PDBsum entry 1b4k

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Lyase PDB id
Protein chains
326 a.a. *
SO4 ×2
SHF ×2
Waters ×572
* Residue conservation analysis
PDB id:
Name: Lyase
Title: High resolution crystal structure of a mg2-dependent 5-amino acid dehydratase
Structure: Protein (5-aminolevulinic acid dehydratase). Chain: a, b. Synonym: porphobilinogen synthase. Engineered: yes. Other_details: schiff base link between atom nz of lys260 a of levulinic acid
Source: Pseudomonas aeruginosa. Organism_taxid: 208964. Strain: pao1. Atcc: atcc 15692. Collection: atcc 15692. Cellular_location: cytoplasm. Gene: hemb. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Biol. unit: Homo-Octamer (from PDB file)
1.67Å     R-factor:   0.178     R-free:   0.208
Authors: N.Frankenberg,D.Jahn,D.W.Heinz
Key ref:
N.Frankenberg et al. (1999). High resolution crystal structure of a Mg2+-dependent porphobilinogen synthase. J Mol Biol, 289, 591-602. PubMed id: 10356331 DOI: 10.1006/jmbi.1999.2808
22-Dec-98     Release date:   13-Jul-99    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
Q59643  (HEM2_PSEAE) -  Delta-aminolevulinic acid dehydratase
337 a.a.
326 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

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

Porphyrin Biosynthesis (early stages)
      Reaction: 2 5-aminolevulinate = porphobilinogen + 2 H2O
2 × 5-aminolevulinate
Bound ligand (Het Group name = SHF)
matches with 77.78% similarity
= porphobilinogen
+ 2 × H(2)O
      Cofactor: Zn(2+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     tetrapyrrole biosynthetic process   4 terms 
  Biochemical function     catalytic activity     4 terms  


    Added reference    
DOI no: 10.1006/jmbi.1999.2808 J Mol Biol 289:591-602 (1999)
PubMed id: 10356331  
High resolution crystal structure of a Mg2+-dependent porphobilinogen synthase.
N.Frankenberg, P.T.Erskine, J.B.Cooper, P.M.Shoolingin-Jordan, D.Jahn, D.W.Heinz.
Common to the biosynthesis of all known tetrapyrroles is the condensation of two molecules of 5-aminolevulinic acid to the pyrrole porphobilinogen catalyzed by the enzyme porphobilinogen synthase (PBGS). Two major classes of PBGS are known. Zn2+-dependent PBGSs are found in mammals, yeast and some bacteria including Escherichia coli, while Mg2+-dependent PBGSs are present mainly in plants and other bacteria. The crystal structure of the Mg2+-dependent PBGS from the human pathogen Pseudomonas aeruginosa in complex with the competitive inhibitor levulinic acid (LA) solved at 1.67 A resolution shows a homooctameric enzyme that consists of four asymmetric dimers. The monomers in each dimer differ from each other by having a "closed" and an "open" active site pocket. In the closed subunit, the active site is completely shielded from solvent by a well-defined lid that is partially disordered in the open subunit. A single molecule of LA binds to a mainly hydrophobic pocket in each monomer where it is covalently attached via a Schiff base to an active site lysine residue. Whereas no metal ions are found in the active site of both monomers, a single well-defined and highly hydrated Mg2+is present only in the closed form about 14 A away from the Schiff base forming nitrogen atom of the active site lysine. We conclude that the observed differences in the active sites of both monomers might be induced by Mg2+-binding to this remote site and propose a structure-based mechanism for this allosteric Mg2+in rate enhancement.
  Selected figure(s)  
Figure 7.
Figure 7. Close-up view of the active site of PBGS. Shown are the side-chain chains of amino acid residues (Phe 86, Asp131, Asp139, Lys205, Tyr211, Phe214, Arg215, Lys229, Gln233, Lys260, Tyr283, Ser286 and Tyr324) forming the A and P-site substrate binding pockets. The competitive inhibitor levulinic acid (LA) covalently attached to the side-chain of Lys260 in the P-site is shown with yellow bonds. A bound sulfate ion (SO4) in the putative A-site is colored green. In addition a well-defined water molecule (H2O) is shown in the A-site. Hydrogen bonds are indicated by grey dotted lines. The side-chains of Asp131 and Asp139 that are substituted by Zn 2+ -coordinating cysteine residues, respectively, in the Zn 2+ -dependent enzymes, are shown with blue bonds.
Figure 8.
