PDBsum entry 2vz9

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Transferase PDB id
Protein chains
2081 a.a. *
NAP ×4
* Residue conservation analysis
PDB id:
Name: Transferase
Title: Crystal structure of mammalian fatty acid synthase in complex with NADP
Structure: Fatty acid synthase. Chain: a, b. Other_details: purified from native source in enzymatically active form
Source: Sus scrofa. Pig. Organism_taxid: 9823. Organ: mammary gland. Other_details: lactating mammary gland
3.30Å     R-factor:   0.193     R-free:   0.244
Authors: T.Maier,M.Leibundgut,N.Ban
Key ref:
T.Maier et al. (2008). The crystal structure of a mammalian fatty acid synthase. Science, 321, 1315-1322. PubMed id: 18772430 DOI: 10.1126/science.1161269
31-Jul-08     Release date:   09-Sep-08    
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Protein chains
Pfam   ArchSchema ?
A5YV76  (A5YV76_PIG) -  Fatty acid synthase
2512 a.a.
2081 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     metabolic process   3 terms 
  Biochemical function     catalytic activity     18 terms  


DOI no: 10.1126/science.1161269 Science 321:1315-1322 (2008)
PubMed id: 18772430  
The crystal structure of a mammalian fatty acid synthase.
T.Maier, M.Leibundgut, N.Ban.
Mammalian fatty acid synthase is a large multienzyme that catalyzes all steps of fatty acid synthesis. We have determined its crystal structure at 3.2 angstrom resolution covering five catalytic domains, whereas the flexibly tethered terminal acyl carrier protein and thioesterase domains remain unresolved. The structure reveals a complex architecture of alternating linkers and enzymatic domains. Substrate shuttling is facilitated by flexible tethering of the acyl carrier protein domain and by the limited contact between the condensing and modifying portions of the multienzyme, which are mainly connected by linkers rather than direct interaction. The structure identifies two additional nonenzymatic domains: (i) a pseudo-ketoreductase and (ii) a peripheral pseudo-methyltransferase that is probably a remnant of an ancestral methyltransferase domain maintained in some related polyketide synthases. The structural comparison of mammalian fatty acid synthase with modular polyketide synthases shows how their segmental construction allows the variation of domain composition to achieve diverse product synthesis.
  Selected figure(s)  
Figure 1.
Fig. 1. Structural overview. (A) Cartoon representation of mFAS, colored by domains as indicated. Linkers and linker domains are depicted in gray. Bound NADP^+ cofactors and the attachment sites for the disordered C-terminal ACP/TE domains are shown as blue and black spheres, respectively. The position of the pseudo-twofold dimer axis is depicted by an arrow; domains of the second chain are indicated by an appended prime. The lower panel (front view) shows a corresponding schematic diagram. (B) Top (upper panel) and bottom (lower panel) views, demonstrating the "S" shape of the modifying (upper) and condensing (lower) parts of mFAS. The pseudo-twofold axis is indicated by an ellipsoid. (C) Linear sequence organization of mFAS, at approximate sequence scale.
Figure 2.
Fig. 2. Interdomain linkers. (A) Surface representation of individual mFAS domains (front view), colored as in Fig. 1. Linking regions are shown as tubes. (B to E) Close-up views of individual linkers. The direction of view is indicated by arrowheads in (A). (B) Linker connecting the two subdomains of the DH domain only loosely interacts with the main body of the double hot dog fold. (C) Linkers in the KR/ER region are wrapped around the domains with close interactions to the domain surfaces and pronounced linker-linker contacts; they mediate interactions between the KR, KR, and ME domains. (D) Modifying upper and condensing lower parts of FAS are only in tangential contact in the region of the central connection. Few residues besides the connecting linkers mediate the sparse interactions via a small interface area. (E) MAT-DH linker meanders through a groove on the surface of the KS domain.
  The above figures are reprinted by permission from the AAAs: Science (2008, 321, 1315-1322) copyright 2008.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
22993090 A.S.Halavaty, Y.Kim, G.Minasov, L.Shuvalova, I.Dubrovska, J.Winsor, M.Zhou, O.Onopriyenko, T.Skarina, L.Papazisi, K.Kwon, S.N.Peterson, A.Joachimiak, A.Savchenko, and W.F.Anderson (2012).
Structural characterization and comparison of three acyl-carrier-protein synthases from pathogenic bacteria.
  Acta Crystallogr D Biol Crystallogr, 68, 1359-1370.
PDB codes: 3f09 3hyk 3qmn 4jm7
20889351 I.J.Lodhi, X.Wei, and C.F.Semenkovich (2011).
Lipoexpediency: de novo lipogenesis as a metabolic signal transmitter.
