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PDBsum entry 1nbu

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protein ligands Protein-protein interface(s) links
Lyase PDB id
1nbu
Jmol
Contents
Protein chains
(+ 2 more) 118 a.a. *
Ligands
PH2 ×8
Waters ×470
* Residue conservation analysis
PDB id:
1nbu
Name: Lyase
Title: 7,8-dihydroneopterin aldolase complexed with product from mycobacterium tuberculosis
Structure: Probable dihydroneopterin aldolase. Chain: a, e, f, g, h. Synonym: dhna. Engineered: yes. Probable dihydroneopterin aldolase. Chain: b, d. Synonym: dhna. Engineered: yes. Mutation: yes.
Source: Mycobacterium tuberculosis. Organism_taxid: 1773. Gene: folb or rv3607c or mt3712.1 or mtcy07h7b.15. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Expressed in: escherichia coli. Expression_system_taxid: 562. Expression_system_taxid: 562
Biol. unit: Octamer (from PQS)
Resolution:
1.60Å     R-factor:   0.177     R-free:   0.257
Authors: C.W.Goulding,M.I.Apostol,M.R.Sawaya,M.Phillips,A.Parseghian, D.Eisenberg,Tb Structural Genomics Consortium (Tbsgc)
Key ref:
C.W.Goulding et al. (2005). Regulation by oligomerization in a mycobacterial folate biosynthetic enzyme. J Mol Biol, 349, 61-72. PubMed id: 15876368 DOI: 10.1016/j.jmb.2005.03.023
Date:
03-Dec-02     Release date:   13-Jan-04    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam  
P9WNC5  (FOLB_MYCTU) -  Probable dihydroneopterin aldolase
Seq:
Struc:
133 a.a.
118 a.a.
Key:    Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.4.1.2.25  - Dihydroneopterin aldolase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

      Pathway:
Folate Biosynthesis (late stages)
      Reaction: 2-amino-4-hydroxy-6-(D-erythro-1,2,3-trihydroxypropyl)-7,8- dihydropteridine = 2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine + glycolaldehyde
2-amino-4-hydroxy-6-(D-erythro-1,2,3-trihydroxypropyl)-7,8- dihydropteridine
=
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine
Bound ligand (Het Group name = PH2)
corresponds exactly
+ glycolaldehyde
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     folic acid-containing compound metabolic process   1 term 
  Biochemical function     dihydroneopterin aldolase activity     1 term  

 

 
    Added reference    
 
 
DOI no: 10.1016/j.jmb.2005.03.023 J Mol Biol 349:61-72 (2005)
PubMed id: 15876368  
 
 
Regulation by oligomerization in a mycobacterial folate biosynthetic enzyme.
C.W.Goulding, M.I.Apostol, M.R.Sawaya, M.Phillips, A.Parseghian, D.Eisenberg.
 
  ABSTRACT  
 
Folate derivatives are essential cofactors in the biosynthesis of purines, pyrimidines and amino acids across all forms of life. Mammals uptake folate from their diets, whereas most bacteria must synthesize folate de novo. Therefore, the enzymes in the folate biosynthetic pathway are attractive drug targets against bacterial pathogens such as Mycobacterium tuberculosis, the cause of the world's most deadly infectious disease, tuberculosis (TB). M.tuberculosis 7,8-dihydroneopterin aldolase (Mtb FolB, DHNA) is the second enzyme in the folate biosynthetic pathway, which catalyzes the conversion of 7,8-dihydroneopterin to 6-hydroxymethyl-7,8-dihydropterin and glycoaldehyde. The 1.6A X-ray crystal structure of Mtb FolB complexed with its product, 6-hydroxymethyl-7,8-dihydropterin, reveals an octameric assembly similar to that seen in crystal structures of other FolB homologs. However, the 2.5A crystal structure of unliganded Mtb FolB reveals a novel tetrameric oligomerization state, with only partially formed active sites. A substrate induced conformational change appears to be necessary to convert the inactive tetramer to the active octamer. Ultracentrifugation confirmed that in solution unliganded Mtb FolB is mainly tetrameric and upon addition of substrate FolB is predominantly octameric. Kinetic analysis of substrate binding gives a Hill coefficient of 2.0, indicating positive cooperativity. We hypothesize that Mtb FolB displays cooperativity in substrate binding to regulate the cellular concentration of 7,8-dihydroneopterin, so that it may function not only as a precursor to folate but also as an antioxidant for the survival of M.tuberculosis against host defenses.
 
