A. W. & Vagelos, P. R. (1965). Acyl carrier protein. IV. The Identification of 4′-phosphopantetheine as the prosthetic group of the acyl carrier protein. Proceedings of the National Academy of Sciences of the United States of America 53, 410–417.Google Scholar
Martin, D. B., Horning, M. G. & Vagelos, P. R. (1961). Fatty acid synthesis in adipose tissue. I. Purification and properties of a long chain fatty acid-synthesizing system. Journal of Biological Chemistry 236, 663–668.Google Scholar
Martin, J. L. & Mcmillan, F. M. (2002). SAM (dependent) I AM: the S-adenosylmethionine-dependent methyltransferase fold. Current Opinion in Structural Biology 12, 783–793.Google Scholar
Mattick, J. S., Zehner, Z. E., Calabro, M. A. & Wakil, S. J. (1981). The isolation and characterization of fatty-acid-synthetase messenger-RNA from rat mammary-gland. European Journal of Biochemistry 114, 643–651.Google Scholar
Meents, A., Wagner, A., Schneider, R., Pradervand, C., Pohl, E. & Schulze-Briese, C. (2007). Reduction of X-ray-induced radiation damage of macromolecular crystals by data collection at 15 K: a systematic study. Acta Crystallographica. Section D, Biological Crystallography 63, 302–309.Google Scholar
Mohamed, A. H., Chirala, S. S., Mody, N. H., Huang, W. Y. & Wakil, S. J. (1988). Primary structure of the multifunctional alpha subunit protein of yeast fatty acid synthase derived from FAS2 gene sequence. Journal of Biological Chemistry 263, 12315–12325.Google Scholar
Molnar, I., Schupp, T., Ono, M., Zirkle, R., Milnamow, M., Nowak-Thompson, B., Engel, N., Toupet, C., Stratmann, A., Cyr, D. D., Gorlach, J., Mayo, J. M., Hu, A., Goff, S., Schmid, J. & Ligon, J. M. (2000). The biosynthetic gene cluster for the microtubule-stabilizing agents epothilones A and B from Sorangium cellulosum So ce90. Chemistry and Biology 7, 97–109.Google Scholar
Mueller, M., Jenni, S. & Ban, N. (2007). Strategies for crystallization and structure determination of very large macromolecular assemblies. Current Opinion in Structural Biology 17, 572–579.Google Scholar
Muesing, R. A. & Porter, J. W. (1975). Fatty acid synthase from pigeon liver. Methods in Enzymology 35, 45–59.Google Scholar
Nordling, E., Jornvall, H. & Persson, B. (2002). Medium-chain dehydrogenases/reductases (MDR). Family characterizations including genome comparisons and active site modeling. European Journal of Biochemistry 269, 4267–4276.Google Scholar
Oefner, C., Schulz, H., D'Arcy, A. & Dale, G. E. (2006). Mapping the active site of Escherichia coli malonyl-CoA-acyl carrier protein transacylase (FabD) by protein crystallography. Acta Crystallographica. Section D, Biological Crystallography 62, 613–618.Google Scholar
Oesterhelt, D., Bauer, H. & Lynen, F. (1969). Crystallization of a multienzyme complex: fatty acid synthetase from yeast. Proceedings of the National Academy of Sciences of the United States of America 63, 1377–1382.Google Scholar
Olsen, J. G., Kadziola, A., Von Wettstein-Knowles, P., Siggaard-Andersen, M. & Larsen, S. (2001). Structures of beta-ketoacyl-acyl carrier protein synthase I complexed with fatty acids elucidate its catalytic machinery. Structure 9, 233–243.Google Scholar
Parris, K. D., Lin, L., Tam, A., Mathew, R., Hixon, J., Stahl, M., Fritz, C. C., Seehra, J. & Somers, W. S. (2000). Crystal structures of substrate binding to Bacillus subtilis holo-(acyl carrier protein) synthase reveal a novel trimeric arrangement of molecules resulting in three active sites. Structure 8, 883–895.Google Scholar
Pemble, C. W. T., Johnson, L. C., Kridel, S. J. & Lowther, W. T. (2007). Crystal structure of the thioesterase domain of human fatty acid synthase inhibited by Orlistat. Nature Structural and Molecular Biology 14, 704–709.Google Scholar
