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PDBsum entry 1nwc

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protein Protein-protein interface(s) links
Oxidoreductase PDB id
1nwc
Jmol
Contents
Protein chains
356 a.a. *
Waters ×366
* Residue conservation analysis
PDB id:
1nwc
Name: Oxidoreductase
Title: Crystal structure of aspartate-semialdehyde dehydrogenase from haemophilus influenzae
Structure: Aspartate-semialdehyde dehydrogenase. Chain: a, b. Synonym: asa dehydrogenase, asadh. Engineered: yes
Source: Haemophilus influenzae. Organism_taxid: 727. Gene: asd. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Biol. unit: Dimer (from PQS)
Resolution:
2.04Å     R-factor:   0.196     R-free:   0.257
Authors: J.Blanco,R.A.Moore,R.E.Viola
Key ref:
J.Blanco et al. (2003). Capture of an intermediate in the catalytic cycle of L-aspartate-beta-semialdehyde dehydrogenase. Proc Natl Acad Sci U S A, 100, 12613-12617. PubMed id: 14559965 DOI: 10.1073/pnas.1634958100
Date:
05-Feb-03     Release date:   04-Nov-03    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P44801  (DHAS_HAEIN) -  Aspartate-semialdehyde dehydrogenase
Seq:
Struc:
371 a.a.
356 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.1.2.1.11  - Aspartate-semialdehyde dehydrogenase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

      Pathway:
Lysine biosynthesis (early stages)
      Reaction: L-aspartate 4-semialdehyde + phosphate + NADP+ = L-4-aspartyl phosphate + NADPH
L-aspartate 4-semialdehyde
+ phosphate
+ NADP(+)
= L-4-aspartyl phosphate
+ NADPH
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     'de novo' L-methionine biosynthetic process   10 terms 
  Biochemical function     oxidoreductase activity     7 terms  

 

 
    reference    
 
 
DOI no: 10.1073/pnas.1634958100 Proc Natl Acad Sci U S A 100:12613-12617 (2003)
PubMed id: 14559965  
 
 
Capture of an intermediate in the catalytic cycle of L-aspartate-beta-semialdehyde dehydrogenase.
J.Blanco, R.A.Moore, R.E.Viola.
 
  ABSTRACT  
 
The structural analysis of an enzymatic reaction intermediate affords a unique opportunity to study a catalytic mechanism in extraordinary detail. Here we present the structure of a tetrahedral intermediate in the catalytic cycle of aspartate-beta-semialdehyde dehydrogenase (ASADH) from Haemophilus influenzae at 2.0-A resolution. ASADH is not found in humans, yet its catalytic activity is required for the biosynthesis of essential amino acids in plants and microorganisms. Diaminopimelic acid, also formed by this enzymatic pathway, is an integral component of bacterial cell walls, thus making ASADH an attractive target for the development of new antibiotics. This enzyme is able to capture the substrates aspartate-beta-semialdehyde and phosphate as an active complex that does not complete the catalytic cycle in the absence of NADP. A distinctive binding pocket in which the hemithioacetal oxygen of the bound substrate is stabilized by interaction with a backbone amide group dictates the R stereochemistry of the tetrahedral intermediate. This pocket, reminiscent of the oxyanion hole found in serine proteases, is completed through hydrogen bonding to the bound phosphate substrate.
 
  Selected figure(s)  
 
Figure 4.
Fig. 4. Schematic representation of the ASADH active site with a bound hemithioacetal reaction intermediate. Interactions between ASA and phosphate and key active site residues are shown.
Figure 6.
Fig. 6. Proposed mechanism for the catalytic cycle of ASADH shown in reverse biological direction. (A) Tetrahedral intermediate derived from reaction with ASA. (B) Proposed acyl intermediate with trigonal planar geometry. (C) Second tetrahedral intermediate with covalently bound aspartyl phosphate.
 
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21369577 A.S.Evitt, and R.J.Cox (2011).
Synthesis and evaluation of conformationally restricted inhibitors of aspartate semialdehyde dehydrogenase.
  Mol Biosyst, 7, 1564-1575.  
19502445 I.C.Chen, W.D.Lin, S.K.Hsu, V.Thiruvengadam, and W.H.Hsu (2009).
Isolation and characterization of a novel lysine racemase from a soil metagenomic library.
  Appl Environ Microbiol, 75, 5161-5166.  
18236087 A.Singh, H.R.Kushwaha, and P.Sharma (2008).
Molecular modelling and comparative structural account of aspartyl beta-semialdehyde dehydrogenase of Mycobacterium tuberculosis (H37Rv).
  J Mol Model, 14, 249-263.  
18323627 R.E.Viola, X.Liu, J.F.Ohren, and C.R.Faehnle (2008).
The structure of a redundant enzyme: a second isoform of aspartate beta-semialdehyde dehydrogenase in Vibrio cholerae.
  Acta Crystallogr D Biol Crystallogr, 64, 321-330.
PDB codes: 2qz9 2r00
  18323599 R.Vyas, V.Kumar, S.Panjikar, S.Karthikeyan, K.V.Kishan, R.Tewari, and M.S.Weiss (2008).
Purification, crystallization and preliminary X-ray diffraction analysis of aspartate semialdehyde dehydrogenase (Rv3708c) from Mycobacterium tuberculosis.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 64, 167-170.  
17579770 C.A.Hutton, M.A.Perugini, and J.A.Gerrard (2007).
Inhibition of lysine biosynthesis: an evolving antibiotic strategy.
  Mol Biosyst, 3, 458-465.  
16261551 R.J.Cox, J.S.Gibson, and A.T.Hadfield (2005).
Design, synthesis and analysis of inhibitors of bacterial aspartate semialdehyde dehydrogenase.
  Chembiochem, 6, 2255-2260.  
16240442 T.Nonaka, A.Kita, J.Miura-Ohnuma, E.Katoh, N.Inagaki, T.Yamazaki, and K.Miki (2005).
Crystal structure of putative N-acetyl-gamma-glutamyl-phosphate reductase (AK071544) from rice (Oryza sativa).
  Proteins, 61, 1137-1140.
PDB code: 2cvo
15583380 C.R.Faehnle, J.Blanco, and R.E.Viola (2004).
Structural basis for discrimination between oxyanion substrates or inhibitors in aspartate-beta-semialdehyde dehydrogenase.
  Acta Crystallogr D Biol Crystallogr, 60, 2320-2324.
PDB codes: 1ta4 1tb4
15272161 J.Blanco, R.A.Moore, C.R.Faehnle, D.M.Coe, and R.E.Viola (2004).
The role of substrate-binding groups in the mechanism of aspartate-beta-semialdehyde dehydrogenase.
  Acta Crystallogr D Biol Crystallogr, 60, 1388-1395.
PDB codes: 1oza 1pqp 1pqu 1pr3 1ps8 1pu2 1q2x
15388927 J.Blanco, R.A.Moore, C.R.Faehnle, and R.E.Viola (2004).
Critical catalytic functional groups in the mechanism of aspartate-beta-semialdehyde dehydrogenase.
  Acta Crystallogr D Biol Crystallogr, 60, 1808-1815.  
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.