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PDBsum entry 2cdh
Go to PDB code: 
protein links
Transferase PDB id
2cdh
Contents
Protein chains
(+ 0 more) 226 a.a.* *
(+ 6 more) 305 a.a.* *
(+ 0 more) 406 a.a.* *
(+ 0 more) 244 a.a.* *
(+ 0 more) 248 a.a.* *
* Residue conservation analysis
* C-alpha coords only
PDB id:
2cdh
Name: Transferase
Title: Architecture of the thermomyces lanuginosus fungal fatty acid synthase at 5 angstrom resolution.
Structure: Enoyl reductase. Chain: 0, 1, 2, 3, y, z. Other_details: from PDB entry 1gox. Malonyl/palmitoyl transferase. Chain: 4, 5, 6, 7, 8, 9, m, n, o, p, q, r. Other_details: PDB entry 1nm2. Ketoacyl synthase. Chain: a, b, c, d, e, f. Other_details: PDB entry 1dd8.
Source: Thermomyces lanuginosus. Organism_taxid: 5541. Other_details: dsmz10635. Other_details: dsmz10635
Biol. unit: 36mer (from PDB file)
Resolution:
4.20Å     R-factor:   not given    
Authors: S.Jenni,M.Leibundgut,T.Maier,N.Ban
Key ref:
S.Jenni et al. (2006). Architecture of a fungal fatty acid synthase at 5 A resolution. Science, 311, 1263-1267. PubMed id: 16513976 DOI: 10.1126/science.1123251
Date:
24-Jan-06     Release date:   07-Mar-06    
 Headers
 References

Protein chains
No UniProt id for this chain
Struc: 226 a.a.
Protein chains
No UniProt id for this chain
Struc: 305 a.a.
Protein chains
Pfam   ArchSchema ?
P0A953  (FABB_ECOLI) -  3-oxoacyl-[acyl-carrier-protein] synthase 1 from Escherichia coli (strain K12)
Seq:
Struc: 		406 a.a.
406 a.a.*
Protein chains
Pfam   ArchSchema ?
Q93X62  (FABG1_BRANA) -  3-oxoacyl-[acyl-carrier-protein] reductase 1, chloroplastic from Brassica napus
Seq:
Struc: 		320 a.a.
244 a.a.*
Protein chains
No UniProt id for this chain
Struc: 248 a.a.
Key:    PfamA domain  Secondary structure
* PDB and UniProt seqs differ at 4 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class 2: Chains A, B, C, D, E, F: E.C.2.3.1.41  - beta-ketoacyl-[acyl-carrier-protein] synthase I.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: a fatty acyl-[ACP] + malonyl-[ACP] + H+ = a 3-oxoacyl-[ACP] + holo- [ACP] + CO2
fatty acyl-[ACP]
 + malonyl-[ACP]
 + H(+)
 = 3-oxoacyl-[ACP]
 + holo- [ACP]
 + CO2
   Enzyme class 3: Chains G, H, I, J, K, L: E.C.1.1.1.100  - 3-oxoacyl-[acyl-carrier-protein] reductase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: a (3R)-hydroxyacyl-[ACP] + NADP+ = a 3-oxoacyl-[ACP] + NADPH + H+
(3R)-hydroxyacyl-[ACP]
 + NADP(+)
 = 3-oxoacyl-[ACP]
 + NADPH
 + H(+)
Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    reference    
 
 
DOI no: 10.1126/science.1123251 Science 311:1263-1267 (2006)
PubMed id: 16513976  
 
 
Architecture of a fungal fatty acid synthase at 5 A resolution.
S.Jenni, M.Leibundgut, T.Maier, N.Ban.
 
  ABSTRACT  
 
All steps of fatty acid synthesis in fungi are catalyzed by the fatty acid synthase, which forms a 2.6-megadalton alpha6beta6 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 approximately 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.
 
  Selected figure(s)  
 
