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PDBsum entry 1rqp

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protein ligands Protein-protein interface(s) links
Transferase PDB id
1rqp
Jmol
Contents
Protein chains
291 a.a. *
Ligands
SAM ×3
Waters ×719
* Residue conservation analysis
PDB id:
1rqp
Name: Transferase
Title: Crystal structure and mechanism of a bacterial fluorinating
Structure: 5'-fluoro-5'-deoxyadenosine synthase. Chain: a, b, c. Ec: 2.5.1.63
Source: Streptomyces cattleya. Organism_taxid: 29303. Strain: nrrl8057
Biol. unit: Hexamer (from PDB file)
Resolution:
1.80Å     R-factor:   0.170     R-free:   0.217
Authors: C.Dong,F.Huang,H.Deng,C.Schaffrath,J.B.Spencer,D.O'Hagan,J.H
Key ref:
C.Dong et al. (2004). Crystal structure and mechanism of a bacterial fluorinating enzyme. Nature, 427, 561-565. PubMed id: 14765200 DOI: 10.1038/nature02280
Date:
06-Dec-03     Release date:   02-Mar-04    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
Q70GK9  (Q70GK9_STRCT) -  5'-fluoro-5'-deoxy-adenosine synthase
Seq:
Struc:
299 a.a.
291 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 

 
DOI no: 10.1038/nature02280 Nature 427:561-565 (2004)
PubMed id: 14765200  
 
 
Crystal structure and mechanism of a bacterial fluorinating enzyme.
C.Dong, F.Huang, H.Deng, C.Schaffrath, J.B.Spencer, D.O'Hagan, J.H.Naismith.
 
  ABSTRACT  
 
Fluorine is the thirteenth most abundant element in the earth's crust, but fluoride concentrations in surface water are low and fluorinated metabolites are extremely rare. The fluoride ion is a potent nucleophile in its desolvated state, but is tightly hydrated in water and effectively inert. Low availability and a lack of chemical reactivity have largely excluded fluoride from biochemistry: in particular, fluorine's high redox potential precludes the haloperoxidase-type mechanism used in the metabolic incorporation of chloride and bromide ions. But fluorinated chemicals are growing in industrial importance, with applications in pharmaceuticals, agrochemicals and materials products. Reactive fluorination reagents requiring specialist process technologies are needed in industry and, although biological catalysts for these processes are highly sought after, only one enzyme that can convert fluoride to organic fluorine has been described. Streptomyces cattleya can form carbon-fluorine bonds and must therefore have evolved an enzyme able to overcome the chemical challenges of using aqueous fluoride. Here we report the sequence and three-dimensional structure of the first native fluorination enzyme, 5'-fluoro-5'-deoxyadenosine synthase, from this organism. Both substrate and products have been observed bound to the enzyme, enabling us to propose a nucleophilic substitution mechanism for this biological fluorination reaction.
 
  Selected figure(s)  
 
Figure 3.
Figure 3: Fo -Fc electron density maps with phases calculated from models that do not include ligand. The colour scheme is the same as in Fig. 2. a, Map contoured at 3 for SAM, shown in magenta chicken wire. b, Map contoured at 2.6 for 5'-FDA and methionine, shown in blue chicken wire.
Figure 4.
Figure 4: Representation of 5'-FDA and methionine bound to the enzyme, showing hydrogen-bonding to the fluoromethyl group from Ser 158, and the anti relationship between the C -F bond (red) and the disconnected C -S bond (dotted red) of SAM that is indicative of an S[N]2 reaction course. Key residues are shown (monomer A, orange; monomer B, blue). Inset, the trajectory of the S[N]2 and the conformation of ribose that minimizes negative stereoelectronic effects.
 