  Trends Endocrinol Metab, 22, 1-8.  
21336932 R.Gurney, and C.M.Thomas (2011).
Mupirocin: biosynthesis, special features and applications of an antibiotic from a Gram-negative bacterium.
  Appl Microbiol Biotechnol, 90, 11-21.  
20662770 D.I.Chan, and H.J.Vogel (2010).
Current understanding of fatty acid biosynthesis and the acyl carrier protein.
  Biochem J, 430, 1.  
20152156 D.L.Akey, J.R.Razelun, J.Tehranisa, D.H.Sherman, W.H.Gerwick, and J.L.Smith (2010).
Crystal structures of dehydratase domains from the curacin polyketide biosynthetic pathway.
  Structure, 18, 94.
PDB codes: 3kg6 3kg7 3kg8 3kg9
20122995 E.Furuta, H.Okuda, A.Kobayashi, and K.Watabe (2010).
Metabolic genes in cancer: their roles in tumor progression and clinical implications.
  Biochim Biophys Acta, 1805, 141-152.  
20237645 E.J.Skellam, D.Hurley, J.Davison, C.M.Lazarus, T.J.Simpson, and R.J.Cox (2010).
Mutation of key residues in the C-methyltransferase domain of a fungal highly reducing polyketide synthase.
  Mol Biosyst, 6, 680-682.  
  20706604 H.Liu, J.Y.Liu, X.Wu, and J.T.Zhang (2010).
Biochemistry, molecular biology, and pharmacology of fatty acid synthase, an emerging therapeutic target and diagnosis/prognosis marker.
  Int J Biochem Mol Biol, 1, 69-89.  
20203700 I.Fujii (2010).
Functional analysis of fungal polyketide biosynthesis genes.
  J Antibiot (Tokyo), 63, 207-218.  
21079635 J.M.Crawford, and C.A.Townsend (2010).
New insights into the formation of fungal aromatic polyketides.
  Nat Rev Microbiol, 8, 879-889.  
20696392 J.Zheng, C.A.Taylor, S.K.Piasecki, and A.T.Keatinge-Clay (2010).
Structural and functional analysis of A-type ketoreductases from the amphotericin modular polyketide synthase.
  Structure, 18, 913-922.
PDB codes: 3mjc 3mje 3mjs 3mjt 3mjv
20373869 R.Flavin, S.Peluso, P.L.Nguyen, and M.Loda (2010).
Fatty acid synthase as a potential therapeutic target in cancer.
  Future Oncol, 6, 551-562.  
20444870 S.Anand, M.V.Prasad, G.Yadav, N.Kumar, J.Shehara, M.Z.Ansari, and D.Mohanty (2010).
SBSPKS: structure based sequence analysis of polyketide synthases.
  Nucleic Acids Res, 38, W487-W496.  
21127271 S.Kapur, A.Y.Chen, D.E.Cane, and C.Khosla (2010).
Molecular recognition between ketosynthase and acyl carrier protein domains of the 6-deoxyerythronolide B synthase.
  Proc Natl Acad Sci U S A, 107, 22066-22071.  
20731893 T.Maier, M.Leibundgut, D.Boehringer, and N.Ban (2010).
Structure and function of eukaryotic fatty acid synthases.
  Q Rev Biophys, 43, 373-422.  
20332208 T.P.Korman, J.M.Crawford, J.W.Labonte, A.G.Newman, J.Wong, C.A.Townsend, and S.C.Tsai (2010).
Structure and function of an iterative polyketide synthase thioesterase domain catalyzing Claisen cyclization in aflatoxin biosynthesis.
  Proc Natl Acad Sci U S A, 107, 6246-6251.
PDB code: 3ils
20080587 Y.Shen, J.Liu, G.Estiu, B.Isin, Y.Y.Ahn, D.S.Lee, A.L.Barabási, V.Kapatral, O.Wiest, and Z.N.Oltvai (2010).
Blueprint for antimicrobial hit discovery targeting metabolic networks.
  Proc Natl Acad Sci U S A, 107, 1082-1087.  
20336235 Z.X.Liang (2010).
Complexity and simplicity in the biosynthesis of enediyne natural products.
  Nat Prod Rep, 27, 499-528.  
19636447 A.Koglin, and C.T.Walsh (2009).
Structural insights into nonribosomal peptide enzymatic assembly lines.
  Nat Prod Rep, 26, 987.  
19217343 C.Khosla, S.Kapur, and D.E.Cane (2009).
Revisiting the modularity of modular polyketide synthases.
  Curr Opin Chem Biol, 13, 135-143.  
