PDBsum entry 1xkt

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protein Protein-protein interface(s) links
Hydroxylase PDB id
Protein chain
260 a.a. *
Waters ×65
* Residue conservation analysis
PDB id:
Name: Hydroxylase
Title: Human fatty acid synthase: structure and substrate selectivity of the thioesterase domain
Structure: Fatty acid synthase. Chain: a, b. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Biol. unit: Tetramer (from PQS)
2.60Å     R-factor:   0.258     R-free:   0.279
Authors: B.Chakravarty,Z.Gu,S.S.Chirala,S.J.Wakil,F.A.Quiocho
Key ref:
B.Chakravarty et al. (2004). Human fatty acid synthase: structure and substrate selectivity of the thioesterase domain. Proc Natl Acad Sci U S A, 101, 15567-15572. PubMed id: 15507492 DOI: 10.1073/pnas.0406901101
29-Sep-04     Release date:   26-Oct-04    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P49327  (FAS_HUMAN) -  Fatty acid synthase
2511 a.a.
260 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class 1: E.C.  - 3-oxoacyl-[acyl-carrier-protein] reductase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: (3R)-3-hydroxyacyl-[acyl-carrier-protein] + NADP+ = 3-oxoacyl-[acyl- carrier-protein] + NADPH
+ NADP(+)
= 3-oxoacyl-[acyl- carrier-protein]
   Enzyme class 2: E.C.  - Enoyl-[acyl-carrier-protein] reductase (Nadph, Re-specific).
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: An acyl-[acyl-carrier protein] + NADP+ = a trans-2,3-dehydroacyl-[acyl- carrier protein] + NADPH
acyl-[acyl-carrier protein]
+ NADP(+)
= trans-2,3-dehydroacyl-[acyl- carrier protein]
   Enzyme class 3: E.C.  - [Acyl-carrier-protein] S-acetyltransferase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Acetyl-CoA + [acyl-carrier-protein] = CoA + acetyl-[acyl-carrier- protein]
+ [acyl-carrier-protein]
= CoA
+ acetyl-[acyl-carrier- protein]
   Enzyme class 4: E.C.  - [Acyl-carrier-protein] S-malonyltransferase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Malonyl-CoA + an [acyl-carrier-protein] = CoA + a malonyl-[acyl-carrier- protein]
+ [acyl-carrier-protein]
= CoA
+ malonyl-[acyl-carrier- protein]
   Enzyme class 5: E.C.  - Beta-ketoacyl-[acyl-carrier-protein] synthase I.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Acyl-[acyl-carrier-protein] + malonyl-[acyl-carrier-protein] = 3-oxoacyl- [acyl-carrier-protein] + CO2 + [acyl-carrier-protein]
+ malonyl-[acyl-carrier-protein]
= 3-oxoacyl- [acyl-carrier-protein]
+ CO(2)
+ [acyl-carrier-protein]
   Enzyme class 6: E.C.  - Fatty-acid synthase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Acetyl-CoA + n malonyl-CoA + 2n NADPH = a long-chain fatty acid + (n+1) CoA + n CO2 + 2n NADP+
+ n malonyl-CoA
+ 2n NADPH
= long-chain fatty acid
+ (n+1) CoA
+ n CO(2)
+ 2n NADP(+)
   Enzyme class 7: E.C.  - Oleoyl-[acyl-carrier-protein] hydrolase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Oleoyl-[acyl-carrier-protein] + H2O = [acyl-carrier-protein] + oleate
+ n H(2)O
= [acyl-carrier-protein]
+ oleate
   Enzyme class 8: E.C.  - 3-hydroxyacyl-[acyl-carrier-protein] dehydratase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: A (3R)-3-hydroxyacyl-[acyl-carrier protein] = a trans-2-enoyl-[acyl- carrier protein] + H2O
(3R)-3-hydroxyacyl-[acyl-carrier protein]
= n trans-2-enoyl-[acyl- carrier protein]
+ H(2)O
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
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     biosynthetic process   2 terms 
  Biochemical function     hydrolase activity, acting on ester bonds     12 terms  


DOI no: 10.1073/pnas.0406901101 Proc Natl Acad Sci U S A 101:15567-15572 (2004)
PubMed id: 15507492  
Human fatty acid synthase: structure and substrate selectivity of the thioesterase domain.