  Selected figure(s)  
 
Figure 1.
Figure 1. The reaction for the second step in folate biosynthesis, 7,8-dihydroneopterin aldolase (FolB or DHNA), which converts 7,8-dihydroneopterin to 6-hydroxymethyl-7,8-dihydropterin and glycoaldehyde.
Figure 4.
Figure 4. Monomers and active sites of Mtb FolB in the P2[1] and I4 forms. (a) and (b) The ribbon diagrams of the Mtb FolB monomers from the P2[1] octamer and the I4 tetramer forms, respectively. Comparing the ribbon diagrams in (a) and (b), the major differences in the two monomers is that loop L1 is disordered, a2a-helix is no longer ordered, 3[10]-helix (a2b) has shifted its position, and loops L2 and L4 have shifted their positions in the tetrameric I4 form (b) compared to the P2[1] octameric form (a). (c) and (d) A view of the composite omit 2F[o] -F[c] electron density maps at the active site of the Mtb FolB P2[1] and I4 forms, respectively. The electron density is contoured at 1.2s. Try54B and Glu74A are labeled in the active sites. A and B represent the monomers at the interface of an active site. The major difference between the two active sites is that 6-hydroxymethyl-7,8-dihydropterin (Hhp) is modeled into the structure of the Mtb FolB octameric P2[1] form (c), whereas there is no electron density of the product in the Mtb FolB tetrameric I4 form (d). In fact, there appears to be electron density for residues in the proposed active site cavity of the Mtb FolB tetrameric I4 form. This is illustrated more clearly in a ribbon diagram of the active sites of the Mtb FolB P2[1] and I4 forms, (e) and (f), respectively. The 6-hydroxymethyl-7,8-dihydropterin is denoted by Hhp in (e). In the Mtb FolB tetrameric I4 form, the 3[10]-helix (colored in yellow) is positioned within the active site, possibly preventing binding of substrate. Try54B and Glu74A are labeled in the active sites. In the ribbon diagrams a-helices, the 3[10]-helix, b-strands and random coil are shown in pink, yellow, cyan and grey, respectively. The atoms of the residues are colored as follows: carbon, nitrogen and oxygen are off-white, blue and red, respectively.
 
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2005, 349, 61-72) copyright 2005.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20060836 N.Chim, R.Riley, J.The, S.Im, B.Segelke, T.Lekin, M.Yu, L.W.Hung, T.Terwilliger, J.P.Whitelegge, and C.W.Goulding (2010).
An extracellular disulfide bond forming protein (DsbF) from Mycobacterium tuberculosis: structural, biochemical, and gene expression analysis.
  J Mol Biol, 396, 1211-1226.
PDB code: 3ios
19767425 B.Sankaran, S.A.Bonnett, K.Shah, S.Gabriel, R.Reddy, P.Schimmel, D.A.Rodionov, V.de Crécy-Lagard, J.D.Helmann, D.Iwata-Reuyl, and M.A.Swairjo (2009).
Zinc-independent folate biosynthesis: genetic, biochemical, and structural investigations reveal new metal dependence for GTP cyclohydrolase IB.
  J Bacteriol, 191, 6936-6949.
PDB codes: 3d1t 3d2o
17331536 J.Blaszczyk, Y.Li, J.Gan, H.Yan, and X.Ji (2007).
Structural basis for the aldolase and epimerase activities of Staphylococcus aureus dihydroneopterin aldolase.
  J Mol Biol, 368, 161-169.
PDB codes: 2nm2 2nm3
17032654 B.El Yacoubi, S.Bonnett, J.N.Anderson, M.A.Swairjo, D.Iwata-Reuyl, and V.de Crécy-Lagard (2006).
Discovery of a new prokaryotic type I GTP cyclohydrolase family.
  J Biol Chem, 281, 37586-37593.  
17176045 Y.Wang, Y.Li, and H.Yan (2006).
Mechanism of dihydroneopterin aldolase: functional roles of the conserved active site glutamate and lysine residues.
  Biochemistry, 45, 15232-15239.  
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