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (2004, 427, 561-565) copyright 2004.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21614074 T.Furuya, A.S.Kamlet, and T.Ritter (2011).
Catalysis for fluorination and trifluoromethylation.
  Nature, 473, 470-477.  
20085308 A.S.Eustáquio, D.O'Hagan, and B.S.Moore (2010).
Engineering fluorometabolite production: fluorinase expression in Salinispora tropica Yields Fluorosalinosporamide.
  J Nat Prod, 73, 378-382.  
20372740 D.O'Hagan, and J.W.Schmidberger (2010).
Enzymes that catalyse SN2 reaction mechanisms.
  Nat Prod Rep, 27, 900-918.  
20024319 M.Onega, J.Domarkas, H.Deng, L.F.Schweiger, T.A.Smith, A.E.Welch, C.Plisson, A.D.Gee, and D.O'Hagan (2010).
An enzymatic route to 5-deoxy-5-[18F]fluoro-D-ribose, a [18F]-fluorinated sugar for PET imaging.
  Chem Commun (Camb), 46, 139-141.  
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
  20927786 T.A.Gulder, and B.S.Moore (2010).
Salinosporamide natural products: potent 20 s proteasome inhibitors as promising cancer chemotherapeutics.
  Angew Chem Int Ed Engl, 49, 9346-9367.  
20852791 X.G.Li, J.Domarkas, and D.O'Hagan (2010).
Fluorinase mediated chemoenzymatic synthesis of [(18)F]-fluoroacetate.
  Chem Commun (Camb), 46, 7819-7821.  
19675645 A.Butler, and M.Sandy (2009).
Mechanistic considerations of halogenating enzymes.
  Nature, 460, 848-854.  
19590008 A.S.Eustáquio, R.P.McGlinchey, Y.Liu, C.Hazzard, L.L.Beer, G.Florova, M.M.Alhamadsheh, A.Lechner, A.J.Kale, Y.Kobayashi, K.A.Reynolds, and B.S.Moore (2009).
Biosynthesis of the salinosporamide A polyketide synthase substrate chloroethylmalonyl-coenzyme A from S-adenosyl-L-methionine.
  Proc Natl Acad Sci U S A, 106, 12295-12300.  
19629474 C.D.Murphy, B.R.Clark, and J.Amadio (2009).
Metabolism of fluoroorganic compounds in microorganisms: impacts for the environment and the production of fine chemicals.
  Appl Microbiol Biotechnol, 84, 617-629.  
19739191 H.Deng, S.A.McMahon, A.S.Eustáquio, B.S.Moore, J.H.Naismith, and D.O'Hagan (2009).
Mechanistic insights into water activation in SAM hydroxide adenosyltransferase (duf-62).
  Chembiochem, 10, 2455-2459.
PDB code: 2wr8
19841722 J.R.Sufrin, S.Finckbeiner, and C.M.Oliver (2009).
Marine-derived metabolites of S-adenosylmethionine as templates for new anti-infectives.
  Mar Drugs, 7, 401-434.  
19374124 Y.A.Chan, A.M.Podevels, B.M.Kevany, and M.G.Thomas (2009).
Biosynthesis of polyketide synthase extender units.
  Nat Prod Rep, 26, 90.  
18059261 A.S.Eustáquio, F.Pojer, J.P.Noel, and B.S.Moore (2008).
Discovery and characterization of a marine bacterial SAM-dependent chlorinase.
  Nat Chem Biol, 4, 69-74.
PDB codes: 2q6i 2q6k 2q6l 2q6o
18720493 A.S.Eustáquio, J.Härle, J.P.Noel, and B.S.Moore (2008).
S-Adenosyl-L-methionine hydrolase (adenosine-forming), a conserved bacterial and archaeal protein related to SAM-dependent halogenases.
  Chembiochem, 9, 2215-2219.  
18291314 C.S.Neumann, D.G.Fujimori, and C.T.Walsh (2008).
Halogenation strategies in natural product biosynthesis.
  Chem Biol, 15, 99.  
  19727327 D.B.Berkowitz, K.R.Karukurichi, R.de la Salud-Bea, D.L.Nelson, and C.D.McCune (2008).
Use of Fluorinated Functionality in Enzyme Inhibitor Development: Mechanistic and Analytical Advantages.
  J Fluor Chem, 129, 731-742.  
18675376 H.Deng, and D.O'Hagan (2008).
The fluorinase, the chlorinase and the duf-62 enzymes.
  Curr Opin Chem Biol, 12, 582-592.  
19101471 H.Deng, S.M.Cross, R.P.McGlinchey, J.T.Hamilton, and D.O'Hagan (2008).