Penczek, P., Radermacher, M. & Frank, J. (1992). Three-dimensional reconstruction of single particles embedded in ice. Ultramicroscopy 40, 33–53.CrossRefGoogle ScholarPubMed
Perham, R. N. (1991). Domains, motifs, and linkers in 2-oxo acid dehydrogenase multienzyme complexes: a paradigm in the design of a multifunctional protein. Biochemistry 30, 8501–8512.Google Scholar
Perham, R. N. (2000). Swinging arms and swinging domains in multifunctional enzymes: catalytic machines for multistep reactions. Annual Review of Biochemistry 69, 961–1004.Google Scholar
Persson, B., Kallberg, Y., Oppermann, U. & Jornvall, H. (2003). Coenzyme-based functional assignments of short-chain dehydrogenases/reductases (SDRs). Chemico-Biological Interactions 143–144, 271–278.Google Scholar
Pilz, I., Herbst, M., Kratky, O., Oesterhelt, D. & Lynen, F. (1970). Small-angle x-ray scattering study of fatty acid synthetase from yeast. European Journal of Biochemistry 13, 55–64.Google Scholar
Pirson, W., Schuhmann, L. & Lynen, F. (1973). The specificity of yeast fatty-acid synthetase with respect to the “priming” substrate. Decanoyl-coA and derivatives as “primers” of fatty-acid synthesis in vitro. European Journal of Biochemistry 36, 16–24.Google Scholar
Ploskon, E., Arthur, C. J., Evans, S. E., Williams, C., Crosby, J., Simpson, T. J. & Crump, M. P. (2008). A mammalian type I fatty acid synthase acyl carrier protein domain does not sequester acyl chains. Journal of Biological Chemistry 283, 518–528.Google Scholar
Price, A. C., Zhang, Y. M., Rock, C. O. & White, S. W. (2001). Structure of beta-ketoacyl-[acyl carrier protein] reductase from Escherichia coli: negative cooperativity and its structural basis. Biochemistry 40, 12772–12781.Google Scholar
Price, A. C., Zhang, Y. M., Rock, C. O. & White, S. W. (2004). Cofactor-induced conformational rearrangements establish a catalytically competent active site and a proton relay conduit in FabG. Structure 12, 417–428.Google Scholar
Pugh, E. L. & Wakil, S. J. (1965). Studies on mechanism of fatty acid synthesis 14. Prosthetic group of acyl carrier protein and mode of its attachment to protein. Journal of Biological Chemistry 240, 4727–4733.Google Scholar
Radermacher, M., Wagenknecht, T., Verschoor, A. & Frank, J. (1987). Three-dimensional reconstruction from a single-exposure, random conical tilt series applied to the 50S ribosomal subunit of Escherichia coli. Journal of Microscopy 146, 113–136.Google Scholar
Radford, S. E., Laue, E. D., Perham, R. N., Martin, S. R. & Appella, E. (1989). Conformational flexibility and folding of synthetic peptides representing an interdomain segment of polypeptide chain in the pyruvate dehydrogenase multienzyme complex of Escherichia coli. Journal of Biological Chemistry 264, 767–775.Google Scholar
Rafi, S., Novichenok, P., Kolappan, S., Zhang, X., Stratton, C. F., Rawat, R., Kisker, C., Simmerling, C. & Tonge, P. J. (2006). Structure of acyl carrier protein bound to FabI, the FASII enoyl reductase from Escherichia coli. Journal of Biological Chemistry 281, 39285–39293.Google Scholar
Rangan, V. S., Joshi, A. K. & Smith, S. (2001). Mapping the functional topology of the animal fatty acid synthase by mutant complementation in vitro. Biochemistry 40, 10792–10799.Google Scholar
Rangan, V. S. & Smith, S. (1997). Alteration of the substrate specificity of the malonyl-CoA/acetyl-CoA:acyl carrier protein S-acyltransferase domain of the multifunctional fatty acid synthase by mutation of a single arginine residue. Journal of Biological Chemistry 272, 11975–11978.Google Scholar
Rittenberg, D. & Bloch, K. (1944). The utilization of acetic acid for fatty acid synthesis. Journal of Biological Chemistry 154, 311–312.Google Scholar
