Conformational flexibility of metazoan fatty acid synthase enables catalysis

Nature Structural and Molecular Biology

Volumn 16, Issue 2, 2009, Pages 190-197

  Brignole, Edward J ^a   Smith, Stuart ^b   Asturias, Francisco J ^a  

^a SCRIPPS RESEARCH INSTITUTE   (United States)

^b CHILDREN S HOSPITAL OAKLAND RESEARCH INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

FATTY ACID SYNTHASE;

ARTICLE; CATALYSIS; CONFORMATIONAL TRANSITION; ENZYME ACTIVITY; ENZYME CONFORMATION; ENZYME SUBSTRATE; HUMAN; POLYMERIZATION; PRIORITY JOURNAL; PROTEIN DOMAIN;

ANIMALS; CATALYSIS; FATTY ACID SYNTHETASE COMPLEX; MICROSCOPY, ELECTRON; MODELS, MOLECULAR; POINT MUTATION; RATS;

METAZOA;

EID: 59649102440     PISSN: 15459993     EISSN: 15459985     Source Type: Journal    
DOI: 10.1038/nsmb.1532     Document Type: Article

References (40)

1. Sul, H.S. & Smith, S. Fatty acid synthesis in eukaryotes. in Biochemistry of Lipids, Lipoproteins and Membranes (ed. Vance, D.E.a.V. J.E.) 155-190 (Elsevier, Amsterdam; Oxford, 2008).
2. Kuhajda, F.P. et al. Fatty acid synthesis: a potential selective target for antineoplastic therapy. Proc. Natl. Acad. Sci. USA 91, 6379-6383 (1994).
3. Loftus, T.M. et al. Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors. Science 288, 2379-2381 (2000).
4. Jenni, S. et al. Structure of fungal fatty acid synthase and implications for iterative substrate shuttling. Science 316, 254-261 (2007).
5. Lomakin, I.B., Xiong, Y. & Steitz, T.A. The crystal structure of yeast fatty acid synthase, a cellular machine with eight active sites working together. Cell 129, 319-332 (2007).
6. Asturias, F.J. et al. Structure and molecular organization of mammalian fatty acid synthase. Nat. Struct. Mol. Biol. 12, 225-232 (2005).
7. Maier, T., Jenni, S. & Ban, N. Architecture of mammalian fatty acid synthase at 4.5 Å resolution. Science 311, 1258-1262 (2006).
8. Rangan, V.S., Joshi, A.K. & Smith, S. Mapping the functional topology of the animal fatty acid synthase by mutant complementation in vitro. Biochemistry 40, 10792-10799 (2001).
9. Witkowski, A. et al. Dibromopropanone cross-linking of the phosphopantetheine and active-site cysteine thiols of the animal fatty acid synthase can occur both inter- and intrasubunit. Reevaluation of the side-by-side, antiparallel subunit model. J. Biol. Chem. 274, 11557-11563 (1999).
10. Burgess, S.A., Walker, M.L., Thirumurugan, K., Trinick, J. & Knight, P.J. Use of negative stain and single-particle image processing to explore dynamic properties of flexible macromolecules. J. Struct. Biol. 147, 247-258 (2004).
11. Joshi, A.K., Witkowski, A., Berman, H.A., Zhang, L. & Smith, S. 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 (2005).
12. Radermacher, M. The three-dimensional reconstruction of single particles from random and non-random tilt series. J. Electron Microsc. Tech. 9, 359-394 (1988).
13. Keatinge-Clay, A.T. & Stroud, R.M. The structure of a ketoreductase determines the organization of the β-carbon processing enzymes of modular polyketide synthases. Structure 14, 737-748 (2006).
14. Smith, S. & Tsai, S.C. The type I fatty acid and polyketide synthases: a tale of two megasynthases. Nat. Prod. Rep. 24, 1041-1072 (2007).
15. Horton, J.R., Sawada, K., Nishibori, M. & Cheng, X. Structural basis for inhibition of histamine N-methyltransferase by diverse drugs. J. Mol. Biol. 353, 334-344 (2005).
16. Tang, Y., Kim, C.Y., Mathews, I.I., Cane, D.E. & Khosla, C. The 2.7-angstrom crystal structure of a 194-kDa homodimeric fragment of the 6-deoxyerythronolide B synthase. Proc. Natl. Acad. Sci. USA 103, 11124-11129 (2006).
17. Cheng, Y. et al. Single particle reconstructions of the transferrin-transferrin receptor complex obtained with different specimen preparation techniques. J. Mol. Biol. 355, 1048-1065 (2006).
18. Joshi, A.K. & Smith, S. Construction, expression, and characterization of a mutated animal fatty acid synthase deficient in the dehydrase function. J. Biol. Chem. 268, 22508-22513 (1993).
