PDBsum entry 1fgh

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Lyase PDB id
Protein chain
753 a.a. *
Waters ×258
* Residue conservation analysis
PDB id:
Name: Lyase
Title: Complex with 4-hydroxy-trans-aconitate
Structure: Aconitase. Chain: a. Other_details: [4fe-4s] bound by cys 358, cys 421, cys 424
Source: Bos taurus. Cattle. Organism_taxid: 9913. Organ: heart. Tissue: heart mitochondria
2.05Å     R-factor:   0.177    
Authors: H.Lauble,M.C.Kennedy,M.H.Emptage,H.Beinert,C.D.Stout
Key ref: H.Lauble et al. (1996). The reaction of fluorocitrate with aconitase and the crystal structure of the enzyme-inhibitor complex. Proc Natl Acad Sci U S A, 93, 13699-13703. PubMed id: 8942997
14-Sep-96     Release date:   23-Dec-96    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P20004  (ACON_BOVIN) -  Aconitate hydratase, mitochondrial
780 a.a.
753 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 13 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.  - Aconitate hydratase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

Aconitate Hydratase
      Reaction: Citrate = isocitrate
Bound ligand (Het Group name = ATH)
corresponds exactly
      Cofactor: Iron-sulfur
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     nucleus   2 terms 
  Biological process     metabolic process   3 terms 
  Biochemical function     lyase activity     6 terms  


Proc Natl Acad Sci U S A 93:13699-13703 (1996)
PubMed id: 8942997  
The reaction of fluorocitrate with aconitase and the crystal structure of the enzyme-inhibitor complex.
H.Lauble, M.C.Kennedy, M.H.Emptage, H.Beinert, C.D.Stout.
It has been known for many years that fluoroacetate and fluorocitrate when metabolized are highly toxic, and that at least one effect of fluorocitrate is to inactivate aconitase. In this paper we present evidence supporting the hypothesis that the (-)-erythro diastereomer of 2-fluorocitrate acts as a mechanism based inhibitor of aconitase by first being converted to fluoro-cis-aconitate, followed by addition of hydroxide and with loss of fluoride to form 4-hydroxy-trans-aconitate (HTn), which binds very tightly, but not covalently, to the enzyme. Formation of HTn by these reactions is in accord with the working model for the enzyme mechanism. That HTn is the product of fluorocitrate inhibition is supported by the crystal structure of the enzyme-inhibitor complex at 2.05-A resolution, release of fluoride stoichiometric with total enzyme when (-)-erythro-2-fluorocitrate is added, HPLC analysis of the product, slow displacement of HTn by 10(6)-fold excess of isocitrate, and previously published Mössbauer experiments. When (+)-erythro-2-fluorocitrate is added to aconitase, the release of fluoride is stoichiometric with total substrate added, and HPLC analysis of the products indicates the formation of oxalosuccinate, and its derivative alpha-ketoglutarate. This is consistent with the proposed mechanism, as is the formation of HTn from (-)-erythro-2-fluorocitrate. The structure of the inhibited complex reveals that HTn binds like the inhibitor trans-aconitate while providing all the interactions of the natural substrate, isocitrate. The structure exhibits four hydrogen bonds < 2.7 A in length involving HTn, H2O bound to the [4Fe-4S] cluster, Asp-165 and His-167, as well as low temperature factors for these moieties, consistent with the observed very tight binding of the inhibitor.

