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PDBsum entry 1jr2

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protein Protein-protein interface(s) links
Lyase PDB id
1jr2
Jmol
Contents
Protein chains
260 a.a. *
Waters ×569
* Residue conservation analysis
PDB id:
1jr2
Name: Lyase
Title: Structure of uroporphyrinogen iii synthase
Structure: Uroporphyrinogen-iii synthase. Chain: a, b. Synonym: uro'gen iii synthase, uros, uroporphyrinogen-iii cosynthetase, hydroxymethylbilane hydrolyase [cyclizing], uroiiis. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: uros. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
1.84Å     R-factor:   0.203     R-free:   0.251
Authors: M.A.Mathews,H.L.Schubert,F.G.Whitby,K.J.Alexander, K.Schadick,H.A.Bergonia,J.D.Phillips,C.P.Hill
Key ref:
M.A.Mathews et al. (2001). Crystal structure of human uroporphyrinogen III synthase. EMBO J, 20, 5832-5839. PubMed id: 11689424 DOI: 10.1093/emboj/20.21.5832
Date:
10-Aug-01     Release date:   07-Nov-01    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P10746  (HEM4_HUMAN) -  Uroporphyrinogen-III synthase
Seq:
Struc:
265 a.a.
260 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.4.2.1.75  - Uroporphyrinogen-III synthase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

      Pathway:
Porphyrin Biosynthesis (early stages)
      Reaction: Hydroxymethylbilane = uroporphyrinogen III + H2O
Hydroxymethylbilane
= uroporphyrinogen III
+ H(2)O
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     mitochondrion   2 terms 
  Biological process     small molecule metabolic process   10 terms 
  Biochemical function     lyase activity     3 terms  

 

 
    Added reference    
 
 
DOI no: 10.1093/emboj/20.21.5832 EMBO J 20:5832-5839 (2001)
PubMed id: 11689424  
 
 
Crystal structure of human uroporphyrinogen III synthase.
M.A.Mathews, H.L.Schubert, F.G.Whitby, K.J.Alexander, K.Schadick, H.A.Bergonia, J.D.Phillips, C.P.Hill.
 
  ABSTRACT  
 
Uroporphyrinogen III synthase, U3S, the fourth enzyme in the porphyrin biosynthetic pathway, catalyzes cyclization of the linear tetrapyrrole, hydroxymethylbilane, to the macrocyclic uroporphyrino gen III, which is used in several different pathways to form heme, siroheme, chlorophyll, F(430) and vitamin B(12). U3S activity is essential in all organisms, and decreased activity in humans leads to the autosomal recessive disorder congenital erythropoetic porphyria. We have determined the crystal structure of recombinant human U3S at 1.85 A resolution. The protein folds into two alpha/beta domains connected by a beta-ladder. The active site appears to be located between the domains, and variations in relative domain positions observed between crystallographically independent molecules indicates the presence of flexibility that may be important in the catalytic cycle. Possible mechanisms of catalysis were probed by mutating each of the four invariant residues in the protein that have titratable side chains. Additionally, six other highly conserved and titratable side chains were also mutated. In no case, however, did one of these mutations abolish enzyme activity, suggesting that the mechanism does not require acid/base catalysis.
 
  Selected figure(s)  
 
Figure 4.
Figure 4 Surface representation of U3S. Conserved residues are colored magenta (see Figure 3). (A) View direction is the same as in Figure 2. No conserved residues are visible when the molecule is viewed from the opposite (back) direction. (B) The two domains of U3S are shown independently, split open at the center to expose the cleft surface.
Figure 6.
Figure 6 Model of uro'gen III bound to U3S and location of the clinical mutations. View direction of this stereo image is similar to that in Figure 5. The side chains of residues identified as clinical mutations are shown in standard atom colors. In purple, an energy minimized model of the product, uro'gen III, has been aligned with the cobalamin molecule shown in Figure 5 and adjusted to avoid steric clashes. Note that uro'gen III is inherently very flexible and the model here is intended only to illustrate the plausibility of binding in the U3S cleft.
 
