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PDBsum entry 1aj0

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Synthase PDB id
1aj0
Jmol
Contents
Protein chain
282 a.a. *
Ligands
SO4
PH2
SAN
Waters ×105
* Residue conservation analysis
PDB id:
1aj0
Name: Synthase
Title: Crystal structure of a ternary complex of e. Coli dihydropte synthase
Structure: Dihydropteroate synthase. Chain: a. Synonym: dhps. Ec: 2.5.1.15
Source: Escherichia coli. Organism_taxid: 562
Resolution:
2.00Å     R-factor:   0.206    
Authors: A.Achari,D.O.Somers,J.N.Champness,P.K.Bryant,J.Rosemond,D.K.
Key ref: A.Achari et al. (1997). Crystal structure of the anti-bacterial sulfonamide drug target dihydropteroate synthase. Nat Struct Biol, 4, 490-497. PubMed id: 9187658
Date:
14-May-97     Release date:   20-May-98    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P0AC13  (DHPS_ECOLI) -  Dihydropteroate synthase
Seq:
Struc:
282 a.a.
282 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.2.5.1.15  - Dihydropteroate synthase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

      Pathway:
Folate Biosynthesis (late stages)
      Reaction: (2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate + 4-aminobenzoate = diphosphate + dihydropteroate
(2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate
+
4-aminobenzoate
Bound ligand (Het Group name = SAN)
matches with 50.00% similarity
= diphosphate
+
dihydropteroate
Bound ligand (Het Group name = PH2)
matches with 54.17% similarity
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cytoplasm   1 term 
  Biological process     cellular metabolic process   7 terms 
  Biochemical function     transferase activity     3 terms  

 

 
    reference    
 
 
Nat Struct Biol 4:490-497 (1997)
PubMed id: 9187658  
 
 
Crystal structure of the anti-bacterial sulfonamide drug target dihydropteroate synthase.
A.Achari, D.O.Somers, J.N.Champness, P.K.Bryant, J.Rosemond, D.K.Stammers.
 