In vitro reconstituted biotransformation of 4-fluorothreonine from fluoride ion: application of the fluorinase.
  Chem Biol, 15, 1268-1276.  
17884311 K.Dvoráková-Hortová, M.Sandera, M.Jursová, J.Vasinová, and J.Peknicová (2008).
The influence of fluorides on mouse sperm capacitation.
  Anim Reprod Sci, 108, 157-170.  
17910070 K.N.Rao, S.K.Burley, and S.Swaminathan (2008).
Crystal structure of a conserved protein of unknown function (MJ1651) from Methanococcus jannaschii.
  Proteins, 70, 572-577.
PDB code: 2f4n
18818720 R.Mazumder, and S.Vasudevan (2008).
Structure-guided comparative analysis of proteins: principles, tools, and applications for predicting function.
  PLoS Comput Biol, 4, e1000151.  
17881282 D.G.Fujimori, and C.T.Walsh (2007).
What's new in enzymatic halogenations.
  Curr Opin Chem Biol, 11, 553-560.  
17555351 S.N.Chen, D.C.Lankin, D.Nikolic, D.S.Fabricant, Z.Z.Lu, B.Ramirez, R.B.van Breemen, H.H.Fong, N.R.Farnsworth, and G.F.Pauli (2007).
Chlorination diversifies Cimicifuga racemosa triterpene glycosides.
  J Nat Prod, 70, 1016-1023.  
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.  
16446840 H.Deng, S.L.Cobb, A.D.Gee, A.Lockhart, L.Martarello, R.P.McGlinchey, D.O'Hagan, and M.Onega (2006).
Fluorinase mediated C-(18)F bond formation, an enzymatic tool for PET labelling.
  Chem Commun (Camb), (), 652-654.  
16370017 H.Deng, S.L.Cobb, A.R.McEwan, R.P.McGlinchey, J.H.Naismith, D.O'Hagan, D.A.Robinson, and J.B.Spencer (2006).
The fluorinase from Streptomyces cattleya is also a chlorinase.
  Angew Chem Int Ed Engl, 45, 759-762.
PDB code: 2c2w
16936924 J.H.Naismith (2006).
Inferring the chemical mechanism from structures of enzymes.
  Chem Soc Rev, 35, 763-770.  
16880954 J.L.Anderson, and S.K.Chapman (2006).
Molecular mechanisms of enzyme-catalysed halogenation.
  Mol Biosyst, 2, 350-357.  
16544142 K.H.van Pée, and E.P.Patallo (2006).
Flavin-dependent halogenases involved in secondary metabolism in bacteria.
  Appl Microbiol Biotechnol, 70, 631-641.  
16604208 S.L.Cobb, H.Deng, A.R.McEwan, J.H.Naismith, D.O'Hagan, and D.A.Robinson (2006).
Substrate specificity in enzymatic fluorination. The fluorinase from Streptomyces cattleya accepts 2'-deoxyadenosine substrates.
  Org Biomol Chem, 4, 1458-1460.
PDB codes: 2c4u 2c5b 2cbx 2cc2
16195462 C.Dong, S.Flecks, S.Unversucht, C.Haupt, K.H.van Pée, and J.H.Naismith (2005).
Tryptophan 7-halogenase (PrnA) structure suggests a mechanism for regioselective chlorination.
  Science, 309, 2216-2219.
PDB codes: 2apg 2aqj 2ar8 2ard
16317469 M.A.Vincent, and I.H.Hillier (2005).
The solvated fluoride anion can be a good nucleophile.
  Chem Commun (Camb), (), 5902-5903.  
16225687 P.Z.Kozbial, and A.R.Mushegian (2005).
Natural history of S-adenosylmethionine-binding proteins.
  BMC Struct Biol, 5, 19.  
16125262 T.C.Galvão, W.W.Mohn, and V.de Lorenzo (2005).
Exploring the microbial biodegradation and biotransformation gene pool.
  Trends Biotechnol, 23, 497-506.  
15272157 A.W.Schüttelkopf, and D.M.van Aalten (2004).
PRODRG: a tool for high-throughput crystallography of protein-ligand complexes.
  Acta Crystallogr D Biol Crystallogr, 60, 1355-1363.  
15122641 C.D.Cadicamo, J.Courtieu, H.Deng, A.Meddour, and D.O'Hagan (2004).
Enzymatic fluorination in Streptomyces cattleya takes place with an inversion of configuration consistent with an SN2 reaction mechanism.
  Chembiochem, 5, 685-690.  
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.