Figure 4.
Fig. 4. The 5 Å electron density map of the fungal FAS. (A) Side view of the electron density along one of the twofold axes of FAS, contoured at 1.8 . The density is colored according to the fitted domains, using the color scheme described in (C). Regions of electron density not corresponding to homologous domains are colored white, including the unassigned domain at the end of the 50 Å–long helix that occludes one of the two large side openings. (B) Top view of the central wheel, which divides the interior of the FAS assembly into two reaction chambers. The KS and KR domains occupy only part of the electron density and are colored orange and yellow, respectively. Additional structural features involved in the formation of the FAS complex are shown in white. Spokes of electron density extend from the central hub of the wheel to the periphery. Bundles of helices connect the KS and KR. (C) Arrangement of the different catalytic domains in the multienzyme complex. To illustrate the localization, the domains are mapped onto the cryoelectron microscopy reconstruction (12). KS is colored orange, KR yellow, MPT red, DH light green, ER dark green, and AT magenta. (D) Distribution of the and ß chains in the FAS complex. Electron density belonging to the chain that forms the central wheel is shown in blue, the density of the ß chain that folds into the arches on both sides of the FAS particle is in green, and the currently unassigned density is in white. 		Figure 5.
Fig. 5. (A) All active sites of the fungal FAS are oriented toward the interior of the reaction chamber. The dome (lower panel) is cut from the central wheel (upper panel) and flipped open. Fitted domains are colored in light brown and unassigned electron density is in gray. The trimeric connection at the apices of the particle observed in the 8 Å–resolution map is also shown in gray. Red cones indicate the entrances to the hydrophobic clefts that lead to the active sites. (B) Set of active sites in the reaction chamber with all enzymatic activities required for the fatty acid synthesis cycle. The view is into the reaction chamber, with one-third of the dome removed. Distances between the central structural feature (indicated by green spheres) and the active sites are indicated with red lines. (C) Schematic path of ACP, shown as a gray sphere, during substrate shuttling between the active sites.
 
  The above figures are reprinted by permission from the AAAs: Science (2006, 311, 1263-1267) copyright 2006.  
  Figures were selected by the author.  
 