Figure 8. The Mg 2+ -binding site in monomer A of PBGS. The metal ion (Mg, pink sphere) is octahedrally coordinated to the side-chain of Glu245 and five water molecules. Also shown are the side-chains of amino acid residues (Asp179, Arg181 and Asp241) that form hydro- gen bonding interactions with the water molecules. The side-chain of Arg190 belongs to the extended N-terminal arm of the neighboring PBGS monomer B and interacts with Glu245. The final 2Fo - Fc electron density map contoured at 1.8s is shown as thin-lined cyan-colored cages. Hydrogen bonding and other close non-covalent interactions are shown as dotted orange lines.
  The above figures are reprinted by permission from Elsevier: J Mol Biol (1999, 289, 591-602) copyright 1999.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21514151 N.Iwai, K.Nakayama, J.Oku, and T.Kitazume (2011).
Synthesis and antibacterial activity of alaremycin derivatives for the porphobilinogen synthase.
  Bioorg Med Chem Lett, 21, 2812-2815.  
20506125 G.Layer, J.Reichelt, D.Jahn, and D.W.Heinz (2010).
Structure and function of enzymes in heme biosynthesis.
  Protein Sci, 19, 1137-1161.  
19822707 I.U.Heinemann, C.Schulz, W.D.Schubert, D.W.Heinz, Y.G.Wang, Y.Kobayashi, Y.Awa, M.Wachi, D.Jahn, and M.Jahn (2010).
Structure of the heme biosynthetic Pseudomonas aeruginosa porphobilinogen synthase in complex with the antibiotic alaremycin.
  Antimicrob Agents Chemother, 54, 267-272.
PDB code: 2woq
20564571 Y.Gogami, A.Kobayashi, T.Ikeuchi, and T.Oikawa (2010).
Site-directed mutagenesis of rice serine racemase: evidence that Glu219 and Asp225 mediate the effects of Mg2+ on the activity.
  Chem Biodivers, 7, 1579-1590.  
19267692 S.A.Lobo, A.Brindley, M.J.Warren, and L.M.Saraiva (2009).
Functional characterization of the early steps of tetrapyrrole biosynthesis and modification in Desulfovibrio vulgaris Hildenborough.
  Biochem J, 420, 317-325.  
18795796 B.Kokona, D.J.Rigotti, A.S.Wasson, S.H.Lawrence, E.K.Jaffe, and R.Fairman (2008).
Probing the oligomeric assemblies of pea porphobilinogen synthase by analytical ultracentrifugation.
  Biochemistry, 47, 10649-10656.  
18559269 S.H.Lawrence, U.D.Ramirez, L.Tang, F.Fazliyez, L.Kundrat, G.D.Markham, and E.K.Jaffe (2008).
Shape shifting leads to small-molecule allosteric drug discovery.
  Chem Biol, 15, 586-596.  
17983264 C.H.Yeang, and D.Haussler (2007).
Detecting coevolution in and among protein domains.
  PLoS Comput Biol, 3, e211.  
17311232 S.Gacond, F.Frère, M.Nentwich, J.P.Faurite, N.Frankenberg-Dinkel, and R.Neier (2007).
Synthesis of bisubstrate inhibitors of porphobilinogen synthase from Pseudomonas aeruginosa.
  Chem Biodivers, 4, 189-202.  
16377642 L.Tang, S.Breinig, L.Stith, A.Mischel, J.Tannir, B.Kokona, R.Fairman, and E.K.Jaffe (2006).
Single amino acid mutations alter the distribution of human porphobilinogen synthase quaternary structure isoforms (morpheeins).
  J Biol Chem, 281, 6682-6690.  
16304458 L.Coates, G.Beaven, P.T.Erskine, S.I.Beale, S.P.Wood, P.M.Shoolingin-Jordan, and J.B.Cooper (2005).
Structure of Chlorobium vibrioforme 5-aminolaevulinic acid dehydratase complexed with a diacid inhibitor.
  Acta Crystallogr D Biol Crystallogr, 61, 1594-1598.
PDB code: 2c1h
15710608 L.Tang, L.Stith, and E.K.Jaffe (2005).
Substrate-induced interconversion of protein quaternary structure isoforms.
  J Biol Chem, 280, 15786-15793.  
15747133 N.Sawada, N.Nagahara, T.Sakai, Y.Nakajima, M.Minami, and T.Kawada (2005).
The activation mechanism of human porphobilinogen synthase by 2-mercaptoethanol: intrasubunit transfer of a reserve zinc ion and coordination with three cysteines in the active center.
  J Biol Inorg Chem, 10, 199-207.  
