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Oxidoreductase PDB id
1gvg
Jmol
Contents
Protein chain
315 a.a. *
Ligands
AKG
SO4 ×3
PCX
HOA
Metals
_FE
Waters ×392
* Residue conservation analysis
PDB id:
1gvg
Name: Oxidoreductase
Title: Crystal structure of clavaminate synthase with nitric oxide
Structure: Clavaminate synthase 1. Chain: a. Synonym: clavaminic acid synthase 1, cas1. Engineered: yes
Source: Streptomyces clavuligerus. Organism_taxid: 1901. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
1.54Å     R-factor:   0.184     R-free:   0.204
Authors: Z.H.Zhang,J.Ren,C.H.Mckinnon,I.J.Clifton,K.Harlos, C.J.Schofield
Key ref:
Z.Zhang et al. (2002). Crystal structure of a clavaminate synthase-Fe(II)-2-oxoglutarate-substrate-NO complex: evidence for metal centered rearrangements. FEBS Lett, 517, 7. PubMed id: 12062399 DOI: 10.1016/S0014-5793(02)02520-6
Date:
12-Feb-02     Release date:   07-Feb-03    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q05581  (CAS1_STRCL) -  Clavaminate synthase 1
Seq:
Struc: 		324 a.a.
315 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.1.14.11.21  - Clavaminate synthase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

      Pathway: 		Clavulanate Biosynthesis
      Reaction:
1. Deoxyamidinoproclavaminate + 2-oxoglutarate + O2 = amidinoproclavaminate + succinate + CO2
2. Proclavaminate + 2-oxoglutarate + O2 = dihydroclavaminate + succinate + CO2 + H2O
3. Dihydroclavaminate + 2-oxoglutarate + O2 = clavaminate + succinate + CO2 + H2O
Deoxyamidinoproclavaminate
Bound ligand (Het Group name = PCX)
corresponds exactly 		+
2-oxoglutarate
Bound ligand (Het Group name = AKG)
corresponds exactly 		+ O(2)
 = amidinoproclavaminate
 + succinate
 + CO(2)
Proclavaminate
Bound ligand (Het Group name = PCX)
matches with 76.00% similarity 		+
2-oxoglutarate
Bound ligand (Het Group name = AKG)
corresponds exactly 		+ O(2)
 = dihydroclavaminate
 + succinate
 + CO(2)
 + H(2)O
Dihydroclavaminate
Bound ligand (Het Group name = PCX)
matches with 76.00% similarity 		+
2-oxoglutarate
Bound ligand (Het Group name = AKG)
corresponds exactly 		+ O(2)
 = clavaminate
 + succinate
 + CO(2)
 + H(2)O
      Cofactor: Iron
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     oxidation reduction   2 terms 
  Biochemical function     oxidoreductase activity     4 terms  

 

 
    reference    
 
 
DOI no: 10.1016/S0014-5793(02)02520-6 FEBS Lett 517:7 (2002)
PubMed id: 12062399  
 
 
Crystal structure of a clavaminate synthase-Fe(II)-2-oxoglutarate-substrate-NO complex: evidence for metal centered rearrangements.
Z.Zhang, J.Ren, K.Harlos, C.H.McKinnon, I.J.Clifton, C.J.Schofield.
 
  ABSTRACT  
 
Clavaminate synthase (CAS), a 2-oxoglutarate (2OG) dependent dioxygenase, catalyses three steps in the biosynthesis of clavulanic acid. Crystals of CAS complexed with Fe(II), 2OG and deoxyguanidinoproclavaminate were exposed to nitric oxide (NO) acting as a dioxygen analogue. Prior to exposure with NO, the active site Fe(II) is octahedrally coordinated by a water molecule, the 2-oxo and 1-carboxylate groups of 2OG, and the side-chains of an aspartyl and two histidinyl residues. NO binds to the position previously occupied by the 2OG 1-carboxylate concomitant with rearrangement of the latter to the position previously occupied by the displaced water.
 