Rock, C. O. & Jackowski, S. (2002). Forty years of bacterial fatty acid synthesis. Biochemical and Biophysical Research Communications 292, 1155–1166.Google Scholar
Roncari, D. A. (1981). Fatty acid synthase from human liver. Methods in Enzymology 71, 73–79.Google Scholar
Roncari, D. A., Bradshaw, R. A. & Vagelos, P. R. (1972). Acyl carrier protein. XIX. Amino acid sequence of liver fatty acid synthetase peptides containing 4′-phosphopantetheine. Journal of Biological Chemistry 247, 6234–6242.Google Scholar
Roujeinikova, A., Baldock, C., Simon, W. J., Gilroy, J., Baker, P. J., Stuitje, A. R., Rice, D. W., Slabas, A. R. & Rafferty, J. B. (2002). X-ray crystallographic studies on butyryl-ACP reveal flexibility of the structure around a putative acyl chain binding site. Structure 10, 825–835.Google Scholar
Roujeinikova, A., Simon, W. J., Gilroy, J., Rice, D. W., Rafferty, J. B. & Slabas, A. R. (2007). Structural studies of fatty acyl-(acyl carrier protein) thioesters reveal a hydrophobic binding cavity that can expand to fit longer substrates. Journal of Molecular Biology 365, 135–145.Google Scholar
Saito, J., Yamada, M., Watanabe, T., Iida, M., Kitagawa, H., Takahata, S., Ozawa, T., Takeuchi, Y. & Ohsawa, F. (2008). Crystal structure of enoyl-acyl carrier protein reductase (FabK) from Streptococcus pneumoniae reveals the binding mode of an inhibitor. Protein Science 17, 691–699.Google Scholar
Schreckenbach, T., Wobser, H. & Lynen, F. (1977). Palmityl binding-sites of fatty-acid synthetase from yeast. European Journal of Biochemistry 80, 13–23.Google Scholar
Schuster, H., Rautenstrauss, B., Mittag, M., Stratmann, D. & Schweizer, E. (1995). Substrate and product binding sites of yeast fatty acid synthase. Stoichiometry and binding kinetics of wild-type and in vitro mutated enzymes. European Journal of Biochemistry 228, 417–424.Google Scholar
Schweizer, E. & Hofmann, J. (2004). Microbial type I fatty acid synthases (FAS): major players in a network of cellular FAS systems. Microbiology and Molecular Biology Reviews 68, 501–517.Google Scholar
Schweizer, E., Kniep, B., Castorph, H. & Holzner, U. (1973). Pantetheine-free mutants of the yeast fatty-acid-synthetase complex. European Journal of Biochemistry 39, 353–362.Google Scholar
Schweizer, E., Lerch, I., Kroeplin-Rueff, L. & Lynen, F. (1970). Fatty acyl transferase. Characterization of the enzyme as part of the yeast fatty acid synthetase complex by the use of radioactively labeled coenzyme A. European Journal of Biochemistry 15, 472–482.Google Scholar
Schweizer, M., Roberts, L. M., Holtke, H. J., Takabayashi, K., Hollerer, E., Hoffmann, B., Muller, G., Kottig, H. & Schweizer, E. (1986). The pentafunctional FAS1 gene of yeast: its nucleotide sequence and order of the catalytic domains. Molecular and General Genetics 203, 479–486.Google Scholar
Sheldrick, G. M. (2008). A short history of SHELX. Acta Crystallographica. Section A, Foundations of Crystallography 64, 112–122.Google Scholar
Shimomura, Y., Kakuta, Y. & Fukuyama, K. (2003). Crystal structures of the quinone oxidoreductase from Thermus thermophilus HB8 and its complex with NADPH: implication for NADPH and substrate recognition. Journal of Bacteriology 185, 4211–4218.Google Scholar
Singh, N., Wakil, S. J. & Stoops, J. K. (1984). On the question of half- or full-site reactivity of animal fatty acid synthetase. Journal of Biological Chemistry 259, 3605–3611.Google Scholar
Smith, S. & Abraham, S. (1975). Fatty acid synthase from lactating rat mammary gland. Methods in Enzymology 35, 65–74.Google Scholar
Smith, S. & Stern, A. (1979). Subunit structure of the mammalian fatty-acid synthetase – further evidence for a homodimer. Archives of Biochemistry and Biophysics 197, 379–387.Google Scholar
Smith, S., Stern, A., Randhawa, Z. I. & Knudsen, J. (1985). Mammalian fatty-acid synthetase is a structurally and functionally symmetrical dimer. European Journal of Biochemistry 152, 547–555.Google Scholar