  The above figures are reprinted from an Open Access publication published by Macmillan Publishers Ltd: EMBO J (2001, 20, 5832-5839) copyright 2001.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20300652 D.E.Almonacid, E.R.Yera, J.B.Mitchell, and P.C.Babbitt (2010).
Quantitative comparison of catalytic mechanisms and overall reactions in convergently evolved enzymes: implications for classification of enzyme function.
  PLoS Comput Biol, 6, e1000700.  
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.  
20485863 S.Clavero, D.F.Bishop, U.Giger, M.E.Haskins, and R.J.Desnick (2010).
Feline congenital erythropoietic porphyria: two homozygous UROS missense mutations cause the enzyme deficiency and porphyrin accumulation.
  Mol Med, 16, 381-388.  
18845122 H.A.Bergonia, J.D.Phillips, and J.P.Kushner (2009).
Reduction of porphyrins to porphyrinogens with palladium on carbon.
  Anal Biochem, 384, 74-78.  
18651750 H.L.Schubert, J.D.Phillips, A.Heroux, and C.P.Hill (2008).
Structure and mechanistic implications of a uroporphyrinogen III synthase-product complex.
  Biochemistry, 47, 8648-8655.
PDB codes: 3d8n 3d8r 3d8s 3d8t
18004775 L.Cunha, M.Kuti, D.F.Bishop, M.Mezei, L.Zeng, M.M.Zhou, and R.J.Desnick (2008).
Human uroporphyrinogen III synthase: NMR-based mapping of the active site.
  Proteins, 71, 855-873.  
18846277 T.Masuda, and Y.Fujita (2008).
Regulation and evolution of chlorophyll metabolism.
  Photochem Photobiol Sci, 7, 1131-1149.  
17962188 V.A.Nagaraj, R.Arumugam, B.Gopalakrishnan, Y.S.Jyothsna, P.N.Rangarajan, and G.Padmanaban (2008).
Unique properties of Plasmodium falciparum porphobilinogen deaminase.
  J Biol Chem, 283, 437-444.  
17360334 J.D.Phillips, H.A.Bergonia, C.A.Reilly, M.R.Franklin, and J.P.Kushner (2007).
A porphomethene inhibitor of uroporphyrinogen decarboxylase causes porphyria cutanea tarda.
  Proc Natl Acad Sci U S A, 104, 5079-5084.  
17763925 N.Li, D.L.Ma, X.Liu, L.Wu, X.Chu, K.Y.Wong, and D.Li (2007).
Characterization of his-tagged rat uroporphyrinogen III synthase wild-type and variant enzymes.
  Protein J, 26, 569-576.  
16453030 T.P.Begley (2006).
Cofactor biosynthesis: an organic chemist's treasure trove.
  Nat Prod Rep, 23, 15-25.  
16162494 H.J.Korza, and M.Bochtler (2005).
Pseudomonas aeruginosa LD-carboxypeptidase, a serine peptidase with a Ser-His-Glu triad and a nucleophilic elbow.
  J Biol Chem, 280, 40802-40812.
PDB codes: 1zrs 2aum 2aun
15665092 L.W.Schultz, L.Liu, M.Cegielski, and J.W.Hastings (2005).
Crystal structure of a pH-regulated luciferase catalyzing the bioluminescent oxidation of an open tetrapyrrole.
  Proc Natl Acad Sci U S A, 102, 1378-1383.
PDB code: 1vpr
15652607 R.Kauppinen (2005).
Porphyrias.
  Lancet, 365, 241-252.  
14633982 J.D.Phillips, F.G.Whitby, J.P.Kushner, and C.P.Hill (2003).
Structural basis for tetrapyrrole coordination by uroporphyrinogen decarboxylase.
  EMBO J, 22, 6225-6233.
PDB codes: 1r3q 1r3r 1r3s 1r3t 1r3v 1r3w 1r3y
12864856 R.Guégan, J.M.Camadro, I.Saint Girons, and M.Picardeau (2003).
Leptospira spp. possess a complete haem biosynthetic pathway and are able to use exogenous haem sources.
  Mol Microbiol, 49, 745-754.  
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.