19. Witkowski, A., Joshi, A.K., Lindqvist, Y. & Smith, S. Conversion of a β-ketoacyl synthase to a malonyl decarboxylase by replacement of the active-site cysteine with glutamine. Biochemistry 38, 11643-11650 (1999).
20. Tang, Y., Chen, A.Y., Kim, C.Y., Cane, D.E. & Khosla, C. Structural and mechanistic analysis of protein interactions in module 3 of the 6-deoxyerythronolide B synthase. Chem. Biol. 14, 931-943 (2007).
21. Chen, Z.J. et al. Structural enzymological studies of 2-enoyl thioester reductase of the human mitochondrial FAS II pathway: new insights into its substrate recognition properties. J. Mol. Biol. 379, 830-844 (2008).
22. Joshi, A.K., Rangan, V.S., Witkowski, A. & Smith, S. Engineering of an active animal fatty acid synthase dimer with only one competent subunit. Chem. Biol. 10, 169-173 (2003).
23. Maier, T., Leibundgut, M. & Ban, N. The crystal structure of a mammalian fatty acid synthase. Science 321, 1315-1322 (2008).
24. Smith, S. & Abraham, S. Fatty acid synthase from lactating rat mammary gland. Methods Enzymol. 35, 65-74 (1975).
25. Tischendorf, G.W., Zeichhardt, H. & Stoffler, G. Determination of the location of proteins L14, L17, L18, L19, L22, L23 on the surface of the 50S ribosomal subunit of Escherichia coli by immune electron microscopy. Mol. Gen. Genet. 134, 187-208 (1974).
26. Suloway, C. et al. Automated molecular microscopy: the new Leginon system. J. Struct. Biol. 151, 41-60 (2005).
27. Frank, J. et al. SPIDER and WEB: processing and visualization of images in 3D electron microscopy and related fields. J. Struct. Biol. 116, 190-199 (1996).
28. Rath, B.K. & Frank, J. Fast automatic particle picking from cryo-electron micrographs using a locally normalized cross-correlation function: a case study. J. Struct. Biol. 145, 84-90 (2004).
29. Penczek, P., Radermacher, M. & Frank, J. Three-dimensional reconstruction of single particles embedded in ice. Ultramicroscopy 40, 33-53 (1992).
30. Bretaudiere, J.P. & Frank, J. Reconstitution of molecule images analysed by correspondence analysis: a tool for structural interpretation. J. Microsc. 144, 1-14 (1986).
31. Radermacher, M., Wagenknecht, T., Verschoor, A. & Frank, J. Three-dimensional reconstruction from a single-exposure, random conical tilt series applied to the 50S ribosomal subunit of Escherichia coli. J. Microsc. 146, 113-136 (1987).
32. Keatinge-Clay, A.T. A tylosin ketoreductase reveals how chirality is determined in polyketides. Chem. Biol. 14, 898-908 (2007).
33. Pasta, S., Witkowski, A., Joshi, A.K. & Smith, S. Catalytic residues are shared between two pseudosubunits of the dehydratase domain of the animal fatty acid synthase. Chem. Biol. 14, 1377-1385 (2007).
34. Soding, J., Biegert, A. & Lupas, A.N. The HHpred interactive server for protein homology detection and structure prediction. Nucleic Acids Res. 33, W244-W248 (2005).
35. Pettersen, E.F. et al. UCSF Chimera - a visualization system for exploratory research and analysis. J. Comput. Chem. 25, 1605-1612 (2004).
36. Ploskon, E. et al. A mammalian type I fatty acid synthase acyl carrier protein domain does not sequester acyl chains. J. Biol. Chem. 283, 518-528 (2008).
37. Volkmann, N. & Hanein, D. Quantitative fitting of atomic models into observed densities derived by electron microscopy. J. Struct. Biol. 125, 176-184 (1999).
38. Koski, M.K., Haapalainen, A.M., Hiltunen, J.K. & Glumoff, T. A two-domain structure of one subunit explains unique features of eukaryotic hydratase 2. J. Biol. Chem. 279, 24666-24672 (2004).
39. Oefner, C., Schulz, H., D'Arcy, A. & Dale, G.E. Mapping the active site of Escherichia coli malonyl-CoA-acyl carrier protein transacylase (FabD) by protein crystallography. Acta Crystallogr. D Biol. Crystallogr. 62, 613-618 (2006).
40. Bunkoczi, G. et al. Mechanism and substrate recognition of human holo ACP synthase. Chem. Biol. 14, 1243-1253 (2007).