Smith, S. & Tsai, S. C. (2007). The type I fatty acid and polyketide synthases: a tale of two megasynthases. Natural Product Reports 24, 1041–1072.Google Scholar
Smith, S., Witkowski, A. & Joshi, A. K. (2003). Structural and functional organization of the animal fatty acid synthase. Progress in Lipid Research 42, 289–317.Google Scholar
Stoops, J. K., Arslanian, M. J., Aune, K. C. & Wakil, S. J. (1978a). Further evidence for multifunctional enzyme characteristic of fatty-acid synthetases of animal-tissues – physicochemical studies of chicken liver fatty-acid synthetase. Archives of Biochemistry and Biophysics 188, 348–359.Google Scholar
Stoops, J. K., Arslanian, M. J., Oh, Y. H., Aune, K. C., Vanaman, T. C. & Wakil, S. J. (1975). Presence of 2 polypeptide-chains comprising fatty-acid synthetase. Proceedings of the National Academy of Sciences of the United States of America 72, 1940–1944.Google Scholar
Stoops, J. K., Awad, E. S., Arslanian, M. J., Gunsberg, S., Wakil, S. J. & Oliver, R. M. (1978b). Studies on yeast fatty-acid synthetase – subunit composition and structural organization of a large multifunctional enzyme complex. Journal of Biological Chemistry 253, 4464–4475.Google Scholar
Stoops, J. K., Kolodziej, S. J., Schroeter, J. P., Bretaudiere, J. P. & Wakil, S. J. (1992). Structure–function relationships of the yeast fatty acid synthase: negative-stain, cryo-electron microscopy, and image analysis studies of the end views of the structure. Proceedings of the National Academy of Sciences of the United States of America 89, 6585–6589.Google Scholar
Stoops, J. K. & Wakil, S. J. (1980). Yeast fatty acid synthetase: structure–function relationship and nature of the beta-ketoacyl synthetase site. Proceedings of the National Academy of Sciences of the United States of America 77, 4544–4548.Google Scholar
Stoops, J. K. & Wakil, S. J. (1981). The yeast fatty acid synthetase. Structure–function relationship and the role of the active cysteine-SH and pantetheine-SH. Journal of Biological Chemistry 256, 8364–8370.Google Scholar
Stoops, J. K., Wakil, S. J., Uberbacher, E. C. & Bunick, G. J. (1987). Small-angle neutron-scattering and electron microscope studies of the chicken liver fatty acid synthase. Journal of Biological Chemistry 262, 10246–10251.Google Scholar
Sumper, M., Oesterhelt, D., Riepertinger, C. & Lynen, F. (1969). Synthesis of various carboxylic acids by the fatty acid synthetase multienzyme complex of yeast and the explanation for their structure. European Journal of Biochemistry 10, 377–387.Google Scholar
Tang, Y., Chen, A. Y., Kim, C. Y., Cane, D. E. & Khosla, C. (2007). Structural and mechanistic analysis of protein interactions in module 3 of the 6-deoxyerythronolide B synthase. Chemistry and Biology 14, 931–943.Google Scholar
Tang, Y., Kim, C. Y., Mathews, , II, Cane, D. E. & Khosla, C. (2006). The 2·7-angstrom crystal structure of a 194-kDa homodimeric fragment of the 6-deoxyerythronolide B synthase. Proceedings of the National Academy of Sciences of the United States of America 103, 11124–11129.Google Scholar
Thompson, B. J., Stern, A. & Smith, S. (1981). Purification and properties of fatty acid synthetase from a human breast cell line. Biochimica et Biophysica Acta 662, 125–130.Google Scholar
Tsukamoto, Y., Wong, H., Mattick, J. S. & Wakil, S. J. (1983). The architecture of the animal fatty acid synthetase complex. IV. Mapping of active centers and model for the mechanism of action. Journal of Biological Chemistry 258, 15312–15322.Google Scholar
Ullman, A. H., Harding, J. W. Jr. & White, H. B. III (1978). Fatty acid synthetase assay employing bicyclic diones as substrates. Analytical Biochemistry 84, 85–96.Google Scholar