Literature references that cite this PDB file's key reference

  PubMed id Reference
20938981 K.Manikandan, A.Geerlof, A.V.Zozulya, D.I.Svergun, and M.S.Weiss (2011).
Structural studies on the enzyme complex isopropylmalate isomerase (LeuCD) from Mycobacterium tuberculosis.
  Proteins, 79, 35-49.
PDB codes: 3h5e 3h5h 3h5j
21307570 T.Kurihara (2011).
A mechanistic analysis of enzymatic degradation of organohalogen compounds.
  Biosci Biotechnol Biochem, 75, 189-198.  
20407036 G.C.Bullock, L.L.Delehanty, A.L.Talbot, S.L.Gonias, W.H.Tong, T.A.Rouault, B.Dewar, J.M.Macdonald, J.J.Chruma, and A.N.Goldfarb (2010).
Iron control of erythroid development by a novel aconitase-associated regulatory pathway.
  Blood, 116, 97.  
20430898 M.V.Dias, F.Huang, D.Y.Chirgadze, M.Tosin, D.Spiteller, E.F.Dry, P.F.Leadlay, J.B.Spencer, and T.L.Blundell (2010).
Structural basis for the activity and substrate specificity of fluoroacetyl-CoA thioesterase FlK.
  J Biol Chem, 285, 22495-22504.
PDB codes: 3kuv 3kuw 3kv7 3kv8 3kvi 3kvu 3kvz 3kw1 3kx7 3kx8
19727587 L.Wang, C.C.Li, G.W.Wang, and J.X.Cai (2009).
The effects of centrally administered fluorocitrate via inhibiting glial cells on working memory in rats.
  Sci China C Life Sci, 52, 701-709.  
19551770 T.Kamachi, T.Nakayama, O.Shitamichi, K.Jitsumori, T.Kurihara, N.Esaki, and K.Yoshizawa (2009).
The catalytic mechanism of fluoroacetate dehalogenase: a computational exploration of biological dehalogenation.
  Chemistry, 15, 7394-7403.  
18784756 L.C.Burow, A.N.Mabbett, and L.L.Blackall (2008).
Anaerobic glyoxylate cycle activity during simultaneous utilization of glycogen and acetate in uncultured Accumulibacter enriched in enhanced biological phosphorus removal communities.
  ISME J, 2, 1040-1051.  
18820013 M.R.Sadykov, M.E.Olson, S.Halouska, Y.Zhu, P.D.Fey, R.Powers, and G.A.Somerville (2008).
Tricarboxylic acid cycle-dependent regulation of Staphylococcus epidermidis polysaccharide intercellular adhesin synthesis.
  J Bacteriol, 190, 7621-7632.  
17469137 D.R.Crooks, M.C.Ghosh, M.Braun-Sommargren, T.A.Rouault, and D.R.Smith (2007).
Manganese targets m-aconitase and activates iron regulatory protein 2 in AF5 GABAergic cells.
  J Neurosci Res, 85, 1797-1809.  
17288493 A.T.Proudfoot, S.M.Bradberry, and J.A.Vale (2006).
Sodium fluoroacetate poisoning.
  Toxicol Rev, 25, 213-219.  
16720268 F.Huang, S.F.Haydock, D.Spiteller, T.Mironenko, T.L.Li, D.O'Hagan, P.F.Leadlay, and J.B.Spencer (2006).
The gene cluster for fluorometabolite biosynthesis in Streptomyces cattleya: a thioesterase confers resistance to fluoroacetyl-coenzyme A.
  Chem Biol, 13, 475-484.  
16252258 N.V.Goncharov, R.O.Jenkins, and A.S.Radilov (2006).
Toxicology of fluoroacetate: a review, with possible directions for therapy research.
  J Appl Toxicol, 26, 148-161.  
16119418 C.S.Goh, D.R.Hodgson, S.M.Fearnside, J.Heller, and N.Malikides (2005).
Sodium monofluoroacetate (Compound 1080) poisoning in dogs.
  Aust Vet J, 83, 474-479.  
15838022 C.Vuong, J.B.Kidder, E.R.Jacobson, M.Otto, R.A.Proctor, and G.A.Somerville (2005).
Staphylococcus epidermidis polysaccharide intercellular adhesin production significantly increases during tricarboxylic acid cycle stress.
  J Bacteriol, 187, 2967-2973.  
15819878 S.Rajagopal, and S.Vishveshwara (2005).
Short hydrogen bonds in proteins.
  FEBS J, 272, 1819-1832.  
12044177 G.Cairo, R.Ronchi, S.Recalcati, A.Campanella, and G.Minotti (2002).
Nitric oxide and peroxynitrite activate the iron regulatory protein-1 of J774A.1 macrophages by direct disassembly of the Fe-S cluster of cytoplasmic aconitase.
  Biochemistry, 41, 7435-7442.  
  9973331 G.Somerville, C.A.Mikoryak, and L.Reitzer (1999).
Physiological characterization of Pseudomonas aeruginosa during exotoxin A synthesis: glutamate, iron limitation, and aconitase activity.
  J Bacteriol, 181, 1072-1078.  
9326580 L.J.Yan, R.L.Levine, and R.S.Sohal (1997).
Oxidative damage during aging targets mitochondrial aconitase.
  Proc Natl Acad Sci U S A, 94, 11168-11172.  
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.