 
    Author's comment    
 
  This work describes the overall architecture of the fungal fatty acid synthase (FAS) complex. The PDB entry 2cdh contains the coordinates of homologous enzymes fitted into the 5 angstrom electron density map of Thermomyces lanuginosus FAS.
For the atomic coordinates and detailed descriptions of the Thermomyces lanuginosus and Saccharomyces cerevisiae FAS structures determined at 3.1Å resolution, compare with PDB entries 2uv9 and 2uva (T. lanuginosus FAS), 2uvb and 2uvc (T. lanuginosus FAS in complex with NADP+) and 2uv8 (S. cerevisiae FAS with phosphopantetheine) and see references "Structure of fungal fatty acid synthase and implications for iterative substrate shuttling" [Jenni et al. (2007) Science 316:254-61] and "Structural basis for substrate delivery by acyl carrier protein in the yeast fatty acid synthase" [Leibundgut et al. (2007) Science 316:288-90].
Marc Leibundgut 		 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20179343 B.P.Pedersen, J.P.Morth, and P.Nissen (2010).
Structure determination using poorly diffracting membrane-protein crystals: the H+-ATPase and Na+,K+-ATPase case history.
  Acta Crystallogr D Biol Crystallogr, 66, 309-313.  
20662770 D.I.Chan, and H.J.Vogel (2010).
Current understanding of fatty acid biosynthesis and the acyl carrier protein.
  Biochem J, 430, 1.  
20014832 G.A.Zornetzer, J.Tanem, B.G.Fox, and J.L.Markley (2010).
The length of the bound fatty acid influences the dynamics of the acyl carrier protein and the stability of the thioester bond.
  Biochemistry, 49, 470-477.  
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.  
19636447 A.Koglin, and C.T.Walsh (2009).
Structural insights into nonribosomal peptide enzymatic assembly lines.
  Nat Prod Rep, 26, 987.  
19551180 J.L.Meier, and M.D.Burkart (2009).
The chemical biology of modular biosynthetic enzymes.
  Chem Soc Rev, 38, 2012-2045.  
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.  
18620418 A.S.Reger, R.Wu, D.Dunaway-Mariano, and A.M.Gulick (2008).
Structural characterization of a 140 degrees domain movement in the two-step reaction catalyzed by 4-chlorobenzoate:CoA ligase.
  Biochemistry, 47, 8016-8025.
PDB codes: 3cw8 3cw9
18583577 A.Tanovic, S.A.Samel, L.O.Essen, and M.A.Marahiel (2008).
Crystal structure of the termination module of a nonribosomal peptide synthetase.
  Science, 321, 659-663.
PDB code: 2vsq
18704088 D.P.Frueh, H.Arthanari, A.Koglin, D.A.Vosburg, A.E.Bennett, C.T.Walsh, and G.Wagner (2008).
Dynamic thiolation-thioesterase structure of a non-ribosomal peptide synthetase.
  Nature, 454, 903-906.
PDB code: 2roq
18410406 F.Pankewitz, and M.Hilker (2008).
Polyketides in insects: ecological role of these widespread chemicals and evolutionary aspects of their biogenesis.
  Biol Rev Camb Philos Soc, 83, 209-226.  
18772425 J.L.Smith, and D.H.Sherman (2008).
Biochemistry. An enzyme assembly line.
  Science, 321, 1304-1305.  
18551496 J.M.Crawford, A.L.Vagstad, K.C.Ehrlich, D.W.Udwary, and C.A.Townsend (2008).
Acyl-carrier protein-phosphopantetheinyltransferase partnerships in fungal fatty acid synthases.
  Chembiochem, 9, 1559-1563.  
18357594 K.J.Weissman, and R.Müller (2008).
Protein-protein interactions in multienzyme megasynthetases.
  Chembiochem, 9, 826-848.  
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.  
  19052664 M.Marcet-Houben, M.Cabré, J.L.Paternáin, and A.Romeu (2008).
Phylogenetic analysis of homologous fatty acid synthase and polyketide synthase involved in aflatoxin biosynthesis.
  Bioinformation, 3, 33-40.  
18725634 P.Johansson, B.Wiltschi, P.Kumari, B.Kessler, C.Vonrhein, J.Vonck, D.Oesterhelt, and M.Grininger (2008).
Inhibition of the fungal fatty acid synthase type I multienzyme complex.
  Proc Natl Acad Sci U S A, 105, 12803-12808.
PDB code: 2vkz
18772430 T.Maier, M.Leibundgut, and N.Ban (2008).
The crystal structure of a mammalian fatty acid synthase.
  Science, 321, 1315-1322.
PDB codes: 2vz8 2vz9
18094470 Y.Xiong (2008).
From electron microscopy to X-ray crystallography: molecular-replacement case studies.
  Acta Crystallogr D Biol Crystallogr, 64, 76-82.  
17653358 A.C.Mercer, and M.D.Burkart (2007).
The ubiquitous carrier protein--a window to metabolite biosynthesis.
  Nat Prod Rep, 24, 750-773.  
17576425 B.Wilkinson, and J.Micklefield (2007).
Mining and engineering natural-product biosynthetic pathways.
  Nat Chem Biol, 3, 379-386.  
18059524 D.M.Byers, and H.Gong (2007).
Acyl carrier protein: structure-function relationships in a conserved multifunctional protein family.
  Biochem Cell Biol, 85, 649-662.  
17719534 H.Riezman (2007).
The long and short of fatty acid synthesis.
  Cell, 130, 587-588.  
17448991 I.B.Lomakin, Y.Xiong, and T.A.Steitz (2007).
The crystal structure of yeast fatty acid synthase, a cellular machine with eight active sites working together.
  Cell, 129, 319-332.
PDB code: 2pff
18045420 L.Yu, W.Zhang, T.Liu, X.Wang, J.Peng, S.Li, and Q.Jin (2007).
Global gene expression of Trichophyton rubrum in response to PH11B, a novel fatty acid synthase inhibitor.
  J Appl Microbiol, 103, 2346-2352.  
18033580 N.Dixon, L.S.Wong, T.H.Geerlings, and J.Micklefield (2007).
Cellular targets of natural products.
  Nat Prod Rep, 24, 1288-1310.  
17190806 P.D.Straight, M.A.Fischbach, C.T.Walsh, D.Z.Rudner, and R.Kolter (2007).
A singular enzymatic megacomplex from Bacillus subtilis.
  Proc Natl Acad Sci U S A, 104, 305-310.  
17485508 S.Sharma, S.K.Sharma, R.Modak, K.Karmodiya, N.Surolia, and A.Surolia (2007).
Mass spectrometry-based systems approach for identification of inhibitors of Plasmodium falciparum fatty acid synthase.
  Antimicrob Agents Chemother, 51, 2552-2558.  
17335097 Y.Liu, and S.D.Bruner (2007).
Rational manipulation of carrier-domain geometry in nonribosomal peptide synthetases.
  Chembiochem, 8, 617-621.  
16632247 C.A.Townsend, J.M.Crawford, and T.Bililign (2006).
New images evoke FAScinating questions.
  Chem Biol, 13, 349-351.  
17046237 J.D.Kittendorf, and D.H.Sherman (2006).
Developing tools for engineering hybrid polyketide synthetic pathways.
  Curr Opin Biotechnol, 17, 597-605.  
16619020 J.E.Cronan (2006).
Remarkable structural variation within fatty acid megasynthases.
  Nat Chem Biol, 2, 232-234.  
17071746 J.M.Crawford, B.C.Dancy, E.A.Hill, D.W.Udwary, and C.A.Townsend (2006).
Identification of a starter unit acyl-carrier protein transacylase domain in an iterative type I polyketide synthase.
  Proc Natl Acad Sci U S A, 103, 16728-16733.  
16815901 L.M.Hicks, C.J.Balibar, C.T.Walsh, N.L.Kelleher, and N.J.Hillson (2006).
Probing intra- versus interchain kinetic preferences of L-Thr acylation on dimeric VibF with mass spectrometry.
  Biophys J, 91, 2609-2619.  
16963641 P.Johansson, A.Castell, T.A.Jones, and K.Bäckbro (2006).
Structure and function of Rv0130, a conserved hypothetical protein from Mycobacterium tuberculosis.
  Protein Sci, 15, 2300-2309.
PDB code: 2c2i
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.

 

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