  Selected figure(s)  
 
Figure 1.
Fig. 1. a: Stoichiometry of a ‘typical’ hydroxylation reaction as catalysed by a 2OG dependent dioxygenase. Incorporation of oxygen from dioxygen into the alcohol group can be less than stoichiometric with ‘exchange’ with oxygen from water sometimes occurring (see text). b: The trifunctional role of CAS in the biosynthesis of clavulanic acid. Each CAS-catalysed step is coupled to the conversion of 2OG and dioxygen to succinate and CO[2]. The first CAS-catalysed step (hydroxylation) is separated from the latter two (oxidative cyclisation/desaturation) by the action of proclavaminate amidinohydrolase. c: Comparison of the coordination chemistry of (i) CAS and (ii) DAOCS. Binding of NO (a dioxygen analogue) to the iron of CAS results in rearrangement such that the position of the 1-carboxylate of the 2OG relative to the other ligands is the same as observed in the DAOCS–Fe(II)–2OG complex. Note the latter structure was obtained in the absence of the ‘prime’ penicillin N substrate. For CAS the approximate binding position of substrate relative to ligands is indicated (substrate). ANS has a similar coordination chemistry to that of DAOCS (with the analogous coordinating residues being His-232, Asp-234, His-288), but structures have been obtained in the presence of ‘prime substrate’. 		Figure 3.
Fig. 3. Proposed mechanistic for the catalytic cycle of 2OG dependent oxygenases involving rearrangement of a ferryl intermediate (path 1). R–H=substrate. R′=CH[2]CH[2]CO[2]^−. Exchange of oxygen from dioxygen for that from water may occur at penta-coordinate ferryl intermediates A or B or at a subsequent intermediate C. Catalysis may also proceed (partially) via dioxygen binding and reaction from the ligation position trans to His-279 (path 2, see text).
 