  ABSTRACT  
 
Sulfonamides were amongst the first clinically useful antibacterial agents to be discovered. The identification of sulfanilamide as the active component of the dye Prontosil rubrum led to the synthesis of clinically useful analogues. Today sulfamethoxazole (in combination with trimethoprim), is used to treat urinary tract infections caused by bacteria such as Escherichia coli and is also a first-line treatment for pneumonia caused by the fungus Pneumocystis carinii, a common condition in AIDS patients. The site of action is the de novo folate biosynthesis enzyme dihydropteroate synthase (DHPS) where sulfonamides act as analogues of one of the substrates, para-aminobenzoic acid (pABA). We report here the crystal structure of E.coli DHPS at 2.0 A resolution refined to an R-factor of 0.185. The single domain of 282 residues forms an eight-stranded alpha/beta-barrel. The 7,8-dihydropterin pyrophosphate (DHPPP) substrate binds in a deep cleft in the barrel, whilst sulfanilamide binds closer to the surface. The DHPPP ligand site is highly conserved amongst prokaryotic and eukaryotic DHPSs.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21513713 A.Fabbretti, C.O.Gualerzi, and L.Brandi (2011).
How to cope with the quest for new antibiotics.
  FEBS Lett, 585, 1673-1681.  
21154844 H.Wang, Y.Li, H.Huang, X.Xu, and Y.Wang (2011).
Toxicity evaluation of single and mixed antifouling biocides using the Strongylocentrotus intermedius sea urchin embryo test.
  Environ Toxicol Chem, 30, 692-703.  
20429775 P.Jayaraman, K.R.Sakharkar, L.C.Sing, V.T.Chow, and M.K.Sakharkar (2011).
Insights into antifolate activity of phytochemicals against Pseudomonas aeruginosa.
  J Drug Target, 19, 179-188.  
21152407 C.W.Pemble, P.K.Mehta, S.Mehra, Z.Li, A.Nourse, R.E.Lee, and S.W.White (2010).
Crystal structure of the 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase•dihydropteroate synthase bifunctional enzyme from Francisella tularensis.
  PLoS One, 5, e14165.
PDB codes: 3mcm 3mcn 3mco
19899766 K.E.Hevener, M.K.Yun, J.Qi, I.D.Kerr, K.Babaoglu, J.G.Hurdle, K.Balakrishna, S.W.White, and R.E.Lee (2010).
Structural studies of pterin-based inhibitors of dihydropteroate synthase.
  J Med Chem, 53, 166-177.
PDB codes: 3h21 3h22 3h23 3h24 3h26 3h2a 3h2c 3h2e 3h2f 3h2m 3h2n 3h2o
20709183 P.G.De Benedetti, and F.Fanelli (2010).
Computational quantum chemistry and adaptive ligand modeling in mechanistic QSAR.
  Drug Discov Today, 15, 859-866.  
19434845 K.E.Hevener, W.Zhao, D.M.Ball, K.Babaoglu, J.Qi, S.W.White, and R.E.Lee (2009).
Validation of molecular docking programs for virtual screening against dihydropteroate synthase.
  J Chem Inf Model, 49, 444-460.  
18482337 G.S.Rao, and M.Kumar (2008).
Structure-based design of a potent and selective small peptide inhibitor of Mycobacterium tuberculosis 6-hydroxymethyl-7, 8-dihydropteroate synthase: a computer modelling approach.
  Chem Biol Drug Des, 71, 540-545.  
18500934 N.Bakkali, F.Fenollar, S.Biswas, J.M.Rolain, and D.Raoult (2008).
Acquired resistance to trimethoprim-sulfamethoxazole during Whipple disease and expression of the causative target gene.
  J Infect Dis, 198, 101-108.  
18804699 S.W.Ragsdale (2008).
Catalysis of methyl group transfers involving tetrahydrofolate and B(12).
  Vitam Horm, 79, 293-324.  
17558331 A.Valerio, E.Tronconi, F.Mazza, G.Fantoni, C.Atzori, F.Tartarone, P.Duca, and A.Cargnel (2007).
Genotyping of Pneumocystis jiroveci pneumonia in Italian AIDS patients. Clinical outcome is influenced by dihydropteroate synthase and not by internal transcribed spacer genotype.
  J Acquir Immune Defic Syndr, 45, 521-528.  
17363968 C.F.Thomas, and A.H.Limper (2007).
Current insights into the biology and pathogenesis of Pneumocystis pneumonia.
  Nat Rev Microbiol, 5, 298-308.  
17222188 E.C.Banks, S.W.Doughty, S.M.Toms, R.T.Wheelhouse, and A.Nicolaou (2007).
Inhibition of cobalamin-dependent methionine synthase by substituted benzo-fused heterocycles.
  FEBS J, 274, 287-299.  
17266529 J.E.Hyde (2007).
Targeting purine and pyrimidine metabolism in human apicomplexan parasites.
  Curr Drug Targets, 8, 31-47.  
17536929 M.W.Valderas, P.C.Bourne, and W.W.Barrow (2007).
Genetic basis for sulfonamide resistance in Bacillus anthracis.
  Microb Drug Resist, 13, 11-20.  
17868687 S.Chakrabarti, S.H.Bryant, and A.R.Panchenko (2007).