B.Chakravarty, Z.Gu, S.S.Chirala, S.J.Wakil, F.A.Quiocho.
Human fatty acid synthase is a large homodimeric multifunctional enzyme that synthesizes palmitic acid. The unique carboxyl terminal thioesterase domain of fatty acid synthase hydrolyzes the growing fatty acid chain and plays a critical role in regulating the chain length of fatty acid released. Also, the up-regulation of human fatty acid synthase in a variety of cancer makes the thioesterase a candidate target for therapeutic treatment. The 2.6-A resolution structure of human fatty acid synthase thioesterase domain reported here is comprised of two dissimilar subdomains, A and B. The smaller subdomain B is composed entirely of alpha-helices arranged in an atypical fold, whereas the A subdomain is a variation of the alpha/beta hydrolase fold. The structure revealed the presence of a hydrophobic groove with a distal pocket at the interface of the two subdomains, which constitutes the candidate substrate binding site. The length and largely hydrophobic nature of the groove and pocket are consistent with the high selectivity of the thioesterase for palmitoyl acyl substrate. The structure also set the identity of the Asp residue of the catalytic triad of Ser, His, and Asp located in subdomain A at the proximal end of the groove.
  Selected figure(s)  
Figure 4.
Fig. 4. Hydrogen bonding network among the various catalytic residues. Dotted lines denote hydrogen bonds connecting the corresponding residues. Hydrogen bond distances range from 2.4 to 3.2 Å.
Figure 5.
Fig. 5. Lipid binding site. (A) Stereoview of the candidate palmitoyl binding groove for the first 11-12 carbons and the pocket for the last 5-4 carbons. The hexadecyl sulfonyl inhibitor is represented as a Corey-Pauling-Koltun space-filling model (C, yellow; O, red; S, green). Side chains lining the groove are shown as ball-and-stick figures (C, yellow; O, red; N, blue). The side chains making up the active site are also shown as ball-and-stick figures with the color scheme similar to that of the residues. The groove surface map is shown in green wire mesh. The residues making up the groove are labeled except for Ile-2250, which cannot be seen because it falls below the inhibitor. The initial 11-12 carbon atoms from the sulfonyl group are solvent-exposed with the 11th and 12th carbon atoms at the mouth of the pocket. (B) A different view of the groove and pocket. The arrows denote the rotations in going from the orientation of the view in A to B. This view shows that most of the fatty acyl chain of hexadecyl inhibitor is exposed to the solvent.
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21351219 Y.Jiang, K.L.Morley, J.D.Schrag, and R.J.Kazlauskas (2011).
Different active-site loop orientation in serine hydrolases versus acyltransferases.
  Chembiochem, 12, 768-776.
PDB code: 3ia2
19603203 C.E.Cassidy, and W.N.Setzer (2010).
Cancer-relevant biochemical targets of cytotoxic Lonchocarpus flavonoids: a molecular docking analysis.
  J Mol Model, 16, 311-326.  
20506386 D.C.Cantu, Y.Chen, and P.J.Reilly (2010).
Thioesterases: a new perspective based on their primary and tertiary structures.
  Protein Sci, 19, 1281-1295.  
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
19103602 H.B.Claxton, D.L.Akey, M.K.Silver, S.J.Admiraal, and J.L.Smith (2009).
Structure and functional analysis of RifR, the type II thioesterase from the rifamycin biosynthetic pathway.
  J Biol Chem, 284, 5021-5029.
PDB codes: 3fla 3flb
19551180 J.L.Meier, and M.D.Burkart (2009).
The chemical biology of modular biosynthetic enzymes.
  Chem Soc Rev, 38, 2012-2045.  
19520851 S.K.Upadhyay, A.Misra, R.Srivastava, N.Surolia, A.Surolia, and M.Sundd (2009).
Structural insights into the acyl intermediates of the Plasmodium falciparum fatty acid synthesis pathway: the mechanism of expansion of the acyl carrier protein core.