  The above figures are reprinted by permission from the Federation of European Biochemical Societies: FEBS Lett (2002, 517, 7-0) copyright 2002.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20728359 C.Loenarz, and C.J.Schofield (2011).
Physiological and biochemical aspects of hydroxylations and demethylations catalyzed by human 2-oxoglutarate oxygenases.
  Trends Biochem Sci, 36, 7.  
20840591 E.Flashman, L.M.Hoffart, R.B.Hamed, J.M.Bollinger, C.Krebs, and C.J.Schofield (2010).
Evidence for the slow reaction of hypoxia-inducible factor prolyl hydroxylase 2 with oxygen.
  FEBS J, 277, 4089-4099.  
21168767 I.K.Leung, T.J.Krojer, G.T.Kochan, L.Henry, F.von Delft, T.D.Claridge, U.Oppermann, M.A.McDonough, and C.J.Schofield (2010).
Structural and mechanistic studies on γ-butyrobetaine hydroxylase.
  Chem Biol, 17, 1316-1324.  
  20428459 B.J.Gaffney (2009).
EPR of Mononuclear Non-Heme Iron Proteins.
  Biol Magn Reson, 28, 233-268.  
19553701 M.K.Koski, R.Hieta, M.Hirsilä, A.Rönkä, J.Myllyharju, and R.K.Wierenga (2009).
The crystal structure of an algal prolyl 4-hydroxylase complexed with a proline-rich peptide reveals a novel buried tripeptide binding motif.
  J Biol Chem, 284, 25290-25301.
PDB code: 3gze
19604478 R.Chowdhury, M.A.McDonough, J.Mecinović, C.Loenarz, E.Flashman, K.S.Hewitson, C.Domene, and C.J.Schofield (2009).
Structural basis for binding of hypoxia-inducible factor to the oxygen-sensing prolyl hydroxylases.
  Structure, 17, 981-989.
PDB codes: 3hqr 3hqu
18459142 R.Martínez-Romero, E.Martínez-Lara, R.Aguilar-Quesada, A.Peralta, F.J.Oliver, and E.Siles (2008).
PARP-1 modulates deferoxamine-induced HIF-1alpha accumulation through the regulation of nitric oxide and oxidative stress.
  J Cell Biochem, 104, 2248-2260.  
18019494 C.A.Joseph, and M.J.Maroney (2007).
Cysteine dioxygenase: structure and mechanism.
  Chem Commun (Camb), 0, 3338-3349.  
17135241 K.S.Hewitson, B.M.Liénard, M.A.McDonough, I.J.Clifton, D.Butler, A.S.Soares, N.J.Oldham, L.A.McNeill, and C.J.Schofield (2007).
Structural and mechanistic studies on the inhibition of the hypoxia-inducible transcription factor hydroxylases by tricarboxylic acid cycle intermediates.
  J Biol Chem, 282, 3293-3301.
PDB codes: 2cgn 2cgo
17940281 M.K.Koski, R.Hieta, C.Böllner, K.I.Kivirikko, J.Myllyharju, and R.K.Wierenga (2007).
The active site of an algal prolyl 4-hydroxylase has a large structural plasticity.
  J Biol Chem, 282, 37112-37123.
PDB codes: 2jig 2jij 2v4a
17060326 U.Berchner-Pfannschmidt, H.Yamac, B.Trinidad, and J.Fandrey (2007).
Nitric oxide modulates oxygen sensing by hypoxia-inducible factor 1-dependent induction of prolyl hydroxylase 2.
  J Biol Chem, 282, 1788-1796.  
17431691 V.Purpero, and G.R.Moran (2007).
The diverse and pervasive chemistries of the alpha-keto acid dependent enzymes.
  J Biol Inorg Chem, 12, 587-601.  
16482161 B.Yu, W.C.Edstrom, J.Benach, Y.Hamuro, P.C.Weber, B.R.Gibney, and J.F.Hunt (2006).
Crystal structures of catalytic complexes of the oxidative DNA/RNA repair enzyme AlkB.
  Nature, 439, 879-884.
PDB codes: 2fd8 2fdf 2fdg 2fdh 2fdi 2fdj 2fdk
16782814 M.A.McDonough, V.Li, E.Flashman, R.Chowdhury, C.Mohr, B.M.Liénard, J.Zondlo, N.J.Oldham, I.J.Clifton, J.Lewis, L.A.McNeill, R.J.Kurzeja, K.S.Hewitson, E.Yang, S.Jordan, R.S.Syed, and C.J.Schofield (2006).
Cellular oxygen sensing: Crystal structure of hypoxia-inducible factor prolyl hydroxylase (PHD2).
  Proc Natl Acad Sci U S A, 103, 9814-9819.
PDB codes: 2g19 2g1m
16521121 T.Borowski, E.Broclawik, C.J.Schofield, and P.E.Siegbahn (2006).