19562111 D.Papapostolou, and S.Howorka (2009).
Engineering and exploiting protein assemblies in synthetic biology.
  Mol Biosyst, 5, 723-732.  
19151726 E.J.Brignole, S.Smith, and F.J.Asturias (2009).
Conformational flexibility of metazoan fatty acid synthase enables catalysis.
  Nat Struct Mol Biol, 16, 190-197.  
19549604 G.Bunkoczi, S.Misquitta, X.Wu, W.H.Lee, A.Rojkova, G.Kochan, K.L.Kavanagh, U.Oppermann, and S.Smith (2009).
Structural basis for different specificities of acyltransferases associated with the human cytosolic and mitochondrial fatty acid synthases.
  Chem Biol, 16, 667-675.
PDB codes: 2c2n 2jfd
19360130 G.Yadav, R.S.Gokhale, and D.Mohanty (2009).
Towards prediction of metabolic products of polyketide synthases: an in silico analysis.
  PLoS Comput Biol, 5, e1000351.  
19847268 J.M.Crawford, T.P.Korman, J.W.Labonte, A.L.Vagstad, E.A.Hill, O.Kamari-Bidkorpeh, S.C.Tsai, and C.A.Townsend (2009).
Structural basis for biosynthetic programming of fungal aromatic polyketide cyclization.
  Nature, 461, 1139-1143.
PDB codes: 3hrq 3hrr
19653071 M.C.Neville (2009).
Introduction: milk lipid synthesis: chain length determination and secretory differentiation.
  J Mammary Gland Biol Neoplasia, 14, 243-244.  
19507202 M.Tosin, D.Spiteller, and J.B.Spencer (2009).
Malonyl carba(dethia)- and malonyl oxa(dethia)-coenzyme A as tools for trapping polyketide intermediates.
  Chembiochem, 10, 1714-1723.  
19381365 P.Beltran-Alvarez, C.J.Arthur, R.J.Cox, J.Crosby, M.P.Crump, and T.J.Simpson (2009).
Preliminary kinetic analysis of acyl carrier protein-ketoacylsynthase interactions in the actinorhodin minimal polyketide synthase.
  Mol Biosyst, 5, 511-518.  
19151923 R.P.Massengo-Tiassé, and J.E.Cronan (2009).
Diversity in enoyl-acyl carrier protein reductases.
  Cell Mol Life Sci, 66, 1507-1517.  
19362634 S.C.Tsai, and B.D.Ames (2009).
Structural enzymology of polyketide synthases.
  Methods Enzymol, 459, 17-47.  
19171964 S.Jenni, and N.Ban (2009).
Imperfect pseudo-merohedral twinning in crystals of fungal fatty acid synthase.
  Acta Crystallogr D Biol Crystallogr, 65, 101-111.  
19351663 T.C.Petrossian, and S.G.Clarke (2009).
Multiple Motif Scanning to identify methyltransferases from the yeast proteome.
  Mol Cell Proteomics, 8, 1516-1526.  
19352381 T.Mashima, H.Seimiya, and T.Tsuruo (2009).
De novo fatty-acid synthesis and related pathways as molecular targets for cancer therapy.
  Br J Cancer, 100, 1369-1372.  
19318631 T.Migita, S.Ruiz, A.Fornari, M.Fiorentino, C.Priolo, G.Zadra, F.Inazuka, C.Grisanzio, E.Palescandolo, E.Shin, C.Fiore, W.Xie, A.L.Kung, P.G.Febbo, A.Subramanian, L.Mucci, J.Ma, S.Signoretti, M.Stampfer, W.C.Hahn, S.Finn, and M.Loda (2009).
Fatty acid synthase: a metabolic enzyme and candidate oncogene in prostate cancer.
  J Natl Cancer Inst, 101, 519-532.  
19530726 X.Xie, M.J.Meehan, W.Xu, P.C.Dorrestein, and Y.Tang (2009).
Acyltransferase mediated polyketide release from a fungal megasynthase.
  J Am Chem Soc, 131, 8388-8389.  
19286367 Y.Cheng (2009).
Toward an atomic model of the 26S proteasome.
  Curr Opin Struct Biol, 19, 203-208.  
18772425 J.L.Smith, and D.H.Sherman (2008).
Biochemistry. An enzyme assembly line.
  Science, 321, 1304-1305.  
19016299 K.J.Weissman (2008).
Taking a closer look at fatty acid biosynthesis.
  Chembiochem, 9, 2929-2931.  
18948193 M.Leibundgut, T.Maier, S.Jenni, and N.Ban (2008).
The multienzyme architecture of eukaryotic fatty acid synthases.
  Curr Opin Struct Biol, 18, 714-725.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.