Functional specificity lies within the properties and evolutionary changes of amino acids.
  J Mol Biol, 373, 801-810.  
17172470 T.I.Doukov, H.Hemmi, C.L.Drennan, and S.W.Ragsdale (2007).
Structural and kinetic evidence for an extended hydrogen-bonding network in catalysis of methyl group transfer. Role of an active site asparagine residue in activation of methyl transfer by methyltransferases.
  J Biol Chem, 282, 6609-6618.
PDB codes: 2e7f 2ogy
16997145 A.Nzila (2006).
Inhibitors of de novo folate enzymes in Plasmodium falciparum.
  Drug Discov Today, 11, 939-944.  
16355335 E.Cambau, L.Carthagena, A.Chauffour, B.Ji, and V.Jarlier (2006).
Dihydropteroate synthase mutations in the folP1 gene predict dapsone resistance in relapsed cases of leprosy.
  Clin Infect Dis, 42, 238-241.  
17016423 P.Imming, C.Sinning, and A.Meyer (2006).
Drugs, their targets and the nature and number of drug targets.
  Nat Rev Drug Discov, 5, 821-834.  
17661690 Y.Yuthavong, S.Kamchonwongpaisan, U.Leartsakulpanich, and P.Chitnumsub (2006).
Folate metabolism as a source of molecular targets for antimalarials.
  Future Microbiol, 1, 113-125.  
16099766 F.Giordanetto, P.W.Fowler, M.Saqi, and P.V.Coveney (2005).
Large scale molecular dynamics simulation of native and mutant dihydropteroate synthase-sulphanilamide complexes suggests the molecular basis for dihydropteroate synthase drug resistance.
  Philos Transact A Math Phys Eng Sci, 363, 2055-2073.  
15759312 G.F.Zhang, K.A.Mortier, S.Storozhenko, J.Van De Steene, D.Van Der Straeten, and W.E.Lambert (2005).
Free and total para-aminobenzoic acid analysis in plants with high-performance liquid chromatography/tandem mass spectrometry.
  Rapid Commun Mass Spectrom, 19, 963-969.  
16191898 M.C.Costa, J.Gaspar, K.Mansinho, F.Esteves, F.Antunes, and O.Matos (2005).
Detection of Pneumocystis jirovecii dihydropteroate synthase polymorphisms in patients with Pneumocystis pneumonia.
  Scand J Infect Dis, 37, 766-771.  
15673759 P.Iliades, S.R.Meshnick, and I.G.Macreadie (2005).
Mutations in the Pneumocystis jirovecii DHPS gene confer cross-resistance to sulfa drugs.
  Antimicrob Agents Chemother, 49, 741-748.  
15215117 I.Meneau, D.Sanglard, J.Bille, and P.M.Hauser (2004).
Pneumocystis jiroveci dihydropteroate synthase polymorphisms confer resistance to sulfadoxine and sulfanilamide in Saccharomyces cerevisiae.
  Antimicrob Agents Chemother, 48, 2610-2616.  
15341734 K.Babaoglu, J.Qi, R.E.Lee, and S.W.White (2004).
Crystal structure of 7,8-dihydropteroate synthase from Bacillus anthracis: mechanism and novel inhibitor design.
  Structure, 12, 1705-1717.
PDB codes: 1tws 1tww 1twz 1tx0 1tx2
15155224 M.Korsinczky, K.Fischer, N.Chen, J.Baker, K.Rieckmann, and Q.Cheng (2004).
Sulfadoxine resistance in Plasmodium vivax is associated with a specific amino acid in dihydropteroate synthase at the putative sulfadoxine-binding site.
  Antimicrob Agents Chemother, 48, 2214-2222.  
15215118 P.Iliades, S.R.Meshnick, and I.G.Macreadie (2004).
Dihydropteroate synthase mutations in Pneumocystis jiroveci can affect sulfamethoxazole resistance in a Saccharomyces cerevisiae model.
  Antimicrob Agents Chemother, 48, 2617-2623.  
14506052 D.E.Bennett, and M.T.Cafferkey (2003).
PCR and restriction endonuclease assay for detection of a novel mutation associated with sulfonamide resistance in Neisseria meningitidis.
  Antimicrob Agents Chemother, 47, 3336-3338.  
14659042 R.E.Davis, R.Jomantiene, Y.Zhao, and E.L.Dally (2003).
Folate biosynthesis pseudogenes, PsifolP and PsifolK, and an O-sialoglycoprotein endopeptidase gene homolog in the phytoplasma genome.
  DNA Cell Biol, 22, 697-706.  
12111724 A.Bermingham, and J.P.Derrick (2002).
The folic acid biosynthesis pathway in bacteria: evaluation of potential for antibacterial drug discovery.
  Bioessays, 24, 637-648.  
12019111 V.I.Enne, A.King, D.M.Livermore, and L.M.Hall (2002).
Sulfonamide resistance in Haemophilus influenzae mediated by acquisition of sul2 or a short insertion in chromosomal folP.
  Antimicrob Agents Chemother, 46, 1934-1939.  
12039964 V.Illarionova, W.Eisenreich, M.Fischer, C.Haussmann, W.Romisch, G.Richter, and A.Bacher (2002).
Biosynthesis of tetrahydrofolate. Stereochemistry of dihydroneopterin aldolase.
  J Biol Chem, 277, 28841-28847.  
11371182 E.E.Trimmer, D.P.Ballou, M.L.Ludwig, and R.G.Matthews (2001).
