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PDBsum entry 2h31

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protein ligands links
Ligase, lyase PDB id
2h31
Jmol
Contents
Protein chain
386 a.a. *
Ligands
CO2
Waters ×23
* Residue conservation analysis
PDB id:
2h31
Name: Ligase, lyase
Title: Crystal structure of human paics, a bifunctional carboxylase synthetase in purine biosynthesis
Structure: Multifunctional protein ade2. Chain: a. Synonym: phosphoribosylaminoimidazole-succinocarboxamide sy phosphoribosylaminoimidazole carboxylase. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: paics, ade2, airc, pais. Expressed in: escherichia coli. Expression_system_taxid: 562
Resolution:
2.80Å     R-factor:   0.241     R-free:   0.287
Authors: S.-X.Li,Y.-P.Tong,X.-C.Xie,S.-G.Li,R.-C.Bi
Key ref:
S.X.Li et al. (2007). Octameric Structure of the Human Bifunctional Enzyme PAICS in Purine Biosynthesis. J Mol Biol, 366, 1603-1614. PubMed id: 17224163 DOI: 10.1016/j.jmb.2006.12.027
Date:
21-May-06     Release date:   30-Jan-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P22234  (PUR6_HUMAN) -  Multifunctional protein ADE2
Seq:
Struc:
425 a.a.
386 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class 1: E.C.4.1.1.21  - Phosphoribosylaminoimidazole carboxylase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

      Pathway:
Purine Biosynthesis (late stages)
      Reaction: 5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxylate = 5-amino-1- (5-phospho-D-ribosyl)imidazole + CO2
5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxylate
= 5-amino-1- (5-phospho-D-ribosyl)imidazole
+
CO(2)
Bound ligand (Het Group name = CO2)
corresponds exactly
   Enzyme class 2: E.C.6.3.2.6  - Phosphoribosylaminoimidazolesuccinocarboxamide synthase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

      Pathway:
      Reaction: ATP + 5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxylate + L-aspartate = ADP + phosphate + (S)-2-(5-amino-1-(5-phospho-D- ribosyl)imidazole-4-carboxamido)succinate
ATP
+ 5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxylate
+ L-aspartate
= ADP
+ phosphate
+ (S)-2-(5-amino-1-(5-phospho-D- ribosyl)imidazole-4-carboxamido)succinate
Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular vesicular exosome   2 terms 
  Biological process     metabolic process   8 terms 
  Biochemical function     catalytic activity     10 terms  

 

 
    reference    
 
 
DOI no: 10.1016/j.jmb.2006.12.027 J Mol Biol 366:1603-1614 (2007)
PubMed id: 17224163  
 
 
Octameric Structure of the Human Bifunctional Enzyme PAICS in Purine Biosynthesis.
S.X.Li, Y.P.Tong, X.C.Xie, Q.H.Wang, H.N.Zhou, Y.Han, Z.Y.Zhang, W.Gao, S.G.Li, X.C.Zhang, R.C.Bi.
 
  ABSTRACT  
 
Phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS) is an important bifunctional enzyme in de novo purine biosynthesis in vertebrate with both 5-aminoimidazole ribonucleotide carboxylase (AIRc) and 4-(N-succinylcarboxamide)-5-aminoimidazole ribonucleotide synthetase (SAICARs) activities. It becomes an attractive target for rational anticancer drug design, since rapidly dividing cancer cells rely heavily on the purine de novo pathway for synthesis of adenine and guanine, whereas normal cells favor the salvage pathway. Here, we report the crystal structure of human PAICS, the first in the entire PAICS family, at 2.8 A resolution. It revealed that eight PAICS subunits, each composed of distinct AIRc and SAICARs domains, assemble a compact homo-octamer with an octameric-carboxylase core and four symmetric periphery dimers formed by synthetase domains. Based on structural comparison and functional complementation analyses, the active sites of SAICARs and AIRc were identified, including a putative substrate CO(2)-binding site. Furthermore, four symmetry-related, separate tunnel systems in the PAICS octamer were found that connect the active sites of AIRc and SAICARs. This study illustrated the octameric nature of the bifunctional enzyme. Each carboxylase active site is formed by structural elements from three AIRc domains, demonstrating that the octamer structure is essential for the carboxylation activity. Furthermore, the existence of the tunnel system implies a mechanism of intermediate channeling and suggests that the quaternary structure arrangement is crucial for effectively executing the sequential reactions. In addition, this study provides essential structural information for designing PAICS-specific inhibitors for use in cancer chemotherapy.
 
  Selected figure(s)  
 
Figure 1.
Figure 1. A diagram of reactions catalyzed by PAICS, PurK, class I PurE, and SAICARs. R represents ribose 5-phosphate. Figure 1. A diagram of reactions catalyzed by PAICS, PurK, class I PurE, and SAICARs. R represents ribose 5-phosphate.
Figure 4.
Figure 4. Structure of the SAICARs domain of human PAICS. (a) Ribbon diagram of the SAICARs domain. Subdomain S is colored yellow, and subdomain L is colored cyan. β-Strands (1–14), α-helices (α1–α5), and selected loops (LA and LB), peptide termini (N and C) are labeled. (b) The putative active site region of human SAICARs domain (red) superposed with EcSAICARs (PDB code: 2GQS, green). Both peptide chains are shown as spaghetti models, and disordered parts are marked with dots. Substrates identified in the EcSAICARs structure are shown as blue stick models. (c) Superposition of human SAICARs domain (red) with EcSAICARs (green), TmSAICARs (PDB code 1KUT, yellow), and ScSAICARs (PDB code 1A48, blue). The C-terminal structural variations are circled. The orientation is the same as in (a). Figure 4. Structure of the SAICARs domain of human PAICS. (a) Ribbon diagram of the SAICARs domain. Subdomain S is colored yellow, and subdomain L is colored cyan. β-Strands (1–14), α-helices (α1–α5), and selected loops (LA and LB), peptide termini (N and C) are labeled. (b) The putative active site region of human SAICARs domain (red) superposed with EcSAICARs (PDB code: 2GQS, green). Both peptide chains are shown as spaghetti models, and disordered parts are marked with dots. Substrates identified in the EcSAICARs structure are shown as blue stick models. (c) Superposition of human SAICARs domain (red) with EcSAICARs (green), TmSAICARs (PDB code 1KUT, yellow), and ScSAICARs (PDB code 1A48, blue). The C-terminal structural variations are circled. The orientation is the same as in (a).
 
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2007, 366, 1603-1614) copyright 2007.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
19716791 L.L.Chen, and G.G.Carmichael (2009).
Altered nuclear retention of mRNAs containing inverted repeats in human embryonic stem cells: functional role of a nuclear noncoding RNA.
  Mol Cell, 35, 467-478.  
19095456 S.M.Firestine, W.Wu, H.Youn, and V.J.Davisson (2009).
Interrogating the mechanism of a tight binding inhibitor of AIR carboxylase.
  Bioorg Med Chem, 17, 794-803.  
18388293 S.An, R.Kumar, E.D.Sheets, and S.J.Benkovic (2008).
Reversible compartmentalization of de novo purine biosynthetic complexes in living cells.
  Science, 320, 103-106.  
18712276 Y.Zhang, M.Morar, and S.E.Ealick (2008).
Structural biology of the purine biosynthetic pathway.
  Cell Mol Life Sci, 65, 3699-3724.  
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.