Volpe, J. J. & Vagelos, P. R. (1973). Saturated fatty-acid biosynthesis and its regulation. Annual Review of Biochemistry 42, 21–60.Google Scholar
Wakil, S. J. (1958). A malonic acid derivative as an intermediate in fatty acid synthesis. Journal of the American Chemical Society 80, 6465–6465.Google Scholar
Wakil, S. J. (1961). Mechanism of fatty acid synthesis. Journal of Lipid Research 2, 1–24.Google Scholar
Wakil, S. J. & Ganguly, J. (1959). On the mechanism of fatty acid synthesis. Journal of the American Chemical Society 81, 2597–2598.Google Scholar
Wakil, S. J., Sauer, F. & Pugh, E. L. (1964). Mechanism of fatty acid synthesis. Proceedings of the National Academy of Sciences of the United States of America 52, 106–114.Google Scholar
Ward, W. H., Holdgate, G. A., Rowsell, S., Mclean, E. G., Pauptit, R. A., Clayton, E., Nichols, W. W., Colls, J. G., Minshull, C. A., Jude, D. A., Mistry, A., Timms, D., Camble, R., Hales, N. J., Britton, C. J. & Taylor, I. W. (1999). Kinetic and structural characteristics of the inhibition of enoyl (acyl carrier protein) reductase by triclosan. Biochemistry 38, 12514–12525.Google Scholar
Weiss, L., Hoffmann, G. E., Schreiber, R., Andres, H., Fuchs, E., Korber, E. & Kolb, H. J. (1986). Fatty-acid biosynthesis in man, a pathway of minor importance. Purification, optimal assay conditions, and organ distribution of fatty-acid synthase. Biological Chemistry Hoppe-Seyler 367, 905–912.Google Scholar
White, S. W., Zheng, J., Zhang, Y. M. & Rock, C. O. (2005). The structural biology of type II fatty acid biosynthesis. Annual Review of Biochemistry 74, 791–831.Google Scholar
Wieland, F., Siess, E. A., Renner, L., Verfurth, C. & Lynen, F. (1978). Distribution of yeast fatty acid synthetase subunits: three-dimensional model of the enzyme. Proceedings of the National Academy of Sciences of the United States of America 75, 5792–5796.Google Scholar
Willecke, K., Ritter, E. & Lynen, F. (1969). Isolation of an acyl carrier protein component from multienzyme complex of yeast fatty acid synthetase. European Journal of Biochemistry 8, 503–509.Google Scholar
Witkowski, A., Ghosal, A., Joshi, A. K., Witkowska, H. E., Asturias, F. J. & Smith, S. (2004). Head-to-head coiled arrangement of the subunits of the animal fatty acid synthase. Chemistry and Biology 11, 1667–1676.Google Scholar
Witkowski, A., Joshi, A. & Smith, S. (1996). Fatty acid synthase: in vitro complementation of inactive mutants. Biochemistry 35, 10569–10575.Google Scholar
Witkowski, A., Rangan, V. S., Randhawa, Z. I., Amy, C. M. & Smith, S. (1991). Structural organization of the multifunctional animal fatty-acid synthase. European Journal of Biochemistry 198, 571–579.Google Scholar
Woloshuk, C. P. & Prieto, R. (1998). Genetic organization and function of the aflatoxin B1 biosynthetic genes. FEMS Microbiology Letters 160, 169–176.Google Scholar
Xiong, Y. (2008). From electron microscopy to X-ray crystallography: molecular-replacement case studies. Acta Crystallographica. Section D, Biological Crystallography 64, 76–82.Google Scholar
Zhang, Y. M., Rao, M. S., Heath, R. J., Price, A. C., Olson, A. J., Rock, C. O. & White, S. W. (2001). Identification and analysis of the acyl carrier protein (ACP) docking site on beta-ketoacyl-ACP synthase III. Journal of Biological Chemistry 276, 8231–8238.Google Scholar
Zhang, Y. M., Wu, B., Zheng, J. & Rock, C. O. (2003). Key residues responsible for acyl carrier protein and beta-ketoacyl-acyl carrier protein reductase (FabG) interaction. Journal of Biological Chemistry 278, 52935–52943.Google Scholar
Zornetzer, G. A., Fox, B. G. & Markley, J. L. (2006). Solution structures of spinach acyl carrier protein with decanoate and stearate. Biochemistry 45, 5217–5227.Google Scholar