Folate activation and catalysis in methylenetetrahydrofolate reductase from Escherichia coli: roles for aspartate 120 and glutamate 28.
  Biochemistry, 40, 6216-6226.  
11181359 L.Ma, and J.A.Kovacs (2001).
Rapid detection of mutations in the human-derived Pneumocystis carinii dihydropteroate synthase gene associated with sulfa resistance.
  Antimicrob Agents Chemother, 45, 776-780.  
11076529 A.E.Smith, and R.G.Matthews (2000).
Protonation state of methyltetrahydrofolate in a binary complex with cobalamin-dependent methionine synthase.
  Biochemistry, 39, 13880-13890.  
  10827116 C.B.Beard, J.L.Carter, S.P.Keely, L.Huang, N.J.Pieniazek, I.N.Moura, J.M.Roberts, A.W.Hightower, M.S.Bens, A.R.Freeman, S.Lee, J.R.Stringer, J.S.Duchin, C.del Rio, D.Rimland, R.P.Baughman, D.A.Levy, V.J.Dietz, P.Simon, and T.R.Navin (2000).
Genetic variation in Pneumocystis carinii isolates from different geographic regions: implications for transmission.
  Emerg Infect Dis, 6, 265-272.  
11498380 O.Sköld (2000).
Sulfonamide resistance: mechanisms and trends.
  Drug Resist Updat, 3, 155-160.  
10997901 T.Doukov, J.Seravalli, J.J.Stezowski, and S.W.Ragsdale (2000).
Crystal structure of a methyltetrahydrofolate- and corrinoid-dependent methyltransferase.
  Structure, 8, 817-830.
PDB code: 1f6y
  10970350 T.Takahashi, N.Hosoya, T.Endo, T.Nakamura, H.Sakashita, K.Kimura, K.Ohnishi, Y.Nakamura, and A.Iwamoto (2000).
Relationship between mutations in dihydropteroate synthase of Pneumocystis carinii f. sp. hominis isolates in Japan and resistance to sulfonamide therapy.
  J Clin Microbiol, 38, 3161-3164.  
10474189 M.Kai, M.Matsuoka, N.Nakata, S.Maeda, M.Gidoh, Y.Maeda, K.Hashimoto, K.Kobayashi, and Y.Kashiwabara (1999).
Diaminodiphenylsulfone resistance of Mycobacterium leprae due to mutations in the dihydropteroate synthase gene.
  FEMS Microbiol Lett, 177, 231-235.  
11504465 T.Triglia, and A.F.Cowman (1999).
The mechanism of resistance to sulfa drugs in Plasmodium falciparum.
  Drug Resist Updat, 2, 15-19.  
  10542185 V.Nopponpunth, W.Sirawaraporn, P.J.Greene, and D.V.Santi (1999).
Cloning and expression of Mycobacterium tuberculosis and Mycobacterium leprae dihydropteroate synthase in Escherichia coli.
  J Bacteriol, 181, 6814-6821.  
9651328 C.Haussmann, F.Rohdich, E.Schmidt, A.Bacher, and G.Richter (1998).
Biosynthesis of pteridines in Escherichia coli. Structural and mechanistic similarity of dihydroneopterin-triphosphate epimerase and dihydroneopterin aldolase.
  J Biol Chem, 273, 17418-17424.  
17092806 D.J.Walker, and S.R.Meshnick (1998).
Drug resistance in Pneumocystis carinii: an emerging problem.
  Drug Resist Updat, 1, 201-204.  
  9593127 G.Swedberg, S.Ringertz, and O.Sköld (1998).
Sulfonamide resistance in Streptococcus pyogenes is associated with differences in the amino acid sequence of its chromosomal dihydropteroate synthase.
  Antimicrob Agents Chemother, 42, 1062-1067.  
  9449266 G.Vedantam, G.G.Guay, N.E.Austria, S.Z.Doktor, and B.P.Nichols (1998).
Characterization of mutations contributing to sulfathiazole resistance in Escherichia coli.
  Antimicrob Agents Chemother, 42, 88-93.  
9586996 M.Hennig, A.D'Arcy, I.C.Hampele, M.G.Page, C.Oefner, and G.E.Dale (1998).
Crystal structure and reaction mechanism of 7,8-dihydroneopterin aldolase from Staphylococcus aureus.
  Nat Struct Biol, 5, 357-362.
PDB codes: 1dhn 2dhn
9745357 M.P.Zanni, B.Schnyder, S.von Greyerz, and W.J.Pichler (1998).
Involvement of T cells in drug-induced allergies.
  Trends Pharmacol Sci, 19, 308-310.  
9631140 P.Kazanjian, A.B.Locke, P.A.Hossler, B.R.Lane, M.S.Bartlett, J.W.Smith, M.Cannon, and S.R.Meshnick (1998).
Pneumocystis carinii mutations associated with sulfa and sulfone prophylaxis failures in AIDS patients.
  AIDS, 12, 873-878.  
9620722 Q.Mei, S.Gurunathan, H.Masur, and J.A.Kovacs (1998).
Failure of co-trimoxazole in Pneumocystis carinii infection and mutations in dihydropteroate synthase gene.
  Lancet, 351, 1631-1632.  
9669998 T.Triglia, P.Wang, P.F.Sims, J.E.Hyde, and A.F.Cowman (1998).
Allelic exchange at the endogenous genomic locus in Plasmodium falciparum proves the role of dihydropteroate synthase in sulfadoxine-resistant malaria.
  EMBO J, 17, 3807-3815.  
9542601 W.J.Pichler, B.Schnyder, M.P.Zanni, Y.Hari, and S.von Greyerz (1998).
Role of T cells in drug allergies.
  Allergy, 53, 225-232.  
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.