  J Biol Chem, 284, 22390-22400.  
19291389 T.Abe, J.Saburi, H.Hasebe, T.Nakagawa, S.Misumi, T.Nade, H.Nakajima, N.Shoji, M.Kobayashi, and E.Kobayashi (2009).
Novel mutations of the FASN gene and their effect on fatty acid composition in Japanese Black beef.
  Biochem Genet, 47, 397-411.  
19549600 T.Awakawa, K.Yokota, N.Funa, F.Doi, N.Mori, H.Watanabe, and S.Horinouchi (2009).
Physically discrete beta-lactamase-type thioesterase catalyzes product release in atrochrysone synthesis by iterative type I polyketide synthase.
  Chem Biol, 16, 613-623.  
18480028 A.Das, M.A.Davis, and L.L.Rudel (2008).
Identification of putative active site residues of ACAT enzymes.
  J Lipid Res, 49, 1770-1781.  
18199837 A.Miyanaga, N.Funa, T.Awakawa, and S.Horinouchi (2008).
Direct transfer of starter substrates from type I fatty acid synthase to type III polyketide synthases in phenolic lipid synthesis.
  Proc Natl Acad Sci U S A, 105, 871-876.  
17847090 F.Cheng, Q.Wang, M.Chen, F.A.Quiocho, and J.Ma (2008).
Molecular docking study of the interactions between the thioesterase domain of human fatty acid synthase and its ligands.
  Proteins, 70, 1228-1234.  
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.  
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
18576636 S.E.Cellitti, D.H.Jones, L.Lagpacan, X.Hao, Q.Zhang, H.Hu, S.M.Brittain, A.Brinker, J.Caldwell, B.Bursulaya, G.Spraggon, A.Brock, Y.Ryu, T.Uno, P.G.Schultz, and B.H.Geierstanger (2008).
In vivo incorporation of unnatural amino acids to probe structure, dynamics, and ligand binding in a large protein by nuclear magnetic resonance spectroscopy.
  J Am Chem Soc, 130, 9268-9281.  
18254736 S.Zhang, T.J.Knight, J.M.Reecy, and D.C.Beitz (2008).
DNA polymorphisms in bovine fatty acid synthase are associated with beef fatty acid composition.
  Anim Genet, 39, 62-70.  
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
17618296 C.W.Pemble, L.C.Johnson, S.J.Kridel, and W.T.Lowther (2007).
Crystal structure of the thioesterase domain of human fatty acid synthase inhibited by Orlistat.
  Nat Struct Mol Biol, 14, 704-709.
PDB code: 2px6
17320476 R.E.Brown, and P.Mattjus (2007).
Glycolipid transfer proteins.
  Biochim Biophys Acta, 1771, 746-760.  
17970640 S.J.Kridel, W.T.Lowther, and C.W.Pemble (2007).
Fatty acid synthase inhibitors: new directions for oncology.
  Expert Opin Investig Drugs, 16, 1817-1829.  
17898897 S.Smith, and S.C.Tsai (2007).
The type I fatty acid and polyketide synthases: a tale of two megasynthases.
  Nat Prod Rep, 24, 1041-1072.  
16969373 J.W.Giraldes, D.L.Akey, J.D.Kittendorf, D.H.Sherman, J.L.Smith, and R.A.Fecik (2006).
Structural and mechanistic insights into polyketide macrolactonization from polyketide-based affinity labels.
  Nat Chem Biol, 2, 531-536.
PDB codes: 2h7x 2h7y
17105344 L.Malinina, M.L.Malakhova, A.T.Kanack, M.Lu, R.Abagyan, R.E.Brown, and D.J.Patel (2006).
The liganding of glycolipid transfer protein is controlled by glycolipid acyl structure.
  PLoS Biol, 4, e362.
PDB codes: 2euk 2eum 2evd 2evl 2evs 2evt
16513973 S.Smith (2006).
Structural biology. Architectural options for a fatty acid synthase.
  Science, 311, 1251-1252.  
15726818 S.S.Chirala, and S.J.Wakil (2004).
Structure and function of animal fatty acid synthase.
  Lipids, 39, 1045-1053.  
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 code is shown on the right.