16131755 P.T.Erskine, L.Coates, R.Newbold, A.A.Brindley, F.Stauffer, G.D.Beaven, R.Gill, A.Coker, S.P.Wood, M.J.Warren, P.M.Shoolingin-Jordan, R.Neier, and J.B.Cooper (2005).
Structure of yeast 5-aminolaevulinic acid dehydratase complexed with the inhibitor 5-hydroxylaevulinic acid.
  Acta Crystallogr D Biol Crystallogr, 61, 1222-1226.
PDB code: 1w31
15555082 D.W.Bollivar, C.Clauson, R.Lighthall, S.Forbes, B.Kokona, R.Fairman, L.Kundrat, and E.K.Jaffe (2004).
Rhodobacter capsulatus porphobilinogen synthase, a high activity metal ion independent hexamer.
  BMC Biochem, 5, 17.  
14638682 S.Dhanasekaran, N.R.Chandra, B.K.Chandrasekhar Sagar, P.N.Rangarajan, and G.Padmanaban (2004).
Delta-aminolevulinic acid dehydratase from Plasmodium falciparum: indigenous versus imported.
  J Biol Chem, 279, 6934-6942.  
12573695 E.K.Jaffe (2003).
An unusual phylogenetic variation in the metal ion binding sites of porphobilinogen synthase.
  Chem Biol, 10, 25-34.  
12794073 L.Kundrat, J.Martins, L.Stith, R.L.Dunbrack, and E.K.Jaffe (2003).
A structural basis for half-of-the-sites metal binding revealed in Drosophila melanogaster porphobilinogen synthase.
  J Biol Chem, 278, 31325-31330.  
12897770 S.Breinig, J.Kervinen, L.Stith, A.S.Wasson, R.Fairman, A.Wlodawer, A.Zdanov, and E.K.Jaffe (2003).
Control of tetrapyrrole biosynthesis by alternate quaternary forms of porphobilinogen synthase.
  Nat Struct Biol, 10, 757-763.
PDB code: 1pv8
12010463 D.V.Vavilin, and W.F.Vermaas (2002).
Regulation of the tetrapyrrole biosynthetic pathway leading to heme and chlorophyll in plants and cyanobacteria.
  Physiol Plant, 115, 9.  
11909869 E.K.Jaffe, J.Kervinen, J.Martins, F.Stauffer, R.Neier, A.Wlodawer, and A.Zdanov (2002).
Species-specific inhibition of porphobilinogen synthase by 4-oxosebacic acid.
  J Biol Chem, 277, 19792-19799.
PDB codes: 1l6s 1l6y
11524417 B.M.Martins, B.Grimm, H.P.Mock, R.Huber, and A.Messerschmidt (2001).
Crystal structure and substrate binding modeling of the uroporphyrinogen-III decarboxylase from Nicotiana tabacum. Implications for the catalytic mechanism.
  J Biol Chem, 276, 44108-44116.
PDB code: 1j93
11828463 F.Stauffer, E.Zizzari, C.Engeloch-Jarret, J.P.Faurite, J.Bobálová, and R.Neier (2001).
Inhibition studies of porphobilinogen synthase from Escherichia coli differentiating between the two recognition sites.
  Chembiochem, 2, 343-354.  
10712932 C.Jarret, F.Stauffer, M.E.Henz, M.Marty, R.M.Lüönd, J.Bobálová, P.Schürmann, and R.Neier (2000).
Inhibition of Escherichia coli porphobilinogen synthase using analogs of postulated intermediates.
  Chem Biol, 7, 185-196.  
10666591 E.K.Jaffe (2000).
The porphobilinogen synthase family of metalloenzymes.
  Acta Crystallogr D Biol Crystallogr, 56, 115-128.  
10644722 E.K.Jaffe, M.Volin, C.R.Bronson-Mullins, R.L.Dunbrack, J.Kervinen, J.Martins, J.F.Quinlan, M.H.Sazinsky, E.M.Steinhouse, and A.T.Yeung (2000).
An artificial gene for human porphobilinogen synthase allows comparison of an allelic variation implicated in susceptibility to lead poisoning.
  J Biol Chem, 275, 2619-2626.  
10913315 J.Kervinen, R.L.Dunbrack, S.Litwin, J.Martins, R.C.Scarrow, M.Volin, A.T.Yeung, E.Yoon, and E.K.Jaffe (2000).
Porphobilinogen synthase from pea: expression from an artificial gene, kinetic characterization, and novel implications for subunit interactions.
  Biochemistry, 39, 9018-9029.  
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.