Epimerization and desaturation by carbapenem synthase (CarC). A hybrid DFT study.
  J Comput Chem, 27, 740-748.  
15942729 A.Karlsson, J.V.Parales, R.E.Parales, D.T.Gibson, H.Eklund, and S.Ramaswamy (2005).
NO binding to naphthalene dioxygenase.
  J Biol Inorg Chem, 10, 483-489.
PDB codes: 1uuv 1uuw
15754339 J.Monfregola, A.Cevenini, A.Terracciano, N.van Vlies, S.Arbucci, R.J.Wanders, M.D'Urso, F.M.Vaz, and M.V.Ursini (2005).
Functional analysis of TMLH variants and definition of domains required for catalytic activity and mitochondrial targeting.
  J Cell Physiol, 204, 839-847.  
15739104 K.D.Koehntop, J.P.Emerson, and L.Que (2005).
The 2-His-1-carboxylate facial triad: a versatile platform for dioxygen activation by mononuclear non-heme iron(II) enzymes.
  J Biol Inorg Chem, 10, 87-93.  
16186124 M.A.McDonough, K.L.Kavanagh, D.Butler, T.Searls, U.Oppermann, and C.J.Schofield (2005).
Structure of human phytanoyl-CoA 2-hydroxylase identifies molecular mechanisms of Refsum disease.
  J Biol Chem, 280, 41101-41110.
PDB code: 2a1x
15122348 C.J.Schofield, and P.J.Ratcliffe (2004).
Oxygen sensing by HIF hydroxylases.
  Nat Rev Mol Cell Biol, 5, 343-354.  
14718929 K.Valegård, A.C.Terwisscha van Scheltinga, A.Dubus, G.Ranghino, L.M.Oster, J.Hajdu, and I.Andersson (2004).
The structural basis of cephalosporin formation in a mononuclear ferrous enzyme.
  Nat Struct Mol Biol, 11, 95.
PDB codes: 1unb 1uo9 1uob 1uof 1uog
15150229 L.M.Lorenzana, R.Pérez-Redondo, I.Santamarta, J.F.Martín, and P.Liras (2004).
Two oligopeptide-permease-encoding genes in the clavulanic acid cluster of Streptomyces clavuligerus are essential for production of the beta-lactamase inhibitor.
  J Bacteriol, 186, 3431-3438.  
14734545 S.Linke, C.Stojkoski, R.J.Kewley, G.W.Booker, M.L.Whitelaw, and D.J.Peet (2004).
Substrate requirements of the oxygen-sensing asparaginyl hydroxylase factor-inhibiting hypoxia-inducible factor.
  J Biol Chem, 279, 14391-14397.  
15489165 Z.Zhang, J.S.Ren, I.J.Clifton, and C.J.Schofield (2004).
Crystal structure and mechanistic implications of 1-aminocyclopropane-1-carboxylic acid oxidase--the ethylene-forming enzyme.
  Chem Biol, 11, 1383-1394.
PDB codes: 1w9y 1wa6
12611886 I.J.Clifton, L.X.Doan, M.C.Sleeman, M.Topf, H.Suzuki, R.C.Wilmouth, and C.J.Schofield (2003).
Crystal structure of carbapenem synthase (CarC).
  J Biol Chem, 278, 20843-20850.
PDB codes: 1nx4 1nx8
12446723 J.M.Elkins, K.S.Hewitson, L.A.McNeill, J.F.Seibel, I.Schlemminger, C.W.Pugh, P.J.Ratcliffe, and C.J.Schofield (2003).
Structure of factor-inhibiting hypoxia-inducible factor (HIF) reveals mechanism of oxidative modification of HIF-1 alpha.
  J Biol Chem, 278, 1802-1806.
PDB codes: 1h2k 1h2l 1h2m 1h2n
  12814641 M.Mukherji, C.J.Schofield, A.S.Wierzbicki, G.A.Jansen, R.J.Wanders, and M.D.Lloyd (2003).
The chemical biology of branched-chain lipid metabolism.
  Prog Lipid Res, 42, 359-376.  
12517755 R.W.Welford, I.Schlemminger, L.A.McNeill, K.S.Hewitson, and C.J.Schofield (2003).
The selectivity and inhibition of AlkB.
  J Biol Chem, 278, 10157-10161.  
  12413541 C.A.Townsend (2002).
New reactions in clavulanic acid biosynthesis.
  Curr Opin Chem Biol, 6, 583-589.  
12042299 K.S.Hewitson, L.A.McNeill, M.V.Riordan, Y.M.Tian, A.N.Bullock, R.W.Welford, J.M.Elkins, N.J.Oldham, S.Bhattacharya, J.M.Gleadle, P.J.Ratcliffe, C.W.Pugh, and C.J.Schofield (2002).
Hypoxia-inducible factor (HIF) asparagine hydroxylase is identical to factor inhibiting HIF (FIH) and is related to the cupin structural family.
  J Biol Chem, 277, 26351-26355.  
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.